Editor’s note: This is the second of two articles on hypogonadism in men and focuses on the appropriate use of testosterone therapy. The first article, published last month, focused in more detail on the differential diagnosis of hypogonadism.

As men age, testosterone production gradually decreases. In our increasingly aged population, clinicians will continue to see an increase in the number of men with seemingly nonspecific symptoms of aging that are possibly due to low serum testosterone (eg, low energy level, depressive symptoms, erectile dysfunction, decreased libido). These clinical symptoms, coupled with low serum testosterone, may adversely affect quality of life and life expectancy. Testosterone replacement therapy (TRT) may improve symptoms and quality of life. Given the nonspecific nature of these symptoms, accurate diagnosis and treatment of clinically significant low testosterone with a goal of symptom and quality of life improvement can prove challenging.

These challenges in diagnosis and treatment result in a lack of standardized nomenclature. The terms male menopause and andropause, although popular, are the least helpful, as they have few correlates with the better-defined female menopause. Late-onset hypogonadism implies a well-defined, later age of decline, which is inaccurate since the decline in serum testosterone in men begins in middle age and is gradual. Testosterone deficiency syndrome implies a set of specific and well-defined symptoms. Androgen deficiency in the aging male (ADAM) and Androgen deficiency in the older male are common terms specifying an age cohort (> 40 years old) and an abnormal laboratory value without mention of symptoms. While all these terms have their limitations, we will primarily use ADAM in this discussion.

PREVALENCE OF LOW TESTOSTERONE

Serum testosterone levels begin to decline in men in their mid-40s, with an approximately 1% to 2% decline annually and a marked decline after age 60.¹

Araujo and colleagues² studied the prevalence of androgen-deficient men, with androgen deficiency defined as at least three signs or symptoms and either a total testosterone less than 200 ng/dL or a total testosterone 200 ng/dL to 400 ng/dL with a free testosterone less than 8.91 ng/dL. The overall prevalence of low testosterone on initial measurement was 6%, which doubled to 12% with repeat measurement.

Serial measures are important: one study that followed untreated men over 15 years found normal testosterone on serial measures in 50%.³ In a multicenter cross-sectional study, 11.8% of men had low testosterone and low or normal luteinizing hormone (LH) levels (secondary hypogonadism/hypothalamic-pituitary failure), with 2% of patients with low testosterone and elevated LH (primary hypogonadism/testicular failure).⁴

CLINICAL PRESENTATION AND DIAGNOSIS

A biochemical diagnosis of low testosterone is dependent on accurate measurement. Testosterone release is diurnal, with the highest levels in the early morning, and often has week-to-week variability. Thus, it is important to collect blood in the early morning and to confirm a diagnosis of low testosterone with at least one repeat measurement several days later, including LH assessment. LH levels will help differentiate primary hypogonadism from secondary hypogonadism, which may alter diagnosis and treatment in certain patients, with secondary hypogonadism associated with pituitary dysfunction, and primary hypogonadism associated with aging.⁴

Testosterone binds in the bloodstream to sex hormone-binding globulin (SHBG), and this bound form is generally considered biologically inactive, although there are in vitro and animal studies suggesting SHBG-bound androgen may indeed have biological activity. ^5,6 “Bioavailable” testosterone is active and includes both free testosterone and testosterone bound to albumin.

There is no general agreement on the acceptable normal range of testosterone, with variability within the literature and between laboratories. “Normal” total testosterone levels have ranged from more than 280 ng/dL to more than 350 ng/dL (12 nmol/L).^7,8 Similarly, there is no generally accepted lower limit of normal, although some studies report a threshold level of testosterone less than 230 ng/dL (8 nmol/L) as “abnormal.” Values between these two upper and lower limits are considered “borderline.”^7,8 These intermediate or borderline values coupled with clinical symptoms of testosterone deficiency syndrome or ADAM should be considered abnormal.

When total testosterone is borderline, measurement of free or bioavailable testosterone (free plus albumin-bound) should be considered. Total testosterone is typically measured using automated immunoassay platforms, with method-related differences leading to significant variability in measurement accuracy and precision. This variability is seen most dramatically in those with low total testosterone.⁹ However, the variability of total testosterone measurements is substantially smaller among mass spectrometry assays than among immunoassays. ¹⁰

The gold standards for free testosterone measurement are centrifugal ultrafiltration and equilibrium dialysis.⁹ However, these techniques are laborious and usually unavailable in local laboratories. Calculated free testosterone values using total testosterone and SHBG are most commonly used and are sufficiently accurate for clinical practice.¹¹

Free testosterone levels can be diagnostic when total testosterone levels do not correspond with clinical presentation. However, the clinical utility of free testosterone is difficult to assess due to the variability among laboratory assays and a lack of consensus on threshold parameters. A threshold free testosterone level of more than 225 pmol/L (65 pg/mL) is generally considered normal.^7,8 Before starting a patient on TRT, measurement of hemoglobin and prostate-specific antigen (PSA) and digital rectal examination of the prostate (if age is > 39) are essential.

Prolactin levels are recommended when low testosterone is confirmed, especially in patients at high clinical risk for hyperprolactinemia. Once hyperprolactinemia is identified, Endocrine Society guidelines recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes of elevated prolactin levels.¹²

Low testosterone values should be treated only in patients with clinically significant symptoms that are likely to be caused by the low testosterone itself. Symptoms associated with age-related decline in testosterone that may improve with TRT include low libido,^13,14 low energy,¹⁴ depressed mood,^15–17 low muscle mass, osteoporosis, and hot flashes. Men with erectile dysfunction have also shown a significant improvement with TRT compared with placebo, but with a variable overall response independent of normalization of testosterone. ^18,19 This is likely due to the multifactorial nature of erectile dysfunction, including vascular, neurologic, psychogenic, and endocrinologic causes.

Screening questionnaires have been developed for symptoms of low testosterone, but their clinical utility is unclear. The ADAM questionnaire is used as a screening tool for low testosterone but not to monitor response to TRT, and it is highly nonspecific.²⁰ The Aging Male Symptom Scale questionnaire includes psychological, somatovegetative, and sexual components and is used both to screen for low testosterone and to measure outcomes.²¹ However, a recent observational study comparing the ability of these questionnaires to assess clinical symptoms revealed a low sensitivity and a low specificity to detect androgen deficiency in men with a total testosterone level less than 300 ng/dL.²² Overall, the current data do not conclusively support the use of hypogonadism questionnaires for screening.

The patient history when evaluating for ADAM should include evaluation of sexual and constitutional symptoms as described above and in Table 1. In addition, a history of traumatic, medical, or surgical events that could affect testosterone production should be obtained, including cryptorchidism, scrotal, inguinal, or abdominal surgery, pituitary surgery or radiation, prior issues with infertility, timing of puberty, history of renal or hepatic failure, chemotherapy (for cancer or autoimmune diseases), and prior use of anabolic steroids or opiates.

A complete physical examination should include assessment of virilization, gynecomastia, and the genitalia, including the size, position, and volume of the testes. The size and consistency of the prostate should be assessed on digital rectal examination.

LOW TESTOSTERONE AND ASSOCIATED COMORBIDITIES

Low testosterone is associated with many comorbidities, including metabolic syndrome, depression, type 2 diabetes mellitus, and cardiovascular disease, as discussed later in this section. Low testosterone has also shown associations with osteoporosis, cognitive impairment, hypertension, hyperlipidemia, decreased physical performance, end-stage renal disease, and treatment with steroids or opiates.^23–26 However, the studies that found these associations included men younger than 40 years and may not be fully applicable to the ADAM population.

The association of metabolic syndrome and type 2 diabetes mellitus with low testosterone is well established in multiple studies. Grossman and colleagues²⁷ investigated the association of type 2 diabetes mellitus and low testosterone, with low total testosterone defined as below 10 nmol/L and low calculated free testosterone less than 0.23 nmol/L. The prevalence of low total testosterone was 43%, and the prevalence of low free testosterone was 57%. In addition, a recent meta-analysis comparing total testosterone of men with and without metabolic syndrome revealed an association between a baseline decrease in mean total and free testosterone levels in men with metabolic syndrome compared with controls. This study found a total testosterone mean difference of –2.64 nmol/L (95% confidence interval [CI] –2.95 to –2.32) and a free testosterone mean difference of –0.26 pmol/L (95% CI –0.39 to –0.13), respectively, when comparing men with metabolic syndrome against those without.²⁸

Testosterone has also been suggested to be protective against type 2 diabetes mellitus, with 42% lower risk of type 2 diabetes mellitus in men with testosterone levels ranging from 450 ng/dL to 605 ng/dL.²⁹

Obesity has been specifically linked with secondary hypogonadism.^4,23,24 A prospective cohort of 58 men with an average age of 46 years and a body mass index ranging from 30 to 45 kg/m² were monitored on a low-calorie diet for 9 weeks. Afterward, biochemical analysis revealed an increase in free testosterone from 185 pmol/L ± 66 to 208 ± 70 pmol/L (P = .002) with a mean weight loss of 16.3 kg ± 4.5 kg.³⁰ This emphasizes the importance of lifestyle changes in the management of hypogonadal men.

LOW TESTOSTERONE AND THE OVERALL MORTALITY RATE

Low testosterone is associated unfavorably with the rate of all-cause mortality. A retrospective study in male veterans over age 40 with repeated testosterone levels over a 5-year period found that the risk of death from all causes in men with normal testosterone (> 250 ng/dL or free testosterone > 0.75 ng/dL) was 20% (95% CI 16.2%–241%) vs 35% (95% CI 28.5%–41.4%) in men with low testosterone (< 250 ng/dL or free testosterone < 0.75 ng/dL). In multivariate analysis, men with testosterone less than 250 ng/dL (< 8.7 nmol/L) or free testosterone less than 0.75 ng/dL (< 0.03 nmol/L) had up to an 88% higher death rate than men with normal testosterone levels.³¹

Low testosterone has also been associated with other end-organ, disease-specific mortality. In men with end-stage renal disease, low testosterone was an independent predictor of death from all causes and from cardiovascular disease.³² A prospective European health study revealed an association between low testosterone and increased risk of death from cardiovascular disease and cancer.³³ A recent meta-analysis of population-based studies confirmed this association, despite significant interstudy heterogeneity. ³⁴ Although multiple studies show an independent association of low testosterone and increased mortality rate, causality remains unconfirmed. This may be difficult to prove, given the available study designs and the nonspecific nature of symptoms related to low testosterone and potentially associated comorbidities.

TRT: INDICATIONS AND CONTRAINDICATIONS

The indications, benefits, and risks of TRT are controversial, with current data lacking long-term follow-up and consistent biochemical target values. Treatment of low testosterone is not indicated at the present time in the absence of clinical symptoms.

According to recently published guidelines, TRT is recommended for symptomatic men with low or borderline total testosterone or free testosterone (< 350 ng/dL or < 65 pg/mL).^7,8 Patients with borderline biochemical values (total testosterone 200–350 ng/dL, free testosterone 40–65 pg/mL) and possible related symptoms should be treated with TRT for at least 3 months and then reevaluated to verify improved testosterone levels and to assess for symptom amelioration or resolution.³⁵ Dose escalation is recommended in patients with subtherapeutic testosterone levels and limited clinical improvement after 3 months of treatment.

Target maintenance testosterone levels have not been defined, with mid to lower young adult male serum testosterone levels recommended at this time.⁸ Given that the current literature does not specify a target testosterone replacement range, we recommend monitoring the clinical response along with total testosterone to decide adjustments in TRT. Ultimately, treatment goals of TRT should be the resolution of signs and symptoms, including improvement of sexual function, libido, and preservation of bone mineral density.^7,8

Contraindications

TRT is not recommended in men with the following:

• Breast cancer
• Polycythemia (hematocrit > 50%)
• Untreated obstructive sleep apnea
• Lower urinary tract symptoms caused by an enlarged prostate; International Prostate Symptom Score > 19
• Poorly controlled heart failure
• Desire for fertility.

The role of TRT in prostate cancer remains controversial (see below) and remains contraindicated in recent Endocrine Society clinical practice guidelines.⁷ Guidelines recommend urologic consultation prior to initiation of TRT in patients at increased risk of prostate cancer,⁷ based on age, race, family history, PSA, PSA velocity, and history of prostate biopsy.

One prominent historic concern about androgen replacement therapy regards the potential for de novo development of prostate cancer. Numerous studies have failed to find elevated risk of new diagnosis, progression, or recurrence of prostate cancer in patients on TRT.^36,37 Nevertheless, patients who develop elevated PSA, increased PSA velocity, or an abnormal digital rectal examination while on TRT should undergo prostate biopsy.

TRT FORMULATIONS AND TREATMENT OPTIONS

A number of effective formulations of TRT are available (Table 2). Transdermal and parenteral formulations are most commonly used. Enteric testosterone formulations are not available in the United States and are associated with hepatotoxicity. While buccal testosterone therapy is available, it often leads to local gingival irritation and has not gained widespread popularity.

Parenteral TRT can be administered intramuscularly (IM) or subcutaneously (SQ). Testosterone cypionate (Depo-Testosterone) is the only IM form available in the United States and is given every 2 to 3 weeks. It is the least expensive form of TRT, but it requires frequent administration (by either the clinical practitioner or the patient himself). Testosterone cypionate injections lead to markedly wide swings of testosterone levels, ranging from supraphysiologic levels for a few days after administration to hypogonadal levels before the next injection. This may be mitigated by more-frequent injections. The longer-acting form testosterone undecanoate is available outside the United States and is given every 12 weeks when stable levels are reached.

The other parenteral option is SQ slow-release pellets (Testopel). These pellets have 75 mg of testosterone. Typically 8 to 14 pellets are placed subcutaneously in the buttock area, which will provide coverage for 3 to 6 months.³⁸ The insertion procedure is simple with a short learning curve, limited compliance issues, and elimination of risk of transdermal transmission of drug to others. Disadvantages include wound infection and pellet extrusion, seen in 0.3% to 12% of patients in various studies.³⁸

Another route of TRT is transdermal, including patches, liquids, and gels. Patches are applied daily and are rotated to different sites with minimal risk for skin transmission to others, although use may be limited by site dermatitis. Three hydro-alcoholic gel formulations are currently available in the United States: Androgel (1% or 1.62%), which is applied to the chest or the shoulders; Testim 1%, which is applied to the shoulders; and Fortesta (2%), which is applied to the thighs. A liquid preparation, Axiron, is applied to the axillae. Because secondary transfer to women and children is possible, it is important to thoroughly wash hands after application and to cover the treated skin with clothing. In 3 to 4 hours, all the medication is absorbed, and the area should then be washed before direct skin contact with others (Table 2).

MONITORING PATIENTS ON TRT

Patients starting TRT will require clinical and biochemical monitoring to evaluate response to therapy as well as possible side effects. The first set of laboratory values should be obtained 6 to 12 weeks after initiation of therapy and then typically quarterly for 1 year, every 6 months for the second year, and annually thereafter. Laboratory values monitored should include total testosterone, PSA, and hematocrit.

Men on daily therapy (patch, gel, liquid) should have testosterone drawn approximately 2 hours after application. Current TRT regimen data lack an appropriate target testosterone value, and guidelines suggest a mid to lower young adult male testosterone level.⁸ Since this is not clearly delineated in the current literature, the authors recommend monitoring clinical symptoms along with testosterone levels when adjusting TRT. It is important to document that serum testosterone was actually increased to the normal range in treated men without clinical improvement.

A rise in PSA of up to 24% would be an acceptable response in a benign prostate gland, but a higher increase or increase above 4.0 ng/dL should prompt consideration of prostate biopsy. ³⁹ Similarly, hemoglobin and hematocrit typically increase, but a hematocrit greater than 55% should prompt dose reduction or cessation.⁷ Transaminases do not need routine monitoring during parenteral or transdermal therapy. Bone mineral density should be monitored every 1 to 2 years.^7,8

CLINICAL BENEFITS OF TRT

There are promising data regarding the clinical benefits of TRT in patients with metabolic syndrome and type 2 diabetes mellitus. A recent meta-analysis investigating the effect of TRT on metabolic syndrome revealed an improvement in fasting plasma glucose, homeostatic model assessment index, triglycerides, treadmill duration, high-density lipoprotein cholesterol, and waist circumference.^40,41 TRT also decreased insulin resistance and improved glycemic control in type 2 diabetic hypogonadal men.⁴² Results from a randomized controlled trial comparing 12 weeks of intramuscular testosterone treatment vs placebo in men with metabolic syndrome revealed an improvement in mean waist circumference from 108 cm ± 8 cm to 105.5 cm ± 7.7 cm. Sixty percent of men initially diagnosed with metabolic syndrome and treated with testosterone no longer met diagnostic criteria for metabolic syndrome according to the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP-ATP III) and the International Diabetes Federation (IDF) guidelines.⁴³

Depression has also been associated with low testosterone, with free testosterone levels below 170 pmol/L associated with frank depressive symptoms and levels below 220 pmol/L predictive of future onset of depressive symptoms.¹⁵ Testosterone replacement therapy has been shown to improve depressive symptoms in hypogonadal men.^16,17 Shores et al¹⁶ conducted a randomized placebo-controlled study of testosterone replacement in men older than 50 years with dysthymia or minor depression. Men treated with testosterone gel for 12 weeks showed an improvement of baseline total testosterone levels from 291 ng/dL to 449 ng/dL. Men treated with testosterone also had a 53% rate of depression remission compared with 19% in the placebo group.¹⁶

The evidence supporting improved sexual function with TRT is variable. Some studies indicate limited or transient improvement of sexual function after TRT in men with erectile dysfunction,^18,19 while others report an improvement in sexual function after 3 months of TRT.⁴⁴ Because of the multifactorial nature of erectile dysfunction, men with erectile dysfunction and ADAM may require TRT and a phosphodiesterase type 5 (PDE5) inhibitor, as TRT alone may be insufficient. In a prospective observational study of men with erectile dysfunction and an initial testosterone lower than 300 ng/dL, testosterone gel was administered for at least 1 year, and improvement in sexual function was seen. Results revealed a correlation between improvement in sexual function and concurrent therapy with a PDE5 inhibitor.⁴⁵ In a recent multicenter placebo-controlled study of PDE5 inhibitor nonresponders, the addition of a testosterone gel to tadalafil (Cialis) improved sexual function, again suggesting a synergistic effect when treating erectile dysfunction with both TRT and a PDE5 inhibitor.⁴⁶

ADVERSE EVENTS RELATED TO TRT

Despite the aforementioned benefits, it must be emphasized that TRT should be used for specific target symptoms related to hypogonadism in older men and that the general health benefits and safety of TRT in an asymptomatic man with a low measured testosterone alone remains unproven.

Cardiovascular events. In a recent study of 209 elderly men with low testosterone and limited mobility associated with other chronic illnesses, 6 months of TRT resulted in the development of cardiovascular-related adverse events in 23 patients compared with 5 men in the placebo group.⁴⁷ This may have been related to how adverse events were reported, with cumulative adverse events reviewed every 6 months, ranging from peripheral edema, hypertension, arrhythmias, and electrocardiographic changes. Serious adverse events were reviewed as they occurred, including stroke and acute myocardial events.

Other studies^41,43 have revealed a favorable effect of TRT on cardiovascular disease and its surrogate markers but have lacked detailed reports and close monitoring of adverse events. Thus, variation of outcome measurement and reporting may obfuscate the detection of adverse cardiovascular events. Outcomes may also depend on the testosterone formulation and the target serum concentration.⁴³

Larger, long-term placebo-controlled trials are needed to elucidate cardiovascular risk as a primary outcome in older androgen-deficient men undergoing TRT.

Other adverse effects related to TRT include erythrocytosis, seen in 3% to 18% of patients with transdermal administration,^48,49 and up to 44% of patients undergoing IM therapy.⁴⁸ Gynecomastia can occur and is more likely to resolve after treatment cessation of transdermal testosterone treatment than IM injections.⁴⁸ Other potential clinical side effects that should prompt dose-reduction or discontinuation are irritability, bothersome acne, fluid retention, testicular atrophy, worsening of lower urinary tract symptoms from an enlarged prostate, and new or worsening heart failure. Infrequently, obstructive sleep apnea may be worsened by TRT, although currently the data linking sleep apnea and TRT are limited.⁵⁰

TRT AND PROSTATE CANCER

The relationship between prostate cancer growth and testosterone is well established, with androgen ablation remaining the cornerstone of treatment for metastatic disease. Since androgen deprivation leads to the regression of prostate cancer, there has been concern that TRT may lead to growth or de novo development of prostate cancer. TRT has thus been strongly prohibited in patients with prostate cancer.⁷ However, recent data challenge this paradigm.

In a retrospective study of 81 men (mean age 56.8 years) treated with TRT, only 4 men (4.9%) developed prostate cancer over a 5-year period.⁵¹ This is less than the estimated 16.7% probability of developing prostate cancer in the general US population.⁵²

Recent accumulating data support the concept of testosterone reaching a saturation level when binding androgen receptors within the prostate at extremely low levels. Increases above this level with TRT as with ADAM do not increase the risk of development or progression of prostate cancer.⁵³ In addition, large doses of dihydrotestosterone do not seem to alter PSA, prostate volume, or International Prostate Symptom Score.⁵⁴ These findings may have implications in future androgen therapies in hypogonadal older men.

Pathologic studies suggest low testosterone is associated with a higher Gleason grade of prostate cancer,⁵⁵ although this association remains unconfirmed.⁵⁶

In men with erectile dysfunction after prostate cancer treatment, TRT appears safe after brachytherapy⁵⁷ or radical prostatectomy.⁵⁸ A small study of 15 hypogonadal men with castrate-resistant prostate cancer and minimal or no metastatic disease showed only 1 patient had symptomatic progression.⁵⁹ Moreover, a recent small study of 13 men with known prostate cancer on active surveillance showed that TRT did not lead to local progression or metastatic disease in any of the patients.⁶⁰

While these data are provocative, it should still be emphasized that the standard of care for prostate cancer screening should be followed in age-appropriate men with ADAM. In addition, hypogonadal men with prostate cancer should only be treated with testosterone in conjunction with careful counseling and ongoing monitoring.

TRT SHOULD NOT REPLACE HEALTHY LIFESTYLE CHANGES

There has been a dramatic increase in TRT initiation for nonspecific symptoms of low testosterone in older androgen-deficient men. With this increase in initiation of TRT, there is a significant risk of overtreating. While there are many encouraging associations between treatment of androgen deficiency and improvement in rates of of morbidity and mortality, much remains unknown about the overall long-term risks and benefits of TRT. It is important to emphasize that TRT should not replace healthy lifestyle changes including regular exercise, weight loss, and diet modifications, which may provide the patient symptom resolution. Thoughtful dialogue with the patient is critical prior to TRT initiation, including thorough disclosure of the risks and benefits of treatment, and the limitations of the data as it evolves.

Editor’s note: This is the second of two articles on hypogonadism in men and focuses on the appropriate use of testosterone therapy. The first article, published last month, focused in more detail on the differential diagnosis of hypogonadism.

As men age, testosterone production gradually decreases. In our increasingly aged population, clinicians will continue to see an increase in the number of men with seemingly nonspecific symptoms of aging that are possibly due to low serum testosterone (eg, low energy level, depressive symptoms, erectile dysfunction, decreased libido). These clinical symptoms, coupled with low serum testosterone, may adversely affect quality of life and life expectancy. Testosterone replacement therapy (TRT) may improve symptoms and quality of life. Given the nonspecific nature of these symptoms, accurate diagnosis and treatment of clinically significant low testosterone with a goal of symptom and quality of life improvement can prove challenging.

These challenges in diagnosis and treatment result in a lack of standardized nomenclature. The terms male menopause and andropause, although popular, are the least helpful, as they have few correlates with the better-defined female menopause. Late-onset hypogonadism implies a well-defined, later age of decline, which is inaccurate since the decline in serum testosterone in men begins in middle age and is gradual. Testosterone deficiency syndrome implies a set of specific and well-defined symptoms. Androgen deficiency in the aging male (ADAM) and Androgen deficiency in the older male are common terms specifying an age cohort (> 40 years old) and an abnormal laboratory value without mention of symptoms. While all these terms have their limitations, we will primarily use ADAM in this discussion.

PREVALENCE OF LOW TESTOSTERONE

Serum testosterone levels begin to decline in men in their mid-40s, with an approximately 1% to 2% decline annually and a marked decline after age 60.¹

Araujo and colleagues² studied the prevalence of androgen-deficient men, with androgen deficiency defined as at least three signs or symptoms and either a total testosterone less than 200 ng/dL or a total testosterone 200 ng/dL to 400 ng/dL with a free testosterone less than 8.91 ng/dL. The overall prevalence of low testosterone on initial measurement was 6%, which doubled to 12% with repeat measurement.

Serial measures are important: one study that followed untreated men over 15 years found normal testosterone on serial measures in 50%.³ In a multicenter cross-sectional study, 11.8% of men had low testosterone and low or normal luteinizing hormone (LH) levels (secondary hypogonadism/hypothalamic-pituitary failure), with 2% of patients with low testosterone and elevated LH (primary hypogonadism/testicular failure).⁴

CLINICAL PRESENTATION AND DIAGNOSIS

A biochemical diagnosis of low testosterone is dependent on accurate measurement. Testosterone release is diurnal, with the highest levels in the early morning, and often has week-to-week variability. Thus, it is important to collect blood in the early morning and to confirm a diagnosis of low testosterone with at least one repeat measurement several days later, including LH assessment. LH levels will help differentiate primary hypogonadism from secondary hypogonadism, which may alter diagnosis and treatment in certain patients, with secondary hypogonadism associated with pituitary dysfunction, and primary hypogonadism associated with aging.⁴

Testosterone binds in the bloodstream to sex hormone-binding globulin (SHBG), and this bound form is generally considered biologically inactive, although there are in vitro and animal studies suggesting SHBG-bound androgen may indeed have biological activity. ^5,6 “Bioavailable” testosterone is active and includes both free testosterone and testosterone bound to albumin.

There is no general agreement on the acceptable normal range of testosterone, with variability within the literature and between laboratories. “Normal” total testosterone levels have ranged from more than 280 ng/dL to more than 350 ng/dL (12 nmol/L).^7,8 Similarly, there is no generally accepted lower limit of normal, although some studies report a threshold level of testosterone less than 230 ng/dL (8 nmol/L) as “abnormal.” Values between these two upper and lower limits are considered “borderline.”^7,8 These intermediate or borderline values coupled with clinical symptoms of testosterone deficiency syndrome or ADAM should be considered abnormal.

When total testosterone is borderline, measurement of free or bioavailable testosterone (free plus albumin-bound) should be considered. Total testosterone is typically measured using automated immunoassay platforms, with method-related differences leading to significant variability in measurement accuracy and precision. This variability is seen most dramatically in those with low total testosterone.⁹ However, the variability of total testosterone measurements is substantially smaller among mass spectrometry assays than among immunoassays. ¹⁰

The gold standards for free testosterone measurement are centrifugal ultrafiltration and equilibrium dialysis.⁹ However, these techniques are laborious and usually unavailable in local laboratories. Calculated free testosterone values using total testosterone and SHBG are most commonly used and are sufficiently accurate for clinical practice.¹¹

Free testosterone levels can be diagnostic when total testosterone levels do not correspond with clinical presentation. However, the clinical utility of free testosterone is difficult to assess due to the variability among laboratory assays and a lack of consensus on threshold parameters. A threshold free testosterone level of more than 225 pmol/L (65 pg/mL) is generally considered normal.^7,8 Before starting a patient on TRT, measurement of hemoglobin and prostate-specific antigen (PSA) and digital rectal examination of the prostate (if age is > 39) are essential.

Prolactin levels are recommended when low testosterone is confirmed, especially in patients at high clinical risk for hyperprolactinemia. Once hyperprolactinemia is identified, Endocrine Society guidelines recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes of elevated prolactin levels.¹²

Low testosterone values should be treated only in patients with clinically significant symptoms that are likely to be caused by the low testosterone itself. Symptoms associated with age-related decline in testosterone that may improve with TRT include low libido,^13,14 low energy,¹⁴ depressed mood,^15–17 low muscle mass, osteoporosis, and hot flashes. Men with erectile dysfunction have also shown a significant improvement with TRT compared with placebo, but with a variable overall response independent of normalization of testosterone. ^18,19 This is likely due to the multifactorial nature of erectile dysfunction, including vascular, neurologic, psychogenic, and endocrinologic causes.

Screening questionnaires have been developed for symptoms of low testosterone, but their clinical utility is unclear. The ADAM questionnaire is used as a screening tool for low testosterone but not to monitor response to TRT, and it is highly nonspecific.²⁰ The Aging Male Symptom Scale questionnaire includes psychological, somatovegetative, and sexual components and is used both to screen for low testosterone and to measure outcomes.²¹ However, a recent observational study comparing the ability of these questionnaires to assess clinical symptoms revealed a low sensitivity and a low specificity to detect androgen deficiency in men with a total testosterone level less than 300 ng/dL.²² Overall, the current data do not conclusively support the use of hypogonadism questionnaires for screening.

The patient history when evaluating for ADAM should include evaluation of sexual and constitutional symptoms as described above and in Table 1. In addition, a history of traumatic, medical, or surgical events that could affect testosterone production should be obtained, including cryptorchidism, scrotal, inguinal, or abdominal surgery, pituitary surgery or radiation, prior issues with infertility, timing of puberty, history of renal or hepatic failure, chemotherapy (for cancer or autoimmune diseases), and prior use of anabolic steroids or opiates.

A complete physical examination should include assessment of virilization, gynecomastia, and the genitalia, including the size, position, and volume of the testes. The size and consistency of the prostate should be assessed on digital rectal examination.

LOW TESTOSTERONE AND ASSOCIATED COMORBIDITIES

Low testosterone is associated with many comorbidities, including metabolic syndrome, depression, type 2 diabetes mellitus, and cardiovascular disease, as discussed later in this section. Low testosterone has also shown associations with osteoporosis, cognitive impairment, hypertension, hyperlipidemia, decreased physical performance, end-stage renal disease, and treatment with steroids or opiates.^23–26 However, the studies that found these associations included men younger than 40 years and may not be fully applicable to the ADAM population.

The association of metabolic syndrome and type 2 diabetes mellitus with low testosterone is well established in multiple studies. Grossman and colleagues²⁷ investigated the association of type 2 diabetes mellitus and low testosterone, with low total testosterone defined as below 10 nmol/L and low calculated free testosterone less than 0.23 nmol/L. The prevalence of low total testosterone was 43%, and the prevalence of low free testosterone was 57%. In addition, a recent meta-analysis comparing total testosterone of men with and without metabolic syndrome revealed an association between a baseline decrease in mean total and free testosterone levels in men with metabolic syndrome compared with controls. This study found a total testosterone mean difference of –2.64 nmol/L (95% confidence interval [CI] –2.95 to –2.32) and a free testosterone mean difference of –0.26 pmol/L (95% CI –0.39 to –0.13), respectively, when comparing men with metabolic syndrome against those without.²⁸

Testosterone has also been suggested to be protective against type 2 diabetes mellitus, with 42% lower risk of type 2 diabetes mellitus in men with testosterone levels ranging from 450 ng/dL to 605 ng/dL.²⁹

Obesity has been specifically linked with secondary hypogonadism.^4,23,24 A prospective cohort of 58 men with an average age of 46 years and a body mass index ranging from 30 to 45 kg/m² were monitored on a low-calorie diet for 9 weeks. Afterward, biochemical analysis revealed an increase in free testosterone from 185 pmol/L ± 66 to 208 ± 70 pmol/L (P = .002) with a mean weight loss of 16.3 kg ± 4.5 kg.³⁰ This emphasizes the importance of lifestyle changes in the management of hypogonadal men.

LOW TESTOSTERONE AND THE OVERALL MORTALITY RATE

Low testosterone is associated unfavorably with the rate of all-cause mortality. A retrospective study in male veterans over age 40 with repeated testosterone levels over a 5-year period found that the risk of death from all causes in men with normal testosterone (> 250 ng/dL or free testosterone > 0.75 ng/dL) was 20% (95% CI 16.2%–241%) vs 35% (95% CI 28.5%–41.4%) in men with low testosterone (< 250 ng/dL or free testosterone < 0.75 ng/dL). In multivariate analysis, men with testosterone less than 250 ng/dL (< 8.7 nmol/L) or free testosterone less than 0.75 ng/dL (< 0.03 nmol/L) had up to an 88% higher death rate than men with normal testosterone levels.³¹

Low testosterone has also been associated with other end-organ, disease-specific mortality. In men with end-stage renal disease, low testosterone was an independent predictor of death from all causes and from cardiovascular disease.³² A prospective European health study revealed an association between low testosterone and increased risk of death from cardiovascular disease and cancer.³³ A recent meta-analysis of population-based studies confirmed this association, despite significant interstudy heterogeneity. ³⁴ Although multiple studies show an independent association of low testosterone and increased mortality rate, causality remains unconfirmed. This may be difficult to prove, given the available study designs and the nonspecific nature of symptoms related to low testosterone and potentially associated comorbidities.

TRT: INDICATIONS AND CONTRAINDICATIONS

The indications, benefits, and risks of TRT are controversial, with current data lacking long-term follow-up and consistent biochemical target values. Treatment of low testosterone is not indicated at the present time in the absence of clinical symptoms.

According to recently published guidelines, TRT is recommended for symptomatic men with low or borderline total testosterone or free testosterone (< 350 ng/dL or < 65 pg/mL).^7,8 Patients with borderline biochemical values (total testosterone 200–350 ng/dL, free testosterone 40–65 pg/mL) and possible related symptoms should be treated with TRT for at least 3 months and then reevaluated to verify improved testosterone levels and to assess for symptom amelioration or resolution.³⁵ Dose escalation is recommended in patients with subtherapeutic testosterone levels and limited clinical improvement after 3 months of treatment.

Target maintenance testosterone levels have not been defined, with mid to lower young adult male serum testosterone levels recommended at this time.⁸ Given that the current literature does not specify a target testosterone replacement range, we recommend monitoring the clinical response along with total testosterone to decide adjustments in TRT. Ultimately, treatment goals of TRT should be the resolution of signs and symptoms, including improvement of sexual function, libido, and preservation of bone mineral density.^7,8

Contraindications

TRT is not recommended in men with the following:

• Breast cancer
• Polycythemia (hematocrit > 50%)
• Untreated obstructive sleep apnea
• Lower urinary tract symptoms caused by an enlarged prostate; International Prostate Symptom Score > 19
• Poorly controlled heart failure
• Desire for fertility.

The role of TRT in prostate cancer remains controversial (see below) and remains contraindicated in recent Endocrine Society clinical practice guidelines.⁷ Guidelines recommend urologic consultation prior to initiation of TRT in patients at increased risk of prostate cancer,⁷ based on age, race, family history, PSA, PSA velocity, and history of prostate biopsy.

One prominent historic concern about androgen replacement therapy regards the potential for de novo development of prostate cancer. Numerous studies have failed to find elevated risk of new diagnosis, progression, or recurrence of prostate cancer in patients on TRT.^36,37 Nevertheless, patients who develop elevated PSA, increased PSA velocity, or an abnormal digital rectal examination while on TRT should undergo prostate biopsy.

TRT FORMULATIONS AND TREATMENT OPTIONS

A number of effective formulations of TRT are available (Table 2). Transdermal and parenteral formulations are most commonly used. Enteric testosterone formulations are not available in the United States and are associated with hepatotoxicity. While buccal testosterone therapy is available, it often leads to local gingival irritation and has not gained widespread popularity.

Parenteral TRT can be administered intramuscularly (IM) or subcutaneously (SQ). Testosterone cypionate (Depo-Testosterone) is the only IM form available in the United States and is given every 2 to 3 weeks. It is the least expensive form of TRT, but it requires frequent administration (by either the clinical practitioner or the patient himself). Testosterone cypionate injections lead to markedly wide swings of testosterone levels, ranging from supraphysiologic levels for a few days after administration to hypogonadal levels before the next injection. This may be mitigated by more-frequent injections. The longer-acting form testosterone undecanoate is available outside the United States and is given every 12 weeks when stable levels are reached.

The other parenteral option is SQ slow-release pellets (Testopel). These pellets have 75 mg of testosterone. Typically 8 to 14 pellets are placed subcutaneously in the buttock area, which will provide coverage for 3 to 6 months.³⁸ The insertion procedure is simple with a short learning curve, limited compliance issues, and elimination of risk of transdermal transmission of drug to others. Disadvantages include wound infection and pellet extrusion, seen in 0.3% to 12% of patients in various studies.³⁸

Another route of TRT is transdermal, including patches, liquids, and gels. Patches are applied daily and are rotated to different sites with minimal risk for skin transmission to others, although use may be limited by site dermatitis. Three hydro-alcoholic gel formulations are currently available in the United States: Androgel (1% or 1.62%), which is applied to the chest or the shoulders; Testim 1%, which is applied to the shoulders; and Fortesta (2%), which is applied to the thighs. A liquid preparation, Axiron, is applied to the axillae. Because secondary transfer to women and children is possible, it is important to thoroughly wash hands after application and to cover the treated skin with clothing. In 3 to 4 hours, all the medication is absorbed, and the area should then be washed before direct skin contact with others (Table 2).

MONITORING PATIENTS ON TRT

Patients starting TRT will require clinical and biochemical monitoring to evaluate response to therapy as well as possible side effects. The first set of laboratory values should be obtained 6 to 12 weeks after initiation of therapy and then typically quarterly for 1 year, every 6 months for the second year, and annually thereafter. Laboratory values monitored should include total testosterone, PSA, and hematocrit.

Men on daily therapy (patch, gel, liquid) should have testosterone drawn approximately 2 hours after application. Current TRT regimen data lack an appropriate target testosterone value, and guidelines suggest a mid to lower young adult male testosterone level.⁸ Since this is not clearly delineated in the current literature, the authors recommend monitoring clinical symptoms along with testosterone levels when adjusting TRT. It is important to document that serum testosterone was actually increased to the normal range in treated men without clinical improvement.

A rise in PSA of up to 24% would be an acceptable response in a benign prostate gland, but a higher increase or increase above 4.0 ng/dL should prompt consideration of prostate biopsy. ³⁹ Similarly, hemoglobin and hematocrit typically increase, but a hematocrit greater than 55% should prompt dose reduction or cessation.⁷ Transaminases do not need routine monitoring during parenteral or transdermal therapy. Bone mineral density should be monitored every 1 to 2 years.^7,8

CLINICAL BENEFITS OF TRT

There are promising data regarding the clinical benefits of TRT in patients with metabolic syndrome and type 2 diabetes mellitus. A recent meta-analysis investigating the effect of TRT on metabolic syndrome revealed an improvement in fasting plasma glucose, homeostatic model assessment index, triglycerides, treadmill duration, high-density lipoprotein cholesterol, and waist circumference.^40,41 TRT also decreased insulin resistance and improved glycemic control in type 2 diabetic hypogonadal men.⁴² Results from a randomized controlled trial comparing 12 weeks of intramuscular testosterone treatment vs placebo in men with metabolic syndrome revealed an improvement in mean waist circumference from 108 cm ± 8 cm to 105.5 cm ± 7.7 cm. Sixty percent of men initially diagnosed with metabolic syndrome and treated with testosterone no longer met diagnostic criteria for metabolic syndrome according to the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP-ATP III) and the International Diabetes Federation (IDF) guidelines.⁴³

Depression has also been associated with low testosterone, with free testosterone levels below 170 pmol/L associated with frank depressive symptoms and levels below 220 pmol/L predictive of future onset of depressive symptoms.¹⁵ Testosterone replacement therapy has been shown to improve depressive symptoms in hypogonadal men.^16,17 Shores et al¹⁶ conducted a randomized placebo-controlled study of testosterone replacement in men older than 50 years with dysthymia or minor depression. Men treated with testosterone gel for 12 weeks showed an improvement of baseline total testosterone levels from 291 ng/dL to 449 ng/dL. Men treated with testosterone also had a 53% rate of depression remission compared with 19% in the placebo group.¹⁶

The evidence supporting improved sexual function with TRT is variable. Some studies indicate limited or transient improvement of sexual function after TRT in men with erectile dysfunction,^18,19 while others report an improvement in sexual function after 3 months of TRT.⁴⁴ Because of the multifactorial nature of erectile dysfunction, men with erectile dysfunction and ADAM may require TRT and a phosphodiesterase type 5 (PDE5) inhibitor, as TRT alone may be insufficient. In a prospective observational study of men with erectile dysfunction and an initial testosterone lower than 300 ng/dL, testosterone gel was administered for at least 1 year, and improvement in sexual function was seen. Results revealed a correlation between improvement in sexual function and concurrent therapy with a PDE5 inhibitor.⁴⁵ In a recent multicenter placebo-controlled study of PDE5 inhibitor nonresponders, the addition of a testosterone gel to tadalafil (Cialis) improved sexual function, again suggesting a synergistic effect when treating erectile dysfunction with both TRT and a PDE5 inhibitor.⁴⁶

ADVERSE EVENTS RELATED TO TRT

Despite the aforementioned benefits, it must be emphasized that TRT should be used for specific target symptoms related to hypogonadism in older men and that the general health benefits and safety of TRT in an asymptomatic man with a low measured testosterone alone remains unproven.

Cardiovascular events. In a recent study of 209 elderly men with low testosterone and limited mobility associated with other chronic illnesses, 6 months of TRT resulted in the development of cardiovascular-related adverse events in 23 patients compared with 5 men in the placebo group.⁴⁷ This may have been related to how adverse events were reported, with cumulative adverse events reviewed every 6 months, ranging from peripheral edema, hypertension, arrhythmias, and electrocardiographic changes. Serious adverse events were reviewed as they occurred, including stroke and acute myocardial events.

Other studies^41,43 have revealed a favorable effect of TRT on cardiovascular disease and its surrogate markers but have lacked detailed reports and close monitoring of adverse events. Thus, variation of outcome measurement and reporting may obfuscate the detection of adverse cardiovascular events. Outcomes may also depend on the testosterone formulation and the target serum concentration.⁴³

Larger, long-term placebo-controlled trials are needed to elucidate cardiovascular risk as a primary outcome in older androgen-deficient men undergoing TRT.

Other adverse effects related to TRT include erythrocytosis, seen in 3% to 18% of patients with transdermal administration,^48,49 and up to 44% of patients undergoing IM therapy.⁴⁸ Gynecomastia can occur and is more likely to resolve after treatment cessation of transdermal testosterone treatment than IM injections.⁴⁸ Other potential clinical side effects that should prompt dose-reduction or discontinuation are irritability, bothersome acne, fluid retention, testicular atrophy, worsening of lower urinary tract symptoms from an enlarged prostate, and new or worsening heart failure. Infrequently, obstructive sleep apnea may be worsened by TRT, although currently the data linking sleep apnea and TRT are limited.⁵⁰

TRT AND PROSTATE CANCER

The relationship between prostate cancer growth and testosterone is well established, with androgen ablation remaining the cornerstone of treatment for metastatic disease. Since androgen deprivation leads to the regression of prostate cancer, there has been concern that TRT may lead to growth or de novo development of prostate cancer. TRT has thus been strongly prohibited in patients with prostate cancer.⁷ However, recent data challenge this paradigm.

In a retrospective study of 81 men (mean age 56.8 years) treated with TRT, only 4 men (4.9%) developed prostate cancer over a 5-year period.⁵¹ This is less than the estimated 16.7% probability of developing prostate cancer in the general US population.⁵²

Recent accumulating data support the concept of testosterone reaching a saturation level when binding androgen receptors within the prostate at extremely low levels. Increases above this level with TRT as with ADAM do not increase the risk of development or progression of prostate cancer.⁵³ In addition, large doses of dihydrotestosterone do not seem to alter PSA, prostate volume, or International Prostate Symptom Score.⁵⁴ These findings may have implications in future androgen therapies in hypogonadal older men.

Pathologic studies suggest low testosterone is associated with a higher Gleason grade of prostate cancer,⁵⁵ although this association remains unconfirmed.⁵⁶

In men with erectile dysfunction after prostate cancer treatment, TRT appears safe after brachytherapy⁵⁷ or radical prostatectomy.⁵⁸ A small study of 15 hypogonadal men with castrate-resistant prostate cancer and minimal or no metastatic disease showed only 1 patient had symptomatic progression.⁵⁹ Moreover, a recent small study of 13 men with known prostate cancer on active surveillance showed that TRT did not lead to local progression or metastatic disease in any of the patients.⁶⁰

While these data are provocative, it should still be emphasized that the standard of care for prostate cancer screening should be followed in age-appropriate men with ADAM. In addition, hypogonadal men with prostate cancer should only be treated with testosterone in conjunction with careful counseling and ongoing monitoring.

TRT SHOULD NOT REPLACE HEALTHY LIFESTYLE CHANGES

There has been a dramatic increase in TRT initiation for nonspecific symptoms of low testosterone in older androgen-deficient men. With this increase in initiation of TRT, there is a significant risk of overtreating. While there are many encouraging associations between treatment of androgen deficiency and improvement in rates of of morbidity and mortality, much remains unknown about the overall long-term risks and benefits of TRT. It is important to emphasize that TRT should not replace healthy lifestyle changes including regular exercise, weight loss, and diet modifications, which may provide the patient symptom resolution. Thoughtful dialogue with the patient is critical prior to TRT initiation, including thorough disclosure of the risks and benefits of treatment, and the limitations of the data as it evolves.

Editor’s note: This is the second of two articles on hypogonadism in men and focuses on the appropriate use of testosterone therapy. The first article, published last month, focused in more detail on the differential diagnosis of hypogonadism.

As men age, testosterone production gradually decreases. In our increasingly aged population, clinicians will continue to see an increase in the number of men with seemingly nonspecific symptoms of aging that are possibly due to low serum testosterone (eg, low energy level, depressive symptoms, erectile dysfunction, decreased libido). These clinical symptoms, coupled with low serum testosterone, may adversely affect quality of life and life expectancy. Testosterone replacement therapy (TRT) may improve symptoms and quality of life. Given the nonspecific nature of these symptoms, accurate diagnosis and treatment of clinically significant low testosterone with a goal of symptom and quality of life improvement can prove challenging.

These challenges in diagnosis and treatment result in a lack of standardized nomenclature. The terms male menopause and andropause, although popular, are the least helpful, as they have few correlates with the better-defined female menopause. Late-onset hypogonadism implies a well-defined, later age of decline, which is inaccurate since the decline in serum testosterone in men begins in middle age and is gradual. Testosterone deficiency syndrome implies a set of specific and well-defined symptoms. Androgen deficiency in the aging male (ADAM) and Androgen deficiency in the older male are common terms specifying an age cohort (> 40 years old) and an abnormal laboratory value without mention of symptoms. While all these terms have their limitations, we will primarily use ADAM in this discussion.

PREVALENCE OF LOW TESTOSTERONE

Serum testosterone levels begin to decline in men in their mid-40s, with an approximately 1% to 2% decline annually and a marked decline after age 60.¹

Araujo and colleagues² studied the prevalence of androgen-deficient men, with androgen deficiency defined as at least three signs or symptoms and either a total testosterone less than 200 ng/dL or a total testosterone 200 ng/dL to 400 ng/dL with a free testosterone less than 8.91 ng/dL. The overall prevalence of low testosterone on initial measurement was 6%, which doubled to 12% with repeat measurement.

Serial measures are important: one study that followed untreated men over 15 years found normal testosterone on serial measures in 50%.³ In a multicenter cross-sectional study, 11.8% of men had low testosterone and low or normal luteinizing hormone (LH) levels (secondary hypogonadism/hypothalamic-pituitary failure), with 2% of patients with low testosterone and elevated LH (primary hypogonadism/testicular failure).⁴

CLINICAL PRESENTATION AND DIAGNOSIS

A biochemical diagnosis of low testosterone is dependent on accurate measurement. Testosterone release is diurnal, with the highest levels in the early morning, and often has week-to-week variability. Thus, it is important to collect blood in the early morning and to confirm a diagnosis of low testosterone with at least one repeat measurement several days later, including LH assessment. LH levels will help differentiate primary hypogonadism from secondary hypogonadism, which may alter diagnosis and treatment in certain patients, with secondary hypogonadism associated with pituitary dysfunction, and primary hypogonadism associated with aging.⁴

Testosterone binds in the bloodstream to sex hormone-binding globulin (SHBG), and this bound form is generally considered biologically inactive, although there are in vitro and animal studies suggesting SHBG-bound androgen may indeed have biological activity. ^5,6 “Bioavailable” testosterone is active and includes both free testosterone and testosterone bound to albumin.

There is no general agreement on the acceptable normal range of testosterone, with variability within the literature and between laboratories. “Normal” total testosterone levels have ranged from more than 280 ng/dL to more than 350 ng/dL (12 nmol/L).^7,8 Similarly, there is no generally accepted lower limit of normal, although some studies report a threshold level of testosterone less than 230 ng/dL (8 nmol/L) as “abnormal.” Values between these two upper and lower limits are considered “borderline.”^7,8 These intermediate or borderline values coupled with clinical symptoms of testosterone deficiency syndrome or ADAM should be considered abnormal.

When total testosterone is borderline, measurement of free or bioavailable testosterone (free plus albumin-bound) should be considered. Total testosterone is typically measured using automated immunoassay platforms, with method-related differences leading to significant variability in measurement accuracy and precision. This variability is seen most dramatically in those with low total testosterone.⁹ However, the variability of total testosterone measurements is substantially smaller among mass spectrometry assays than among immunoassays. ¹⁰

The gold standards for free testosterone measurement are centrifugal ultrafiltration and equilibrium dialysis.⁹ However, these techniques are laborious and usually unavailable in local laboratories. Calculated free testosterone values using total testosterone and SHBG are most commonly used and are sufficiently accurate for clinical practice.¹¹

Free testosterone levels can be diagnostic when total testosterone levels do not correspond with clinical presentation. However, the clinical utility of free testosterone is difficult to assess due to the variability among laboratory assays and a lack of consensus on threshold parameters. A threshold free testosterone level of more than 225 pmol/L (65 pg/mL) is generally considered normal.^7,8 Before starting a patient on TRT, measurement of hemoglobin and prostate-specific antigen (PSA) and digital rectal examination of the prostate (if age is > 39) are essential.

Prolactin levels are recommended when low testosterone is confirmed, especially in patients at high clinical risk for hyperprolactinemia. Once hyperprolactinemia is identified, Endocrine Society guidelines recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes of elevated prolactin levels.¹²

Low testosterone values should be treated only in patients with clinically significant symptoms that are likely to be caused by the low testosterone itself. Symptoms associated with age-related decline in testosterone that may improve with TRT include low libido,^13,14 low energy,¹⁴ depressed mood,^15–17 low muscle mass, osteoporosis, and hot flashes. Men with erectile dysfunction have also shown a significant improvement with TRT compared with placebo, but with a variable overall response independent of normalization of testosterone. ^18,19 This is likely due to the multifactorial nature of erectile dysfunction, including vascular, neurologic, psychogenic, and endocrinologic causes.

Screening questionnaires have been developed for symptoms of low testosterone, but their clinical utility is unclear. The ADAM questionnaire is used as a screening tool for low testosterone but not to monitor response to TRT, and it is highly nonspecific.²⁰ The Aging Male Symptom Scale questionnaire includes psychological, somatovegetative, and sexual components and is used both to screen for low testosterone and to measure outcomes.²¹ However, a recent observational study comparing the ability of these questionnaires to assess clinical symptoms revealed a low sensitivity and a low specificity to detect androgen deficiency in men with a total testosterone level less than 300 ng/dL.²² Overall, the current data do not conclusively support the use of hypogonadism questionnaires for screening.

The patient history when evaluating for ADAM should include evaluation of sexual and constitutional symptoms as described above and in Table 1. In addition, a history of traumatic, medical, or surgical events that could affect testosterone production should be obtained, including cryptorchidism, scrotal, inguinal, or abdominal surgery, pituitary surgery or radiation, prior issues with infertility, timing of puberty, history of renal or hepatic failure, chemotherapy (for cancer or autoimmune diseases), and prior use of anabolic steroids or opiates.

A complete physical examination should include assessment of virilization, gynecomastia, and the genitalia, including the size, position, and volume of the testes. The size and consistency of the prostate should be assessed on digital rectal examination.

LOW TESTOSTERONE AND ASSOCIATED COMORBIDITIES

Low testosterone is associated with many comorbidities, including metabolic syndrome, depression, type 2 diabetes mellitus, and cardiovascular disease, as discussed later in this section. Low testosterone has also shown associations with osteoporosis, cognitive impairment, hypertension, hyperlipidemia, decreased physical performance, end-stage renal disease, and treatment with steroids or opiates.^23–26 However, the studies that found these associations included men younger than 40 years and may not be fully applicable to the ADAM population.

The association of metabolic syndrome and type 2 diabetes mellitus with low testosterone is well established in multiple studies. Grossman and colleagues²⁷ investigated the association of type 2 diabetes mellitus and low testosterone, with low total testosterone defined as below 10 nmol/L and low calculated free testosterone less than 0.23 nmol/L. The prevalence of low total testosterone was 43%, and the prevalence of low free testosterone was 57%. In addition, a recent meta-analysis comparing total testosterone of men with and without metabolic syndrome revealed an association between a baseline decrease in mean total and free testosterone levels in men with metabolic syndrome compared with controls. This study found a total testosterone mean difference of –2.64 nmol/L (95% confidence interval [CI] –2.95 to –2.32) and a free testosterone mean difference of –0.26 pmol/L (95% CI –0.39 to –0.13), respectively, when comparing men with metabolic syndrome against those without.²⁸

Testosterone has also been suggested to be protective against type 2 diabetes mellitus, with 42% lower risk of type 2 diabetes mellitus in men with testosterone levels ranging from 450 ng/dL to 605 ng/dL.²⁹

Obesity has been specifically linked with secondary hypogonadism.^4,23,24 A prospective cohort of 58 men with an average age of 46 years and a body mass index ranging from 30 to 45 kg/m² were monitored on a low-calorie diet for 9 weeks. Afterward, biochemical analysis revealed an increase in free testosterone from 185 pmol/L ± 66 to 208 ± 70 pmol/L (P = .002) with a mean weight loss of 16.3 kg ± 4.5 kg.³⁰ This emphasizes the importance of lifestyle changes in the management of hypogonadal men.

LOW TESTOSTERONE AND THE OVERALL MORTALITY RATE

Low testosterone is associated unfavorably with the rate of all-cause mortality. A retrospective study in male veterans over age 40 with repeated testosterone levels over a 5-year period found that the risk of death from all causes in men with normal testosterone (> 250 ng/dL or free testosterone > 0.75 ng/dL) was 20% (95% CI 16.2%–241%) vs 35% (95% CI 28.5%–41.4%) in men with low testosterone (< 250 ng/dL or free testosterone < 0.75 ng/dL). In multivariate analysis, men with testosterone less than 250 ng/dL (< 8.7 nmol/L) or free testosterone less than 0.75 ng/dL (< 0.03 nmol/L) had up to an 88% higher death rate than men with normal testosterone levels.³¹

Low testosterone has also been associated with other end-organ, disease-specific mortality. In men with end-stage renal disease, low testosterone was an independent predictor of death from all causes and from cardiovascular disease.³² A prospective European health study revealed an association between low testosterone and increased risk of death from cardiovascular disease and cancer.³³ A recent meta-analysis of population-based studies confirmed this association, despite significant interstudy heterogeneity. ³⁴ Although multiple studies show an independent association of low testosterone and increased mortality rate, causality remains unconfirmed. This may be difficult to prove, given the available study designs and the nonspecific nature of symptoms related to low testosterone and potentially associated comorbidities.

TRT: INDICATIONS AND CONTRAINDICATIONS

The indications, benefits, and risks of TRT are controversial, with current data lacking long-term follow-up and consistent biochemical target values. Treatment of low testosterone is not indicated at the present time in the absence of clinical symptoms.

According to recently published guidelines, TRT is recommended for symptomatic men with low or borderline total testosterone or free testosterone (< 350 ng/dL or < 65 pg/mL).^7,8 Patients with borderline biochemical values (total testosterone 200–350 ng/dL, free testosterone 40–65 pg/mL) and possible related symptoms should be treated with TRT for at least 3 months and then reevaluated to verify improved testosterone levels and to assess for symptom amelioration or resolution.³⁵ Dose escalation is recommended in patients with subtherapeutic testosterone levels and limited clinical improvement after 3 months of treatment.

Target maintenance testosterone levels have not been defined, with mid to lower young adult male serum testosterone levels recommended at this time.⁸ Given that the current literature does not specify a target testosterone replacement range, we recommend monitoring the clinical response along with total testosterone to decide adjustments in TRT. Ultimately, treatment goals of TRT should be the resolution of signs and symptoms, including improvement of sexual function, libido, and preservation of bone mineral density.^7,8

Contraindications

TRT is not recommended in men with the following:

• Breast cancer
• Polycythemia (hematocrit > 50%)
• Untreated obstructive sleep apnea
• Lower urinary tract symptoms caused by an enlarged prostate; International Prostate Symptom Score > 19
• Poorly controlled heart failure
• Desire for fertility.

The role of TRT in prostate cancer remains controversial (see below) and remains contraindicated in recent Endocrine Society clinical practice guidelines.⁷ Guidelines recommend urologic consultation prior to initiation of TRT in patients at increased risk of prostate cancer,⁷ based on age, race, family history, PSA, PSA velocity, and history of prostate biopsy.

One prominent historic concern about androgen replacement therapy regards the potential for de novo development of prostate cancer. Numerous studies have failed to find elevated risk of new diagnosis, progression, or recurrence of prostate cancer in patients on TRT.^36,37 Nevertheless, patients who develop elevated PSA, increased PSA velocity, or an abnormal digital rectal examination while on TRT should undergo prostate biopsy.

TRT FORMULATIONS AND TREATMENT OPTIONS

A number of effective formulations of TRT are available (Table 2). Transdermal and parenteral formulations are most commonly used. Enteric testosterone formulations are not available in the United States and are associated with hepatotoxicity. While buccal testosterone therapy is available, it often leads to local gingival irritation and has not gained widespread popularity.

Parenteral TRT can be administered intramuscularly (IM) or subcutaneously (SQ). Testosterone cypionate (Depo-Testosterone) is the only IM form available in the United States and is given every 2 to 3 weeks. It is the least expensive form of TRT, but it requires frequent administration (by either the clinical practitioner or the patient himself). Testosterone cypionate injections lead to markedly wide swings of testosterone levels, ranging from supraphysiologic levels for a few days after administration to hypogonadal levels before the next injection. This may be mitigated by more-frequent injections. The longer-acting form testosterone undecanoate is available outside the United States and is given every 12 weeks when stable levels are reached.

The other parenteral option is SQ slow-release pellets (Testopel). These pellets have 75 mg of testosterone. Typically 8 to 14 pellets are placed subcutaneously in the buttock area, which will provide coverage for 3 to 6 months.³⁸ The insertion procedure is simple with a short learning curve, limited compliance issues, and elimination of risk of transdermal transmission of drug to others. Disadvantages include wound infection and pellet extrusion, seen in 0.3% to 12% of patients in various studies.³⁸

Another route of TRT is transdermal, including patches, liquids, and gels. Patches are applied daily and are rotated to different sites with minimal risk for skin transmission to others, although use may be limited by site dermatitis. Three hydro-alcoholic gel formulations are currently available in the United States: Androgel (1% or 1.62%), which is applied to the chest or the shoulders; Testim 1%, which is applied to the shoulders; and Fortesta (2%), which is applied to the thighs. A liquid preparation, Axiron, is applied to the axillae. Because secondary transfer to women and children is possible, it is important to thoroughly wash hands after application and to cover the treated skin with clothing. In 3 to 4 hours, all the medication is absorbed, and the area should then be washed before direct skin contact with others (Table 2).

MONITORING PATIENTS ON TRT

Patients starting TRT will require clinical and biochemical monitoring to evaluate response to therapy as well as possible side effects. The first set of laboratory values should be obtained 6 to 12 weeks after initiation of therapy and then typically quarterly for 1 year, every 6 months for the second year, and annually thereafter. Laboratory values monitored should include total testosterone, PSA, and hematocrit.

Men on daily therapy (patch, gel, liquid) should have testosterone drawn approximately 2 hours after application. Current TRT regimen data lack an appropriate target testosterone value, and guidelines suggest a mid to lower young adult male testosterone level.⁸ Since this is not clearly delineated in the current literature, the authors recommend monitoring clinical symptoms along with testosterone levels when adjusting TRT. It is important to document that serum testosterone was actually increased to the normal range in treated men without clinical improvement.

A rise in PSA of up to 24% would be an acceptable response in a benign prostate gland, but a higher increase or increase above 4.0 ng/dL should prompt consideration of prostate biopsy. ³⁹ Similarly, hemoglobin and hematocrit typically increase, but a hematocrit greater than 55% should prompt dose reduction or cessation.⁷ Transaminases do not need routine monitoring during parenteral or transdermal therapy. Bone mineral density should be monitored every 1 to 2 years.^7,8

CLINICAL BENEFITS OF TRT

There are promising data regarding the clinical benefits of TRT in patients with metabolic syndrome and type 2 diabetes mellitus. A recent meta-analysis investigating the effect of TRT on metabolic syndrome revealed an improvement in fasting plasma glucose, homeostatic model assessment index, triglycerides, treadmill duration, high-density lipoprotein cholesterol, and waist circumference.^40,41 TRT also decreased insulin resistance and improved glycemic control in type 2 diabetic hypogonadal men.⁴² Results from a randomized controlled trial comparing 12 weeks of intramuscular testosterone treatment vs placebo in men with metabolic syndrome revealed an improvement in mean waist circumference from 108 cm ± 8 cm to 105.5 cm ± 7.7 cm. Sixty percent of men initially diagnosed with metabolic syndrome and treated with testosterone no longer met diagnostic criteria for metabolic syndrome according to the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP-ATP III) and the International Diabetes Federation (IDF) guidelines.⁴³

Depression has also been associated with low testosterone, with free testosterone levels below 170 pmol/L associated with frank depressive symptoms and levels below 220 pmol/L predictive of future onset of depressive symptoms.¹⁵ Testosterone replacement therapy has been shown to improve depressive symptoms in hypogonadal men.^16,17 Shores et al¹⁶ conducted a randomized placebo-controlled study of testosterone replacement in men older than 50 years with dysthymia or minor depression. Men treated with testosterone gel for 12 weeks showed an improvement of baseline total testosterone levels from 291 ng/dL to 449 ng/dL. Men treated with testosterone also had a 53% rate of depression remission compared with 19% in the placebo group.¹⁶

The evidence supporting improved sexual function with TRT is variable. Some studies indicate limited or transient improvement of sexual function after TRT in men with erectile dysfunction,^18,19 while others report an improvement in sexual function after 3 months of TRT.⁴⁴ Because of the multifactorial nature of erectile dysfunction, men with erectile dysfunction and ADAM may require TRT and a phosphodiesterase type 5 (PDE5) inhibitor, as TRT alone may be insufficient. In a prospective observational study of men with erectile dysfunction and an initial testosterone lower than 300 ng/dL, testosterone gel was administered for at least 1 year, and improvement in sexual function was seen. Results revealed a correlation between improvement in sexual function and concurrent therapy with a PDE5 inhibitor.⁴⁵ In a recent multicenter placebo-controlled study of PDE5 inhibitor nonresponders, the addition of a testosterone gel to tadalafil (Cialis) improved sexual function, again suggesting a synergistic effect when treating erectile dysfunction with both TRT and a PDE5 inhibitor.⁴⁶

ADVERSE EVENTS RELATED TO TRT

Despite the aforementioned benefits, it must be emphasized that TRT should be used for specific target symptoms related to hypogonadism in older men and that the general health benefits and safety of TRT in an asymptomatic man with a low measured testosterone alone remains unproven.

Cardiovascular events. In a recent study of 209 elderly men with low testosterone and limited mobility associated with other chronic illnesses, 6 months of TRT resulted in the development of cardiovascular-related adverse events in 23 patients compared with 5 men in the placebo group.⁴⁷ This may have been related to how adverse events were reported, with cumulative adverse events reviewed every 6 months, ranging from peripheral edema, hypertension, arrhythmias, and electrocardiographic changes. Serious adverse events were reviewed as they occurred, including stroke and acute myocardial events.

Other studies^41,43 have revealed a favorable effect of TRT on cardiovascular disease and its surrogate markers but have lacked detailed reports and close monitoring of adverse events. Thus, variation of outcome measurement and reporting may obfuscate the detection of adverse cardiovascular events. Outcomes may also depend on the testosterone formulation and the target serum concentration.⁴³

Larger, long-term placebo-controlled trials are needed to elucidate cardiovascular risk as a primary outcome in older androgen-deficient men undergoing TRT.

Other adverse effects related to TRT include erythrocytosis, seen in 3% to 18% of patients with transdermal administration,^48,49 and up to 44% of patients undergoing IM therapy.⁴⁸ Gynecomastia can occur and is more likely to resolve after treatment cessation of transdermal testosterone treatment than IM injections.⁴⁸ Other potential clinical side effects that should prompt dose-reduction or discontinuation are irritability, bothersome acne, fluid retention, testicular atrophy, worsening of lower urinary tract symptoms from an enlarged prostate, and new or worsening heart failure. Infrequently, obstructive sleep apnea may be worsened by TRT, although currently the data linking sleep apnea and TRT are limited.⁵⁰

TRT AND PROSTATE CANCER

The relationship between prostate cancer growth and testosterone is well established, with androgen ablation remaining the cornerstone of treatment for metastatic disease. Since androgen deprivation leads to the regression of prostate cancer, there has been concern that TRT may lead to growth or de novo development of prostate cancer. TRT has thus been strongly prohibited in patients with prostate cancer.⁷ However, recent data challenge this paradigm.

In a retrospective study of 81 men (mean age 56.8 years) treated with TRT, only 4 men (4.9%) developed prostate cancer over a 5-year period.⁵¹ This is less than the estimated 16.7% probability of developing prostate cancer in the general US population.⁵²

Recent accumulating data support the concept of testosterone reaching a saturation level when binding androgen receptors within the prostate at extremely low levels. Increases above this level with TRT as with ADAM do not increase the risk of development or progression of prostate cancer.⁵³ In addition, large doses of dihydrotestosterone do not seem to alter PSA, prostate volume, or International Prostate Symptom Score.⁵⁴ These findings may have implications in future androgen therapies in hypogonadal older men.

Pathologic studies suggest low testosterone is associated with a higher Gleason grade of prostate cancer,⁵⁵ although this association remains unconfirmed.⁵⁶

In men with erectile dysfunction after prostate cancer treatment, TRT appears safe after brachytherapy⁵⁷ or radical prostatectomy.⁵⁸ A small study of 15 hypogonadal men with castrate-resistant prostate cancer and minimal or no metastatic disease showed only 1 patient had symptomatic progression.⁵⁹ Moreover, a recent small study of 13 men with known prostate cancer on active surveillance showed that TRT did not lead to local progression or metastatic disease in any of the patients.⁶⁰

While these data are provocative, it should still be emphasized that the standard of care for prostate cancer screening should be followed in age-appropriate men with ADAM. In addition, hypogonadal men with prostate cancer should only be treated with testosterone in conjunction with careful counseling and ongoing monitoring.

TRT SHOULD NOT REPLACE HEALTHY LIFESTYLE CHANGES

There has been a dramatic increase in TRT initiation for nonspecific symptoms of low testosterone in older androgen-deficient men. With this increase in initiation of TRT, there is a significant risk of overtreating. While there are many encouraging associations between treatment of androgen deficiency and improvement in rates of of morbidity and mortality, much remains unknown about the overall long-term risks and benefits of TRT. It is important to emphasize that TRT should not replace healthy lifestyle changes including regular exercise, weight loss, and diet modifications, which may provide the patient symptom resolution. Thoughtful dialogue with the patient is critical prior to TRT initiation, including thorough disclosure of the risks and benefits of treatment, and the limitations of the data as it evolves.

Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.

Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.

Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:

• Early age of onset of cancer (eg, colorectal cancer before age 50)
• More than 10 colorectal adenomas
• Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
• Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
• A family member with a known hereditary colorectal cancer syndrome (Table 1).

Any of these red flags should prompt a referral for genetic counseling.

SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS

Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).

These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.

In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.

LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.

Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.¹ The median age at onset is 45 years.¹ For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.²

Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.¹

Other extracolonic cancers in Lynch syndrome include cancers of the:

• Stomach (1%–10% risk by age 70 years)
• Ovaries (1%–20% risk)
• Hepatobiliary tract (1%–2% risk)
• Urinary tract (1%–12% risk)
• Small bowel (1%–2% risk)
• Brain (1%–8% risk)
• Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).^1,3,4

Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.

Genetics of Lynch syndrome

Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.⁵ These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.

These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.⁶

In whom should Lynch syndrome be suspected?

Lynch syndrome can be suspected on the basis of family history and clinical criteria.

In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it¹:

• At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
• At least two successive generations involved
• At least one of the cancers diagnosed before age 50
• Familial adenomatous polyposis is excluded.

Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.⁷ In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).⁸

Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.

The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.

Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.⁹

In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.¹⁰

Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).

Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.^11,12

While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.¹⁰ The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.

Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.¹³ This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.

Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.¹⁰

Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.^9,14

Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.¹⁵

If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.

Management of Lynch syndrome

Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.

Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.^16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.^19–21

Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.²²

For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.² Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.

Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.^23,24

Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.⁴ Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.⁴

Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.¹⁴

ADENOMATOUS POLYPOSIS SYNDROMES

Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.

FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.^25,26

Genetics of familial adenomatous polyposis

APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.²⁷

Clinical presentation of familial adenomatous polyposis

Familial adenomatous polyposis is classified by the burden of colorectal adenomas.

Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.²⁸

Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.

Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.²⁹ Fundic gland polyposis occurs in nearly 90% of patients,³⁰ while gastric adenomas are reported in fewer than 15% of patients.

Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.

Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.

In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.³¹

Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:

• Pancreatic cancer (2% lifetime risk)
• Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)³²
• Hepatoblastoma (1% to 2% lifetime risk)
• Brain tumors (< 1% lifetime risk)
• Biliary cancer (higher risk than in the general population).³³

Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.³³ The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.³⁴ These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.

Diagnosing familial adenomatous polyposis

The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.

Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.

The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.

It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.¹⁴ Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.

Management of familial adenomatous polyposis

Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.^35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.

For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.^35–37 If polyps are found, colonoscopy should be performed every year.

The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.³⁸ Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.

Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.^39,40

Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.²⁹ The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.⁴¹

Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.⁴² Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.³⁰

People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.³²

MYH-ASSOCIATED POLYPOSIS

Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.

Genetics of MYH-associated polyposis

MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.⁴³ These two mutations are estimated to occur in 1% to 2% of the general population.⁴⁴

Clinical presentation of MYH-associated polyposis

MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.^45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.⁴⁸ Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.⁴⁹ Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.⁴⁹

Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.^50,51

Diagnosis of MYH-associated polyposis

Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. ¹⁴ It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.⁵² The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.

Management of MYH-associated polyposis

The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.¹⁴ Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.⁴⁹

GENETIC COUNSELING AND GENETIC TESTING

The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.¹⁶ They further recommend genetic counseling and informed consent before genetic testing.¹⁶

Genetic counseling is a process of working with patients and families whereby:

• A detailed medical and family history is obtained
• A formal risk assessment is performed
• Education about the disease in question and about genetic testing is provided
• Psychosocial concerns are assessed
• Informed consent is obtained when genetic testing is recommended.⁵³

This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.

In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.⁵⁴ In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.

When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.

Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.

Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.

Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.

Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.

Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:

• Early age of onset of cancer (eg, colorectal cancer before age 50)
• More than 10 colorectal adenomas
• Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
• Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
• A family member with a known hereditary colorectal cancer syndrome (Table 1).

Any of these red flags should prompt a referral for genetic counseling.

SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS

Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).

These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.

In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.

LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.

Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.¹ The median age at onset is 45 years.¹ For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.²

Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.¹

Other extracolonic cancers in Lynch syndrome include cancers of the:

• Stomach (1%–10% risk by age 70 years)
• Ovaries (1%–20% risk)
• Hepatobiliary tract (1%–2% risk)
• Urinary tract (1%–12% risk)
• Small bowel (1%–2% risk)
• Brain (1%–8% risk)
• Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).^1,3,4

Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.

Genetics of Lynch syndrome

Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.⁵ These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.

These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.⁶

In whom should Lynch syndrome be suspected?

Lynch syndrome can be suspected on the basis of family history and clinical criteria.

In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it¹:

• At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
• At least two successive generations involved
• At least one of the cancers diagnosed before age 50
• Familial adenomatous polyposis is excluded.

Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.⁷ In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).⁸

Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.

The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.

Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.⁹

In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.¹⁰

Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).

Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.^11,12

While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.¹⁰ The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.

Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.¹³ This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.

Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.¹⁰

Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.^9,14

Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.¹⁵

If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.

Management of Lynch syndrome

Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.

Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.^16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.^19–21

Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.²²

For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.² Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.

Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.^23,24

Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.⁴ Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.⁴

Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.¹⁴

ADENOMATOUS POLYPOSIS SYNDROMES

Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.

FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.^25,26

Genetics of familial adenomatous polyposis

APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.²⁷

Clinical presentation of familial adenomatous polyposis

Familial adenomatous polyposis is classified by the burden of colorectal adenomas.

Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.²⁸

Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.

Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.²⁹ Fundic gland polyposis occurs in nearly 90% of patients,³⁰ while gastric adenomas are reported in fewer than 15% of patients.

Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.

Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.

In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.³¹

Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:

• Pancreatic cancer (2% lifetime risk)
• Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)³²
• Hepatoblastoma (1% to 2% lifetime risk)
• Brain tumors (< 1% lifetime risk)
• Biliary cancer (higher risk than in the general population).³³

Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.³³ The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.³⁴ These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.

Diagnosing familial adenomatous polyposis

The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.

Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.

The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.

It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.¹⁴ Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.

Management of familial adenomatous polyposis

Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.^35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.

For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.^35–37 If polyps are found, colonoscopy should be performed every year.

The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.³⁸ Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.

Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.^39,40

Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.²⁹ The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.⁴¹

Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.⁴² Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.³⁰

People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.³²

MYH-ASSOCIATED POLYPOSIS

Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.

Genetics of MYH-associated polyposis

MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.⁴³ These two mutations are estimated to occur in 1% to 2% of the general population.⁴⁴

Clinical presentation of MYH-associated polyposis

MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.^45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.⁴⁸ Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.⁴⁹ Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.⁴⁹

Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.^50,51

Diagnosis of MYH-associated polyposis

Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. ¹⁴ It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.⁵² The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.

Management of MYH-associated polyposis

The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.¹⁴ Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.⁴⁹

GENETIC COUNSELING AND GENETIC TESTING

The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.¹⁶ They further recommend genetic counseling and informed consent before genetic testing.¹⁶

Genetic counseling is a process of working with patients and families whereby:

• A detailed medical and family history is obtained
• A formal risk assessment is performed
• Education about the disease in question and about genetic testing is provided
• Psychosocial concerns are assessed
• Informed consent is obtained when genetic testing is recommended.⁵³

This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.

In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.⁵⁴ In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.

When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.

Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.

Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.

Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.

Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.

Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:

• Early age of onset of cancer (eg, colorectal cancer before age 50)
• More than 10 colorectal adenomas
• Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
• Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
• A family member with a known hereditary colorectal cancer syndrome (Table 1).

Any of these red flags should prompt a referral for genetic counseling.

SYNDROMES ARE CLASSIFIED AS WITH OR WITHOUT POLYPOSIS

Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).

These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.

In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.

LYNCH SYNDROME (HEREDITARY NONPOLYPOSIS COLORECTAL CANCER)

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.

Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.¹ The median age at onset is 45 years.¹ For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.²

Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.¹

Other extracolonic cancers in Lynch syndrome include cancers of the:

• Stomach (1%–10% risk by age 70 years)
• Ovaries (1%–20% risk)
• Hepatobiliary tract (1%–2% risk)
• Urinary tract (1%–12% risk)
• Small bowel (1%–2% risk)
• Brain (1%–8% risk)
• Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).^1,3,4

Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.

Genetics of Lynch syndrome

Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.⁵ These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.

These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.⁶

In whom should Lynch syndrome be suspected?

Lynch syndrome can be suspected on the basis of family history and clinical criteria.

In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it¹:

• At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
• At least two successive generations involved
• At least one of the cancers diagnosed before age 50
• Familial adenomatous polyposis is excluded.

Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.⁷ In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).⁸

Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.

The diagnosis of Lynch syndrome is based on molecular pathologic analysis (performed on tumor samples) and confirmed by genetic testing.

Molecular pathologic evidence of Lynch syndrome includes microsatellite instability and loss of expression of one or more of the DNA mismatch repair proteins (detected using immunohistochemistry) (more on these below). The revised Bethesda guidelines (TABLE 3) were intended to identify individuals whose tumors should be tested for one or both of these phenomena.⁹

In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended that all patients with newly diagnosed colorectal cancer undergo microsatellite instability analysis, immunohistochemistry testing, or both, regardless of whether they meet the Amsterdam II or the Bethesda guideline criteria.¹⁰

Microsatellite instability analysis. Microsatellites are short sequences of repeated DNA. The tumor cells of patients who carry defective mismatch repair genes have microsatellites that are longer or shorter than in normal cells, a condition called microsatellite instability (ie, “MSI-high”).

Microsatellite instability testing, using a standardized panel of five DNA markers, is performed on normal and tumor tissue. If more than two of the five microsatellite markers in the tumor show instability, the lesion is considered to have a high level of microsatellite instability. About 15% of colorectal cancers have this high level, although most are not associated with Lynch syndrome and lose MLH1 expression by promoter methylation.^11,12

While only 2% of patients with colorectal cancer have Lynch syndrome, from 90% to 95% of colorectal cancers from patients with Lynch syndrome have high levels of microsatellite instability.¹⁰ The presence of MLH1 promoter hypermethylation, the BRAF mutation V600E, or both within the tumor suggests that the cancer is not associated with Lynch syndrome.

Some families that meet the Amsterdam I criteria have microsatellite-stable tumors: their condition has been called familial colorectal cancer type X.¹³ This condition is associated with a higher risk of colorectal cancer but not the other malignancies observed in Lynch syndrome.

Immunohistochemistry is performed to assess for expression of the mismatch repair proteins MSH2, MSH6, MLH1, and PMS2. Absence of expression of the specific protein within tumor cells compared with normal cells within the specimen suggests dysfunction of the specific gene and guides germline mutation testing (Figure 1). For example, a patient who lacks expression of the MSH2 protein in his or her colon cancer most likely has a mutation in the MSH2 gene. Therefore, germ-line genetic testing should initially target the MSH2 gene. Approximately 88% of Lynch syndrome-associated colorectal cancers have abnormal immunohistochemical staining.¹⁰

Testing for microsatellite instability and mismatch repair gene expression ideally precedes germline genetic testing and helps to guide which gene or genes should be tested.^9,14

Genetic testing for Lynch syndrome is routinely performed on a blood or saliva sample, using DNA from white blood cells and sequencing the gene or genes involved to look for mutations. Positive results from a germline genetic test confirm the diagnosis of Lynch syndrome and allow for predictive testing for relatives at risk. The term Lynch syndrome is used exclusively to describe individuals with evidence of a mutation in one of the mismatch repair genes.¹⁵

If a patient’s results are positive, genetic counseling and genetic testing should be offered to at-risk relatives age 18 and over.

Management of Lynch syndrome

Aggressive cancer surveillance is essential for people with Lynch syndrome and for those who are considered at risk but have not pursued genetic testing, such as a sibling of a person with Lynch syndrome.

Colorectal cancer. Colonoscopy is recommended every 1 to 2 years beginning at the age of 20 to 25 years, or 2 to 5 years earlier than the age of the youngest relative affected with colorectal cancer if the initial diagnosis was before age 25. When patients turn 40 years old, colonoscopy is done annually.^16–18 A significant reduction in cancer incidence and in the mortality rate has been shown with colonoscopic surveillance.^19–21

Chemoprevention may also have a role. Patients with Lynch syndrome who took aspirin 600 mg per day for an average of 25 months had a significantly lower incidence of colorectal cancer during a 55-month follow-up period compared with patients randomized to placebo.²²

For patients with Lynch syndrome who are diagnosed with colorectal cancer, the high risk of metachronous cancers after standard segmental colectomy calls for a more extended resection. Retrospective analysis of 382 Lynch syndrome patients found that none of the 50 who underwent total or subtotal colectomy were diagnosed with metachronous colorectal cancer, whereas a metachronous cancer developed in 74 (22%) of the 332 patients who had had segmented resection.² Annual surveillance of the remaining colon, rectum, or both is indicated postoperatively.

Gynecologic cancers. Women with Lynch syndrome should also consider gynecologic surveillance and risk-reducing surgery. This includes annual gynecologic examination, transvaginal ultrasonography, and endometrial aspiration, beginning at age 30 to 35 years. Although this surveillance does detect premalignant lesions and early symptomatic cancers, its effect on the mortality rate is unknown. Hysterectomy with bilateral salpingo-oophorectomy has been shown to significantly reduce endometrial and ovarian cancers in women with Lynch syndrome.^23,24

Urothelial cancers. Carriers of MSH2 mutations have a significantly higher risk of urothelial cancers.⁴ Therefore, MSH2 carriers should consider ultrasonography of the urinary tract, urinary cytology, and urinalysis every 1 to 2 years beginning at age 40.⁴

Other extracolonic cancers. Poor evidence exists for systematic screening for the other extracolonic tumors associated with Lynch syndrome. However, the National Comprehensive Cancer Network advises considering esophagogastroduodenoscopy with extended duodenoscopy as well as capsule endoscopy every 2 to 3 years beginning at age 30 to 35.¹⁴

ADENOMATOUS POLYPOSIS SYNDROMES

Familial adenomatous polyposis and MYH-associated polyposis are the next most common hereditary colorectal cancer syndromes. Each of these accounts for about 1% of cases of colorectal cancer. Clinically, these two syndromes can be challenging to distinguish because they overlap phenotypically to a significant degree.

FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis is caused by mutations in the APC gene. Its prevalence is 2.29 to 3.2 per 100,000 individuals.^25,26

Genetics of familial adenomatous polyposis

APC is the only gene known to cause familial adenomatous polyposis. Mutations in APC are inherited in an autosomal dominant manner. Approximately 25% of cases of familial adenomatous polyposis are due to a de novo mutation in APC.²⁷

Clinical presentation of familial adenomatous polyposis

Familial adenomatous polyposis is classified by the burden of colorectal adenomas.

Patients who have fewer than 100 adenomas have an attenuated form of the disease. In this group, polyps usually begin to form in the late teenage years or early 20s and tend to develop in the proximal colon. The attenuated form is associated with an approximately 70% lifetime risk of colorectal cancer.²⁸

Patients who have more than 100 polyps are considered to have the classic form of the disease, and those with more than 1,000 polyps have profuse familial adenomatous polyposis (Figure 2). In these groups, polyps typically begin to develop in the preteenage to mid-teenage years. Without surgery, there is nearly a 100% risk of colorectal cancer. The average age at diagnosis of colorectal cancer is 39 years for patients with classic disease.

Upper gastrointestinal polyps are common in familial adenomatous polyposis. Nearly 90% of patients develop duodenal adenomas by a mean age of 44, with a cumulative lifetime risk of nearly 100%.²⁹ Fundic gland polyposis occurs in nearly 90% of patients,³⁰ while gastric adenomas are reported in fewer than 15% of patients.

Duodenal and periampullary cancer is the second most common malignancy in familial adenomatous polyposis. The lifetime risk ranges from 2% to 36%, depending on the Spigelman stage. People with Spigelman stage I, II, or III have a 2.5% risk of duodenal cancer, while those with stage IV disease have up to a 36% lifetime risk.

Gastric cancer, arising from fundic gland polyps, has been reported but is rare in Western populations.

In familial adenomatous polyposis, the incidence of jejunal adenomas and cancer is less than 10%, and the risk of ileal adenomas and cancer is less than 1%.³¹

Familial adenomatous polyposis is also associated with a higher risk of other malignancies, including:

• Pancreatic cancer (2% lifetime risk)
• Thyroid cancer (2% to 3% lifetime risk, typically papillary carcinoma)³²
• Hepatoblastoma (1% to 2% lifetime risk)
• Brain tumors (< 1% lifetime risk)
• Biliary cancer (higher risk than in the general population).³³

Benign extracolonic manifestations that have been observed include osteomas, dental abnormalities (supernumerary teeth, unerupted or absent teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium, benign cutaneous lesions (epidermoid cysts and fibromas), and desmoid tumors.³³ The term “Gardner syndrome” has been used to describe patients who have familial adenomatous polyposis but also have osteomas and soft-tissue tumors.³⁴ These patients carry the same risk of colorectal cancer as other patients with familial adenomatous polyposis.

Diagnosing familial adenomatous polyposis

The diagnosis of familial adenomatous polyposis is suspected when a patient has more than 10 adenomatous polyps.

Seventy-five percent of patients with familial adenomatous polyposis have a family history of the condition. Therefore, most cases are identified at a young age on screening sigmoidoscopy or colonoscopy or by predictive gene testing. Patients rarely have cancer at the time of diagnosis.

The other 25% of patients typically are diagnosed when symptoms develop from the polyps or cancer. Over 50% of these symptomatic patients have cancer at the time of diagnosis.

It is recommended that people who have more than 10 adenomas detected on a single colonoscopy or who are first-degree relatives of patients with familial adenomatous polyposis undergo a genetic evaluation and testing for mutations in the APC gene.¹⁴ Once an APC mutation is identified in the family, at-risk relatives should be offered testing around age 10 years for families with classic familial adenomatous polyposis or in the mid to late teenage years for those with the attenuated form. It also appropriate to refer patients with desmoid tumors, duodenal adenomas, and bilateral or multifocal congenital hypertrophy of the retinal pigment epithelium for a genetic evaluation.

Management of familial adenomatous polyposis

Flexible sigmoidoscopy every 1 to 2 years beginning at age 10 to 12 years is recommended for individuals and families who have been phenotypically or genetically diagnosed with familial adenomatous polyposis.^35–37 If colorectal adenomas are found, surgical options should be discussed and annual colonoscopic surveillance should commence.

For people with the attenuated form, because of the later age of disease onset and the tendency for right-sided disease, colonoscopy every 1 to 2 years should commence at about age 18.^35–37 If polyps are found, colonoscopy should be performed every year.

The decision of when to offer colectomy is based on polyp burden (taking into account the number, pathologic appearance, and size of the polyps) and psychosocial factors such as patient maturity. Surgical options include total colectomy and ileorectal anastomosis or total proctocolectomy and ileal pouch anal anastomosis.³⁸ Colonic and extracolonic phenotype as well as genotype should factor into the type of operation recommended. After colectomy, annual endoscopic surveillance of the rectum or ileal pouch is indicated to screen for recurrent polyposis and cancer.

Chemoprevention with sulindac (Clinoril) 150 mg or celecoxib (Celebrex) 400 mg twice a day causes regression of colorectal adenomas in familial adenomatous polyposis and may be useful as an adjunct to endoscopy in managing the colorectal polyp burden.^39,40

Forward and side-viewing upper endoscopy should commence at age 20. This should include visualization and biopsy of the papilla and periampulllary region.²⁹ The frequency of endoscopic surveillance depends on the Spigelman stage, which reflects the duodenal polyp burden. It is recommended that patients with Spigelman stage IV duodenal polyposis be seen in consultation with an experienced gastrointestinal surgeon for consideration of a prophylactic, pylorus-preserving, pancreas-sparing duodenectomy. This procedure has been shown to be more effective in polyp control and cancer prevention than endoscopic polyp ablation and local surgical resection.⁴¹

Some evidence for the utility of celecoxib 400 mg twice daily for the regression of duodenal polyposis was noted in a 6-month placebo-controlled trial.⁴² Some experts recommend removal of large duodenal adenomas, with adjunctive celecoxib therapy to control polyposis burden.³⁰

People with familial adenomatous polyposis have been shown to have a 2.6% risk of thyroid cancer, and ultrasonography of the neck with attention to the thyroid is recommended for them.³²

MYH-ASSOCIATED POLYPOSIS

Biallelic mutations in the MYH gene result in an adenomatous polyposis syndrome that may be indistinguishable from the attenuated or classic forms of familial adenomatous polyposis. A characteristic autosomal recessive pattern of inheritance in the family can be useful for identifying these patients in the clinic.

Genetics of MYH-associated polyposis

MYH-associated polyposis is the only known autosomal recessive hereditary colorectal cancer syndrome. In white populations, the most commonly reported mutations in MYH are Y179C (previously called Y165C) and G396D (previously called G382D), which account for up to 80% of cases.⁴³ These two mutations are estimated to occur in 1% to 2% of the general population.⁴⁴

Clinical presentation of MYH-associated polyposis

MYH-associated polyposis typically presents as multiple adenomatous polyps and is diagnosed at a mean age of 47 years. Eleven percent to 42% of affected individuals are reported to have fewer than 100 adenomas, while a minority (7.5% to 29%) of patients present with classic polyposis.^45–47 In one study, an estimated 19% of patients presented with colorectal cancer and reported no history of colorectal polyps.⁴⁸ Synchronous colorectal cancer is seen in more than 60% of patients with biallelic MYH mutations.⁴⁹ Patients with monoallelic (heterozygous) MYH mutations appear to have the same risk of developing colorectal adenomas and cancer as the general population.⁴⁹

Upper-gastrointestinal polyps have been reported in MYH-associated polyposis; as many as 17% to 25% of patients have duodenal adenomas.^50,51

Diagnosis of MYH-associated polyposis

Genetic testing for biallelic MYH mutations should be performed in patients who test negative for an APC mutation but who have clinical features of familial adenomatous polyposis, a personal history of more than 10 colorectal adenomas, or a recessive family history of polyposis. ¹⁴ It has been shown that up to 29% of patients with familial adenomatous polyposis who are APC-negative will have biallelic mutations in the MYH gene.⁵² The siblings of a patient with biallelic MYH mutations should be offered genetic counseling and testing in their late teens or early 20s. All children of an individual with MYH-associated polyposis will carry one MYH mutation and are only at risk of having the syndrome if the other parent is also a MYH carrier and passed on his or her mutation.

Management of MYH-associated polyposis

The management of patients with MYH-associated polyposis is similar to that recommended for attenuated and classic familial adenomatous polyposis.¹⁴ Genetic counseling and testing and colonic and extracolonic surveillance are warranted. There are no data on the use of chemoprevention in MYH-associated polyposis. Surgery should be considered early because of the high risk of colorectal cancer, even in individuals with very few adenomas. Patients with monoallelic MYH mutations should follow the general population screening guidelines for colorectal cancer.⁴⁹

GENETIC COUNSELING AND GENETIC TESTING

The American College of Gastroenterology advises that patients suspected of having hereditary colorectal cancer syndromes be advised to pursue genetic counseling and, if appropriate, genetic testing.¹⁶ They further recommend genetic counseling and informed consent before genetic testing.¹⁶

Genetic counseling is a process of working with patients and families whereby:

• A detailed medical and family history is obtained
• A formal risk assessment is performed
• Education about the disease in question and about genetic testing is provided
• Psychosocial concerns are assessed
• Informed consent is obtained when genetic testing is recommended.⁵³

This process is important for helping patients better understand their cancer risks, the benefits and limitations of genetic testing, and the protections that are in place for people who undergo genetic testing, including the Genetic Information Non-Discrimination Act.

In 1996 the American Society of Clinical Oncology issued a policy statement highlighting the essential elements of informed consent for genetic testing for cancer susceptibility, and this was updated in 2003.⁵⁴ In particular, it notes that patients should be informed of the implications of positive and negative results and of the possibility that the test may be uninformative.

When a hereditary colorectal cancer syndrome is suspected, a positive genetic test result confirms the diagnosis and allows for predictive testing of the patient’s relatives. However, no genetic test for a hereditary colorectal cancer syndrome is 100% sensitive. Therefore, a negative result does not rule out the syndrome in question.

Further, all cancer susceptibility genes have variants of uncertain significance, which are genetic alterations for which there are insufficient data to determine if the mutation is disease-causing or polymorphic (benign). Both negative and uninformative results can be confusing for patients and providers and can lead to false reassurance or undue worry when patients are not properly educated about these potential outcomes of testing.

Genetic testing is an evolving field, and with additional research and improved testing technologies, appropriate diagnoses can be made over time. That is why it is important for the genetic counseling relationship to continue over time.

A 49-year-old man presented with pigmentation on the nails of both hands during the past 6 months. He had no history of significant medical conditions, but he complained of generalized asthenia, with no fever, during the previous 6 weeks. He said that he was a volcanologist and had recently returned from an expedition in the mountains of Peru that involved intense physical activity at high altitudes. He was a non-smoker and did not drink alcohol; he was not taking any medications or nutritional supplements. A biochemical profile including a white blood cell count 3 months ago was normal.

On physical examination, he had splenomegaly (about 2 cm below the costal margin) and low systolic blood pressure (90 mm Hg, with the diastolic pressure at 60 mm Hg). Heart and lung examinations, including chest radiography, were normal.

Q: What is the diagnosis?

• Addison disease
• Onychotillomania
• Longitudinal melanonychia in human immunodeficiency virus (HIV) infection
• Systemic lupus erythematosus

A: The patient was diagnosed with longitudinal melanonychia with underlying HIV infection.

In addition to the clinical findings noted above, laboratory testing now revealed a low white blood cell count (2.9 × 10⁹/L, reference range 4.5–11.0) and a low CD4⁺ T-cell count (182 cells/mL). An enzyme-linked immunosorbent assay and a Western blot assay were positive for HIV, and his viral load was 120,000 copies/mL as determined by reverse transcription-polymerase chain reaction testing. On more detailed questioning, the patient admitted to sexual practices that put him at high risk for HIV infection.

Longitudinal melanonychia is characterized by a tan, brown, or black longitudinal streak, originating in the matrix and resulting from increased synthesis of melanin (by either normal or abnormal melanocytes) and its deposition within the nail plate.¹

If the cause is not apparent (eg, trauma, application of chemical agents, concomitant onychomycosis or treatments), this pigmentation usually reflects the presence of a benign lesion within the matrix caused by a melanocytic nevus, simple lentigo, or increased activation of benign melanocytes. This finding has been reported in a US study² to be more common in people with dark skin, occurring in 77% of blacks over age 20 and in almost 100% of those over age 50.

Melanoma and other nonmelanocytic tumors may present as longitudinal melanonychia, but these rarely involve more than one digit simultaneously, and they are usually detected with specific clinical clues, such as the Hutchinson sign, ie, periungual spread of pigmentation into the proximal and lateral nail folds.

A SIGN OF BENIGN AND MALIGNANT CONDITIONS

Longitudinal melanonychia can have benign causes, and these need to be investigated. It can occur with repeated trauma, friction, or pressure on the nails. The physician should question the patient about habits such as picking or chewing of the finger tips or pushing back the cuticles, as well as about athletic activities or manual work that could affect the nails. In addition, blood thinners can cause nail discoloration via subungual hemorrhage.

A number of pathologic conditions can cause longitudinal discoloration of the nails. Infection with certain dermatophytes can cause discoloration, but this pigmentation is usually wider and more distal at the hyponychium rather than proximal, with a black streak with several pointed extensions proximally.

Adrenocortical insufficiency (Addison disease), nutritional disorders (deficiency of folic acid or vitamin B₁₂), and, more rarely, systemic lupus erythematosus and scleroderma should be ruled out, as they are typically associated with cutaneous and mucosal hyperpigmentation.

Chemotherapeutic agents such as doxorubicin (Adriamycin), hydroxyurea (Droxea), and cyclophosphamide and drugs such as antimalarials and tetracyclines can also cause longitudinal melanonychia.^1,3

Nail lesions with a similar pattern are often seen in patients (especially black patients) taking zidovudine (Retrovir), and these lesions seem not to be related to drug dosage, HIV risk group, or severity of the infection. Nail discoloration in HIV patients not taking antiretroviral therapy has not been well documented.

The significance of melanonychia in the course of HIV remains unclear. A key role of overexpression of alpha-melanocyte-stimulating-hormone has been proposed.⁴ Although rare in fair-skinned people, longitudinal melanonychia represents an important clinical sign of disease progression. In reported cases, however, no significant improvement has been noted with treatment despite favorable virologic and immunologic responses.^4,5

A 49-year-old man presented with pigmentation on the nails of both hands during the past 6 months. He had no history of significant medical conditions, but he complained of generalized asthenia, with no fever, during the previous 6 weeks. He said that he was a volcanologist and had recently returned from an expedition in the mountains of Peru that involved intense physical activity at high altitudes. He was a non-smoker and did not drink alcohol; he was not taking any medications or nutritional supplements. A biochemical profile including a white blood cell count 3 months ago was normal.

On physical examination, he had splenomegaly (about 2 cm below the costal margin) and low systolic blood pressure (90 mm Hg, with the diastolic pressure at 60 mm Hg). Heart and lung examinations, including chest radiography, were normal.

Q: What is the diagnosis?

• Addison disease
• Onychotillomania
• Longitudinal melanonychia in human immunodeficiency virus (HIV) infection
• Systemic lupus erythematosus

A: The patient was diagnosed with longitudinal melanonychia with underlying HIV infection.

In addition to the clinical findings noted above, laboratory testing now revealed a low white blood cell count (2.9 × 10⁹/L, reference range 4.5–11.0) and a low CD4⁺ T-cell count (182 cells/mL). An enzyme-linked immunosorbent assay and a Western blot assay were positive for HIV, and his viral load was 120,000 copies/mL as determined by reverse transcription-polymerase chain reaction testing. On more detailed questioning, the patient admitted to sexual practices that put him at high risk for HIV infection.

Longitudinal melanonychia is characterized by a tan, brown, or black longitudinal streak, originating in the matrix and resulting from increased synthesis of melanin (by either normal or abnormal melanocytes) and its deposition within the nail plate.¹

If the cause is not apparent (eg, trauma, application of chemical agents, concomitant onychomycosis or treatments), this pigmentation usually reflects the presence of a benign lesion within the matrix caused by a melanocytic nevus, simple lentigo, or increased activation of benign melanocytes. This finding has been reported in a US study² to be more common in people with dark skin, occurring in 77% of blacks over age 20 and in almost 100% of those over age 50.

Melanoma and other nonmelanocytic tumors may present as longitudinal melanonychia, but these rarely involve more than one digit simultaneously, and they are usually detected with specific clinical clues, such as the Hutchinson sign, ie, periungual spread of pigmentation into the proximal and lateral nail folds.

A SIGN OF BENIGN AND MALIGNANT CONDITIONS

Longitudinal melanonychia can have benign causes, and these need to be investigated. It can occur with repeated trauma, friction, or pressure on the nails. The physician should question the patient about habits such as picking or chewing of the finger tips or pushing back the cuticles, as well as about athletic activities or manual work that could affect the nails. In addition, blood thinners can cause nail discoloration via subungual hemorrhage.

A number of pathologic conditions can cause longitudinal discoloration of the nails. Infection with certain dermatophytes can cause discoloration, but this pigmentation is usually wider and more distal at the hyponychium rather than proximal, with a black streak with several pointed extensions proximally.

Adrenocortical insufficiency (Addison disease), nutritional disorders (deficiency of folic acid or vitamin B₁₂), and, more rarely, systemic lupus erythematosus and scleroderma should be ruled out, as they are typically associated with cutaneous and mucosal hyperpigmentation.

Chemotherapeutic agents such as doxorubicin (Adriamycin), hydroxyurea (Droxea), and cyclophosphamide and drugs such as antimalarials and tetracyclines can also cause longitudinal melanonychia.^1,3

Nail lesions with a similar pattern are often seen in patients (especially black patients) taking zidovudine (Retrovir), and these lesions seem not to be related to drug dosage, HIV risk group, or severity of the infection. Nail discoloration in HIV patients not taking antiretroviral therapy has not been well documented.

The significance of melanonychia in the course of HIV remains unclear. A key role of overexpression of alpha-melanocyte-stimulating-hormone has been proposed.⁴ Although rare in fair-skinned people, longitudinal melanonychia represents an important clinical sign of disease progression. In reported cases, however, no significant improvement has been noted with treatment despite favorable virologic and immunologic responses.^4,5

A 49-year-old man presented with pigmentation on the nails of both hands during the past 6 months. He had no history of significant medical conditions, but he complained of generalized asthenia, with no fever, during the previous 6 weeks. He said that he was a volcanologist and had recently returned from an expedition in the mountains of Peru that involved intense physical activity at high altitudes. He was a non-smoker and did not drink alcohol; he was not taking any medications or nutritional supplements. A biochemical profile including a white blood cell count 3 months ago was normal.

On physical examination, he had splenomegaly (about 2 cm below the costal margin) and low systolic blood pressure (90 mm Hg, with the diastolic pressure at 60 mm Hg). Heart and lung examinations, including chest radiography, were normal.

Q: What is the diagnosis?

• Addison disease
• Onychotillomania
• Longitudinal melanonychia in human immunodeficiency virus (HIV) infection
• Systemic lupus erythematosus

A: The patient was diagnosed with longitudinal melanonychia with underlying HIV infection.

In addition to the clinical findings noted above, laboratory testing now revealed a low white blood cell count (2.9 × 10⁹/L, reference range 4.5–11.0) and a low CD4⁺ T-cell count (182 cells/mL). An enzyme-linked immunosorbent assay and a Western blot assay were positive for HIV, and his viral load was 120,000 copies/mL as determined by reverse transcription-polymerase chain reaction testing. On more detailed questioning, the patient admitted to sexual practices that put him at high risk for HIV infection.

Longitudinal melanonychia is characterized by a tan, brown, or black longitudinal streak, originating in the matrix and resulting from increased synthesis of melanin (by either normal or abnormal melanocytes) and its deposition within the nail plate.¹

If the cause is not apparent (eg, trauma, application of chemical agents, concomitant onychomycosis or treatments), this pigmentation usually reflects the presence of a benign lesion within the matrix caused by a melanocytic nevus, simple lentigo, or increased activation of benign melanocytes. This finding has been reported in a US study² to be more common in people with dark skin, occurring in 77% of blacks over age 20 and in almost 100% of those over age 50.

Melanoma and other nonmelanocytic tumors may present as longitudinal melanonychia, but these rarely involve more than one digit simultaneously, and they are usually detected with specific clinical clues, such as the Hutchinson sign, ie, periungual spread of pigmentation into the proximal and lateral nail folds.

A SIGN OF BENIGN AND MALIGNANT CONDITIONS

Longitudinal melanonychia can have benign causes, and these need to be investigated. It can occur with repeated trauma, friction, or pressure on the nails. The physician should question the patient about habits such as picking or chewing of the finger tips or pushing back the cuticles, as well as about athletic activities or manual work that could affect the nails. In addition, blood thinners can cause nail discoloration via subungual hemorrhage.

A number of pathologic conditions can cause longitudinal discoloration of the nails. Infection with certain dermatophytes can cause discoloration, but this pigmentation is usually wider and more distal at the hyponychium rather than proximal, with a black streak with several pointed extensions proximally.

Adrenocortical insufficiency (Addison disease), nutritional disorders (deficiency of folic acid or vitamin B₁₂), and, more rarely, systemic lupus erythematosus and scleroderma should be ruled out, as they are typically associated with cutaneous and mucosal hyperpigmentation.

Chemotherapeutic agents such as doxorubicin (Adriamycin), hydroxyurea (Droxea), and cyclophosphamide and drugs such as antimalarials and tetracyclines can also cause longitudinal melanonychia.^1,3

Nail lesions with a similar pattern are often seen in patients (especially black patients) taking zidovudine (Retrovir), and these lesions seem not to be related to drug dosage, HIV risk group, or severity of the infection. Nail discoloration in HIV patients not taking antiretroviral therapy has not been well documented.

The significance of melanonychia in the course of HIV remains unclear. A key role of overexpression of alpha-melanocyte-stimulating-hormone has been proposed.⁴ Although rare in fair-skinned people, longitudinal melanonychia represents an important clinical sign of disease progression. In reported cases, however, no significant improvement has been noted with treatment despite favorable virologic and immunologic responses.^4,5

In the United States, nearly 50 million legal abortions were performed between 1973 and 2008.¹ About half of pregnancies in American women are unintended, and 4 out of 10 unintended pregnancies are terminated by abortion.² Of the women who had abortions, 54% had used a contraceptive method during the month they became pregnant.³

It is hoped that the expanded use of emergency contraception will translate into fewer abortions. However, in a 2006–2008 survey conducted by the US Centers for Disease Control and Prevention, only 9.7% of women ages 15 to 44 reported ever having used emergency contraception.⁴ (To put this figure in perspective, a similar number—about 10%—of women in this age group become pregnant in any given year, half of them unintentionally.⁴) Clearly, patients need to be better educated in the methods of contraception and emergency contraception.

Hospitals are not meeting the need. Pretending to be in need of emergency contraception, Harrison⁵ called the emergency departments of all 597 Catholic hospitals in the United States and 615 (17%) of the non-Catholic hospitals. About half of the staff she spoke to said they do not dispense emergency contraception, even in cases of sexual assault. This was the case for both Catholic and non-Catholic hospitals. Of the people she talked to who said they did not provide emergency contraception under any circumstance, only about half gave her a phone number for another facility to try, and most of these phone numbers were wrong, were for facilities that were not open on weekends, or were for facilities that did not offer emergency contraception either. This is in spite of legal precedent, which indicates that failure to provide complete post-rape counseling, including emergency contraception, constitutes inadequate care and gives a woman the standing to sue the hospital.⁶

Clearly, better provider education is also needed in the area of emergency contraception. The Association of Reproductive Health Professionals has a helpful Web site for providers and for patients. In addition to up-to-date information about contraceptive and emergency contraceptive choices, it provides advice on how to discuss emergency contraception with patients (www.arhp.org). We can test our own knowledge of this topic by reviewing the following questions.

WHICH PRODUCT IS MOST EFFECTIVE?

Q: True or false? Levonorgestrel monotherapy (Plan B One-Step, Next Choice) is the most effective oral emergency contraceptive.

A: False, although this statement was true before the US approval of ulipristal acetate (ella) in August 2010.

For many years levonorgestrel monotherapy has been the mainstay of emergency contraception, having replaced the combination estrogen-progestin (Yuzpe) regimen because of better tolerability and improved efficacy.⁷ Its main mechanism of action involves delaying ovulation. Levonorgestrel is given in two doses of 0.75 mg 12 hours apart, or as a single 1.5-mg dose (Table 1). Both formulations of levonorgestrel are available over the counter to women age 17 and older, or by prescription if they are under age 17.

However, a randomized controlled trial showed that women treated with ulipristal had about half the number of pregnancies than in those treated with levonorgestrel, with pregnancy rates of 0.9% vs 1.7%.⁸

HOW WIDE IS THE WINDOW OF OPPORTUNITY?

Q: True or false? Both ulipristal and levonorgestrel can be taken up to 120 hours (5 days) after unprotected intercourse. However, ulipristal maintains its effectiveness throughout this time, whereas levonorgestrel becomes less effective the longer a patient waits to take it.

A: True. Ulipristal is a second-generation selective progesterone receptor modulator. These drugs can function as agonists, antagonists, or mixed agonist-antagonists at the progesterone receptor, depending on the tissue affected. Ulipristal is given as a one-time, 30-mg dose within 120 hours of intercourse.

In a study of 1,696 women, 844 of whom received ulipristal acetate and 852 of whom received levonorgestrel, ulipristal was at least as effective as levonorgestrel when used within 72 hours of intercourse for emergency contraception, with 15 pregnancies in the ulipristal group and 22 pregnancies in the levonorgestrel group (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.35–1.31]). However, ulipristal prevented significantly more pregnancies than levonorgestrel at 72 to 120 hours, with no pregnancies in the ulipristal group and three pregnancies in the levonorgestrel group.⁹

Because ulipristal has a long half-life (32 hours), it can delay ovulation beyond the life span of sperm, thereby extending the window of opportunity for emergency contraception. However, patients should be advised to avoid further unprotected intercourse after the use of emergency contraception. Because emergency contraception works mainly by delaying ovulation, it may increase the likelihood of pregnancy if the patient has unprotected intercourse again several days later.

IS MIFEPRISTONE AN EMERGENCY CONTRACEPTIVE?

Q: True or false? In the United States, mifepristone (Mifeprex), also known as RU-486, is available for use as an emergency contraceptive in addition to its use in abortion.

A: False, even though mifepristone, another selective progesterone receptor modulator, is highly effective when used up to 120 hours after intercourse. In fact, it might be effective up to 17 days after unprotected intercourse.¹⁰

Although mifepristone is one of the most effective forms of emergency contraception, social and political controversy has prevented its approval in the United States. However, it is approved for use as an abortifacient, at a higher dose than would be used for emergency contraception.

Unlike levonorgestrel, mifepristone exerts its effect via two potential mechanisms: delaying ovulation and preventing implantation.¹¹

IUDs AS EMERGENCY CONTRACEPTION

Q: True or false? Insertion of a 5-year intrauterine device (IUD), ie, the levonorgestrel-releasing intrauterine system (Mirena), is 99.8% effective at preventing pregnancy when used within 5 days of unprotected intercourse.

A: False. The Mirena IUD has not been studied as a form of emergency contraception. However, this statement would be true for the 10-year copper IUD ParaGard. Copper-releasing IUDs are considered a very effective method of emergency contraception, with associated pregnancy rates of 0.0% to 0.2% when inserted up until implantation (within 5 days after ovulation).^12,13 If desired, the IUD can then be kept in place for up to 10 years as a method of birth control.

However, this method requires the ready availability of a health professional trained to do the insertion. It is also important to make sure that the patient will not be at increased risk of sexually transmitted infections from further unprotected intercourse. The American Congress of Obstetricians and Gynecologists (ACOG) recommends that an IUD be placed within 5 days of unprotected intercourse for use as emergency contraception.

A recent review looked at 42 published studies of copper IUDs used for emergency contraception around the world. It found copper IUDs to be a safe and highly effective method of emergency contraception, with the additional advantage of simultaneously offering one of the most reliable and cost-effective contraceptive options.¹⁴

EMERGENCY CONTRACEPTION AT MID-CYCLE

Q: True or false? When choosing a method of emergency contraception, it is important to consider whether a woman is near ovulation during the time of intercourse.

A: True. Emergency contraception can prevent pregnancy after unprotected intercourse, but it does not always work. The most widely used method, levonorgestrel 1.5 mg orally within 72 hours of intercourse, prevents at least 50% of pregnancies that would have occurred in the absence of its use.¹⁵ Glasier et al¹⁶ showed that emergency contraception was more likely to fail if a woman had unprotected intercourse around the time of ovulation.¹⁶

Though it can be difficult for women to tell if they are in the fertile times of their cycle, it might be helpful to try to identify women who have intercourse at mid-cycle, when the risk of pregnancy is greatest. Because insertion of an IUD and use of ulipristal acetate probably prevent more pregnancies, these methods might be preferred over levonorgestrel-based regimens during these higher-risk situations.

OBESE PATIENTS

Q: True or false? Hormonal emergency contraception is more likely to fail in obese patients.

A: True. Most recent evidence shows that whichever oral emergency contraceptive drug is taken, the risk of pregnancy is more than 3 times greater for obese women (OR 3.60, 95% CI 1.96–6.53) and 1.5 times greater for overweight women (OR 1.53, 95% CI 0.75–2.95).¹⁶ Of all covariates tested, those that were shown to increase the odds of failure of the emergency contraception were higher body mass index, further unprotected intercourse, and conception probability (based on time of fertility cycle). In fact, among obese women treated with levonorgestrel, the observed pregnancy rate was 5.8%, which is slightly above the overall pregnancy rate expected in the absence of emergency contraception, suggesting that for obese women levonorgestrel-based emergency contraception may even be ineffective.

This is in line with recent reports suggesting that oral contraceptives are less effective in obese women. More effective regimens such as an IUD or ulipristal might be preferred in these women. However, obesity should not be used as a reason not to offer emergency contraception, as this is the last chance these women have to prevent pregnancy.

IS IT ABORTION?

Q: True or false? Emergency contraception does not cause abortion.

A: True, but patients may ask for more details about this. Hormonal emergency contraception works primarily by delaying or inhibiting ovulation and inhibiting fertilization.

Levonorgestrel or combined estrogen-progestin-based methods would be unlikely to have any adverse effects on the endometrium after fertilization, since they would only serve to enhance the progesterone effect. Therefore, they are unlikely to affect the ability of the embryo to attach to the endometrium.

Ulipristal, on the other hand, can have just the opposite effect on the postovulatory endometrium because of its inhibitory action on progesterone. Ulipristal is structurally similar to mifepristone, and its mechanism of action varies depending on the time of administration during the menstrual cycle. When unprotected intercourse occurs during a time when fertility is not possible, ulipristal behaves like a placebo. When intercourse occurs just before ovulation, ulipristal acts by delaying ovulation and thereby preventing fertilization (similar to levonorgestrel). Ulipristal may have an additional action of affecting the ability of the embryo to either attach to the endometrium or maintain its attachment, by a variety of mechanisms of action.^17,18 Because of this, some in the popular press and on the Internet have spoken out against the use of ulipristal.

The ACOG considers pregnancy to begin not with fertilization of the egg but with implantation, as demonstrated by a positive pregnancy test.

Of note, the copper IUD also prevents implantation after fertilization, which likely explains its high efficacy.

Women who have detailed questions about this can be counseled that levonorgestrel works mostly by preventing ovulation, and that ulipristal and the copper IUD might also work via postfertilization mechanisms. However, they are not considered to be abortive, based on standard definitions of pregnancy.

If a woman is pregnant and she takes levonorgestrel-based emergency contraception, this has not been shown to have any adverse effects on the fetus (similar to oral contraceptives).

Ulipristal is classified as pregnancy category X, and therefore its use during pregnancy is contraindicated. Based on information provided by the manufacturer, there are no adequate, well-controlled studies of ulipristal use in pregnant women. Although fetal loss was observed in animal studies after ulipristal administration (during the period of organogenesis), no malformations or adverse events were present in the surviving fetuses. Ulipristal is not indicated for termination of an existing pregnancy.

DO THE USUAL CONTRAINDICATIONS TO HORMONAL CONTRACEPTIVES APPLY?

Q: True or false? Because emergency contraception has such a short duration of exposure, the usual medical contraindications to hormonal therapies do not apply to it.

A: True. The usual contraindications to the use of hormonal contraceptives (eg, migraine with aura, hypertension, history of venous thromboembolism) do not apply to emergency contraception because of the short time of exposure.¹⁹ Furthermore, the risks associated with pregnancy in these women would likely outweigh any risks associated with emergency contraception.

However, one must be cognizant of potential drug interactions. According to the manufacturer, the use of ulipristal did not inhibit or induce cytochrome P 450 enzymes in vitro; therefore, in vivo studies were not performed. But because ulipristal is metabolized primarily via CYP3A4, an interaction between agents that induce or inhibit CYP3A4 could occur.²⁰ Thus, concomitant use of drugs such as barbiturates, rifampin (Rifadin), St. John’s wort, or antiseizure drugs such as topiramate (Topamax) may lower ulipristal concentrations. These medications may also affect levonorgestrel levels, similar to their effects on combined hormonal contraception. However, it is not known whether this translates to decreased efficacy.

When a woman is taking medications that can potentially decrease the effectiveness of hormonal emergency contraception, a more effective method such as a copper IUD might be more strongly considered. If a woman is not interested in an IUD, oral emergency contraception should still be offered, given that this is one of the last chances to prevent pregnancy, especially if she is on a potential teratogen.

Oral contraceptive pills have not been studied in combination with ulipristal. However, because ulipristal binds with high affinity to progesterone receptors (thus competing with the contraceptive), use of additional barrier contraceptives is recommended for the remainder of the menstrual cycle.

EMERGENCY CONTRACEPTION AND BREASTFEEDING

Q: True of false? Emergency contraceptives can be used if a woman is breastfeeding.

A: That depends on which method is used. Both the ACOG and the World Health Organization state that it is safe for breastfeeding women to use emergency contraception, but these are older guidelines addressing progestin-only regimens (ie, levonorgestrel).^19,21 It is unknown whether ulipristal is secreted into human breast milk, although excretion was seen in animal studies. Therefore, ulipristal is not recommended for use by women who are breastfeeding.^20,22 To minimize the infant’s exposure to levonorgestrel, mothers should consider not nursing for at least 8 hours after ingestion, but no more than 24 hours is needed.²³

In the United States, nearly 50 million legal abortions were performed between 1973 and 2008.¹ About half of pregnancies in American women are unintended, and 4 out of 10 unintended pregnancies are terminated by abortion.² Of the women who had abortions, 54% had used a contraceptive method during the month they became pregnant.³

It is hoped that the expanded use of emergency contraception will translate into fewer abortions. However, in a 2006–2008 survey conducted by the US Centers for Disease Control and Prevention, only 9.7% of women ages 15 to 44 reported ever having used emergency contraception.⁴ (To put this figure in perspective, a similar number—about 10%—of women in this age group become pregnant in any given year, half of them unintentionally.⁴) Clearly, patients need to be better educated in the methods of contraception and emergency contraception.

Hospitals are not meeting the need. Pretending to be in need of emergency contraception, Harrison⁵ called the emergency departments of all 597 Catholic hospitals in the United States and 615 (17%) of the non-Catholic hospitals. About half of the staff she spoke to said they do not dispense emergency contraception, even in cases of sexual assault. This was the case for both Catholic and non-Catholic hospitals. Of the people she talked to who said they did not provide emergency contraception under any circumstance, only about half gave her a phone number for another facility to try, and most of these phone numbers were wrong, were for facilities that were not open on weekends, or were for facilities that did not offer emergency contraception either. This is in spite of legal precedent, which indicates that failure to provide complete post-rape counseling, including emergency contraception, constitutes inadequate care and gives a woman the standing to sue the hospital.⁶

Clearly, better provider education is also needed in the area of emergency contraception. The Association of Reproductive Health Professionals has a helpful Web site for providers and for patients. In addition to up-to-date information about contraceptive and emergency contraceptive choices, it provides advice on how to discuss emergency contraception with patients (www.arhp.org). We can test our own knowledge of this topic by reviewing the following questions.

WHICH PRODUCT IS MOST EFFECTIVE?

Q: True or false? Levonorgestrel monotherapy (Plan B One-Step, Next Choice) is the most effective oral emergency contraceptive.

A: False, although this statement was true before the US approval of ulipristal acetate (ella) in August 2010.

For many years levonorgestrel monotherapy has been the mainstay of emergency contraception, having replaced the combination estrogen-progestin (Yuzpe) regimen because of better tolerability and improved efficacy.⁷ Its main mechanism of action involves delaying ovulation. Levonorgestrel is given in two doses of 0.75 mg 12 hours apart, or as a single 1.5-mg dose (Table 1). Both formulations of levonorgestrel are available over the counter to women age 17 and older, or by prescription if they are under age 17.

However, a randomized controlled trial showed that women treated with ulipristal had about half the number of pregnancies than in those treated with levonorgestrel, with pregnancy rates of 0.9% vs 1.7%.⁸

HOW WIDE IS THE WINDOW OF OPPORTUNITY?

Q: True or false? Both ulipristal and levonorgestrel can be taken up to 120 hours (5 days) after unprotected intercourse. However, ulipristal maintains its effectiveness throughout this time, whereas levonorgestrel becomes less effective the longer a patient waits to take it.

A: True. Ulipristal is a second-generation selective progesterone receptor modulator. These drugs can function as agonists, antagonists, or mixed agonist-antagonists at the progesterone receptor, depending on the tissue affected. Ulipristal is given as a one-time, 30-mg dose within 120 hours of intercourse.

In a study of 1,696 women, 844 of whom received ulipristal acetate and 852 of whom received levonorgestrel, ulipristal was at least as effective as levonorgestrel when used within 72 hours of intercourse for emergency contraception, with 15 pregnancies in the ulipristal group and 22 pregnancies in the levonorgestrel group (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.35–1.31]). However, ulipristal prevented significantly more pregnancies than levonorgestrel at 72 to 120 hours, with no pregnancies in the ulipristal group and three pregnancies in the levonorgestrel group.⁹

Because ulipristal has a long half-life (32 hours), it can delay ovulation beyond the life span of sperm, thereby extending the window of opportunity for emergency contraception. However, patients should be advised to avoid further unprotected intercourse after the use of emergency contraception. Because emergency contraception works mainly by delaying ovulation, it may increase the likelihood of pregnancy if the patient has unprotected intercourse again several days later.

IS MIFEPRISTONE AN EMERGENCY CONTRACEPTIVE?

Q: True or false? In the United States, mifepristone (Mifeprex), also known as RU-486, is available for use as an emergency contraceptive in addition to its use in abortion.

A: False, even though mifepristone, another selective progesterone receptor modulator, is highly effective when used up to 120 hours after intercourse. In fact, it might be effective up to 17 days after unprotected intercourse.¹⁰

Although mifepristone is one of the most effective forms of emergency contraception, social and political controversy has prevented its approval in the United States. However, it is approved for use as an abortifacient, at a higher dose than would be used for emergency contraception.

Unlike levonorgestrel, mifepristone exerts its effect via two potential mechanisms: delaying ovulation and preventing implantation.¹¹

IUDs AS EMERGENCY CONTRACEPTION

Q: True or false? Insertion of a 5-year intrauterine device (IUD), ie, the levonorgestrel-releasing intrauterine system (Mirena), is 99.8% effective at preventing pregnancy when used within 5 days of unprotected intercourse.

A: False. The Mirena IUD has not been studied as a form of emergency contraception. However, this statement would be true for the 10-year copper IUD ParaGard. Copper-releasing IUDs are considered a very effective method of emergency contraception, with associated pregnancy rates of 0.0% to 0.2% when inserted up until implantation (within 5 days after ovulation).^12,13 If desired, the IUD can then be kept in place for up to 10 years as a method of birth control.

However, this method requires the ready availability of a health professional trained to do the insertion. It is also important to make sure that the patient will not be at increased risk of sexually transmitted infections from further unprotected intercourse. The American Congress of Obstetricians and Gynecologists (ACOG) recommends that an IUD be placed within 5 days of unprotected intercourse for use as emergency contraception.

A recent review looked at 42 published studies of copper IUDs used for emergency contraception around the world. It found copper IUDs to be a safe and highly effective method of emergency contraception, with the additional advantage of simultaneously offering one of the most reliable and cost-effective contraceptive options.¹⁴

EMERGENCY CONTRACEPTION AT MID-CYCLE

Q: True or false? When choosing a method of emergency contraception, it is important to consider whether a woman is near ovulation during the time of intercourse.

A: True. Emergency contraception can prevent pregnancy after unprotected intercourse, but it does not always work. The most widely used method, levonorgestrel 1.5 mg orally within 72 hours of intercourse, prevents at least 50% of pregnancies that would have occurred in the absence of its use.¹⁵ Glasier et al¹⁶ showed that emergency contraception was more likely to fail if a woman had unprotected intercourse around the time of ovulation.¹⁶

Though it can be difficult for women to tell if they are in the fertile times of their cycle, it might be helpful to try to identify women who have intercourse at mid-cycle, when the risk of pregnancy is greatest. Because insertion of an IUD and use of ulipristal acetate probably prevent more pregnancies, these methods might be preferred over levonorgestrel-based regimens during these higher-risk situations.

OBESE PATIENTS

Q: True or false? Hormonal emergency contraception is more likely to fail in obese patients.

A: True. Most recent evidence shows that whichever oral emergency contraceptive drug is taken, the risk of pregnancy is more than 3 times greater for obese women (OR 3.60, 95% CI 1.96–6.53) and 1.5 times greater for overweight women (OR 1.53, 95% CI 0.75–2.95).¹⁶ Of all covariates tested, those that were shown to increase the odds of failure of the emergency contraception were higher body mass index, further unprotected intercourse, and conception probability (based on time of fertility cycle). In fact, among obese women treated with levonorgestrel, the observed pregnancy rate was 5.8%, which is slightly above the overall pregnancy rate expected in the absence of emergency contraception, suggesting that for obese women levonorgestrel-based emergency contraception may even be ineffective.

This is in line with recent reports suggesting that oral contraceptives are less effective in obese women. More effective regimens such as an IUD or ulipristal might be preferred in these women. However, obesity should not be used as a reason not to offer emergency contraception, as this is the last chance these women have to prevent pregnancy.

IS IT ABORTION?

Q: True or false? Emergency contraception does not cause abortion.

A: True, but patients may ask for more details about this. Hormonal emergency contraception works primarily by delaying or inhibiting ovulation and inhibiting fertilization.

Levonorgestrel or combined estrogen-progestin-based methods would be unlikely to have any adverse effects on the endometrium after fertilization, since they would only serve to enhance the progesterone effect. Therefore, they are unlikely to affect the ability of the embryo to attach to the endometrium.

Ulipristal, on the other hand, can have just the opposite effect on the postovulatory endometrium because of its inhibitory action on progesterone. Ulipristal is structurally similar to mifepristone, and its mechanism of action varies depending on the time of administration during the menstrual cycle. When unprotected intercourse occurs during a time when fertility is not possible, ulipristal behaves like a placebo. When intercourse occurs just before ovulation, ulipristal acts by delaying ovulation and thereby preventing fertilization (similar to levonorgestrel). Ulipristal may have an additional action of affecting the ability of the embryo to either attach to the endometrium or maintain its attachment, by a variety of mechanisms of action.^17,18 Because of this, some in the popular press and on the Internet have spoken out against the use of ulipristal.

The ACOG considers pregnancy to begin not with fertilization of the egg but with implantation, as demonstrated by a positive pregnancy test.

Of note, the copper IUD also prevents implantation after fertilization, which likely explains its high efficacy.

Women who have detailed questions about this can be counseled that levonorgestrel works mostly by preventing ovulation, and that ulipristal and the copper IUD might also work via postfertilization mechanisms. However, they are not considered to be abortive, based on standard definitions of pregnancy.

If a woman is pregnant and she takes levonorgestrel-based emergency contraception, this has not been shown to have any adverse effects on the fetus (similar to oral contraceptives).

Ulipristal is classified as pregnancy category X, and therefore its use during pregnancy is contraindicated. Based on information provided by the manufacturer, there are no adequate, well-controlled studies of ulipristal use in pregnant women. Although fetal loss was observed in animal studies after ulipristal administration (during the period of organogenesis), no malformations or adverse events were present in the surviving fetuses. Ulipristal is not indicated for termination of an existing pregnancy.

DO THE USUAL CONTRAINDICATIONS TO HORMONAL CONTRACEPTIVES APPLY?

Q: True or false? Because emergency contraception has such a short duration of exposure, the usual medical contraindications to hormonal therapies do not apply to it.

A: True. The usual contraindications to the use of hormonal contraceptives (eg, migraine with aura, hypertension, history of venous thromboembolism) do not apply to emergency contraception because of the short time of exposure.¹⁹ Furthermore, the risks associated with pregnancy in these women would likely outweigh any risks associated with emergency contraception.

However, one must be cognizant of potential drug interactions. According to the manufacturer, the use of ulipristal did not inhibit or induce cytochrome P 450 enzymes in vitro; therefore, in vivo studies were not performed. But because ulipristal is metabolized primarily via CYP3A4, an interaction between agents that induce or inhibit CYP3A4 could occur.²⁰ Thus, concomitant use of drugs such as barbiturates, rifampin (Rifadin), St. John’s wort, or antiseizure drugs such as topiramate (Topamax) may lower ulipristal concentrations. These medications may also affect levonorgestrel levels, similar to their effects on combined hormonal contraception. However, it is not known whether this translates to decreased efficacy.

When a woman is taking medications that can potentially decrease the effectiveness of hormonal emergency contraception, a more effective method such as a copper IUD might be more strongly considered. If a woman is not interested in an IUD, oral emergency contraception should still be offered, given that this is one of the last chances to prevent pregnancy, especially if she is on a potential teratogen.

Oral contraceptive pills have not been studied in combination with ulipristal. However, because ulipristal binds with high affinity to progesterone receptors (thus competing with the contraceptive), use of additional barrier contraceptives is recommended for the remainder of the menstrual cycle.

EMERGENCY CONTRACEPTION AND BREASTFEEDING

Q: True of false? Emergency contraceptives can be used if a woman is breastfeeding.

A: That depends on which method is used. Both the ACOG and the World Health Organization state that it is safe for breastfeeding women to use emergency contraception, but these are older guidelines addressing progestin-only regimens (ie, levonorgestrel).^19,21 It is unknown whether ulipristal is secreted into human breast milk, although excretion was seen in animal studies. Therefore, ulipristal is not recommended for use by women who are breastfeeding.^20,22 To minimize the infant’s exposure to levonorgestrel, mothers should consider not nursing for at least 8 hours after ingestion, but no more than 24 hours is needed.²³

In the United States, nearly 50 million legal abortions were performed between 1973 and 2008.¹ About half of pregnancies in American women are unintended, and 4 out of 10 unintended pregnancies are terminated by abortion.² Of the women who had abortions, 54% had used a contraceptive method during the month they became pregnant.³

It is hoped that the expanded use of emergency contraception will translate into fewer abortions. However, in a 2006–2008 survey conducted by the US Centers for Disease Control and Prevention, only 9.7% of women ages 15 to 44 reported ever having used emergency contraception.⁴ (To put this figure in perspective, a similar number—about 10%—of women in this age group become pregnant in any given year, half of them unintentionally.⁴) Clearly, patients need to be better educated in the methods of contraception and emergency contraception.

Hospitals are not meeting the need. Pretending to be in need of emergency contraception, Harrison⁵ called the emergency departments of all 597 Catholic hospitals in the United States and 615 (17%) of the non-Catholic hospitals. About half of the staff she spoke to said they do not dispense emergency contraception, even in cases of sexual assault. This was the case for both Catholic and non-Catholic hospitals. Of the people she talked to who said they did not provide emergency contraception under any circumstance, only about half gave her a phone number for another facility to try, and most of these phone numbers were wrong, were for facilities that were not open on weekends, or were for facilities that did not offer emergency contraception either. This is in spite of legal precedent, which indicates that failure to provide complete post-rape counseling, including emergency contraception, constitutes inadequate care and gives a woman the standing to sue the hospital.⁶

Clearly, better provider education is also needed in the area of emergency contraception. The Association of Reproductive Health Professionals has a helpful Web site for providers and for patients. In addition to up-to-date information about contraceptive and emergency contraceptive choices, it provides advice on how to discuss emergency contraception with patients (www.arhp.org). We can test our own knowledge of this topic by reviewing the following questions.

WHICH PRODUCT IS MOST EFFECTIVE?

Q: True or false? Levonorgestrel monotherapy (Plan B One-Step, Next Choice) is the most effective oral emergency contraceptive.

A: False, although this statement was true before the US approval of ulipristal acetate (ella) in August 2010.

For many years levonorgestrel monotherapy has been the mainstay of emergency contraception, having replaced the combination estrogen-progestin (Yuzpe) regimen because of better tolerability and improved efficacy.⁷ Its main mechanism of action involves delaying ovulation. Levonorgestrel is given in two doses of 0.75 mg 12 hours apart, or as a single 1.5-mg dose (Table 1). Both formulations of levonorgestrel are available over the counter to women age 17 and older, or by prescription if they are under age 17.

However, a randomized controlled trial showed that women treated with ulipristal had about half the number of pregnancies than in those treated with levonorgestrel, with pregnancy rates of 0.9% vs 1.7%.⁸

HOW WIDE IS THE WINDOW OF OPPORTUNITY?

Q: True or false? Both ulipristal and levonorgestrel can be taken up to 120 hours (5 days) after unprotected intercourse. However, ulipristal maintains its effectiveness throughout this time, whereas levonorgestrel becomes less effective the longer a patient waits to take it.

A: True. Ulipristal is a second-generation selective progesterone receptor modulator. These drugs can function as agonists, antagonists, or mixed agonist-antagonists at the progesterone receptor, depending on the tissue affected. Ulipristal is given as a one-time, 30-mg dose within 120 hours of intercourse.

In a study of 1,696 women, 844 of whom received ulipristal acetate and 852 of whom received levonorgestrel, ulipristal was at least as effective as levonorgestrel when used within 72 hours of intercourse for emergency contraception, with 15 pregnancies in the ulipristal group and 22 pregnancies in the levonorgestrel group (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.35–1.31]). However, ulipristal prevented significantly more pregnancies than levonorgestrel at 72 to 120 hours, with no pregnancies in the ulipristal group and three pregnancies in the levonorgestrel group.⁹

Because ulipristal has a long half-life (32 hours), it can delay ovulation beyond the life span of sperm, thereby extending the window of opportunity for emergency contraception. However, patients should be advised to avoid further unprotected intercourse after the use of emergency contraception. Because emergency contraception works mainly by delaying ovulation, it may increase the likelihood of pregnancy if the patient has unprotected intercourse again several days later.

IS MIFEPRISTONE AN EMERGENCY CONTRACEPTIVE?

Q: True or false? In the United States, mifepristone (Mifeprex), also known as RU-486, is available for use as an emergency contraceptive in addition to its use in abortion.

A: False, even though mifepristone, another selective progesterone receptor modulator, is highly effective when used up to 120 hours after intercourse. In fact, it might be effective up to 17 days after unprotected intercourse.¹⁰

Although mifepristone is one of the most effective forms of emergency contraception, social and political controversy has prevented its approval in the United States. However, it is approved for use as an abortifacient, at a higher dose than would be used for emergency contraception.

Unlike levonorgestrel, mifepristone exerts its effect via two potential mechanisms: delaying ovulation and preventing implantation.¹¹

IUDs AS EMERGENCY CONTRACEPTION

Q: True or false? Insertion of a 5-year intrauterine device (IUD), ie, the levonorgestrel-releasing intrauterine system (Mirena), is 99.8% effective at preventing pregnancy when used within 5 days of unprotected intercourse.

A: False. The Mirena IUD has not been studied as a form of emergency contraception. However, this statement would be true for the 10-year copper IUD ParaGard. Copper-releasing IUDs are considered a very effective method of emergency contraception, with associated pregnancy rates of 0.0% to 0.2% when inserted up until implantation (within 5 days after ovulation).^12,13 If desired, the IUD can then be kept in place for up to 10 years as a method of birth control.

However, this method requires the ready availability of a health professional trained to do the insertion. It is also important to make sure that the patient will not be at increased risk of sexually transmitted infections from further unprotected intercourse. The American Congress of Obstetricians and Gynecologists (ACOG) recommends that an IUD be placed within 5 days of unprotected intercourse for use as emergency contraception.

A recent review looked at 42 published studies of copper IUDs used for emergency contraception around the world. It found copper IUDs to be a safe and highly effective method of emergency contraception, with the additional advantage of simultaneously offering one of the most reliable and cost-effective contraceptive options.¹⁴

EMERGENCY CONTRACEPTION AT MID-CYCLE

Q: True or false? When choosing a method of emergency contraception, it is important to consider whether a woman is near ovulation during the time of intercourse.

A: True. Emergency contraception can prevent pregnancy after unprotected intercourse, but it does not always work. The most widely used method, levonorgestrel 1.5 mg orally within 72 hours of intercourse, prevents at least 50% of pregnancies that would have occurred in the absence of its use.¹⁵ Glasier et al¹⁶ showed that emergency contraception was more likely to fail if a woman had unprotected intercourse around the time of ovulation.¹⁶

Though it can be difficult for women to tell if they are in the fertile times of their cycle, it might be helpful to try to identify women who have intercourse at mid-cycle, when the risk of pregnancy is greatest. Because insertion of an IUD and use of ulipristal acetate probably prevent more pregnancies, these methods might be preferred over levonorgestrel-based regimens during these higher-risk situations.

OBESE PATIENTS

Q: True or false? Hormonal emergency contraception is more likely to fail in obese patients.

A: True. Most recent evidence shows that whichever oral emergency contraceptive drug is taken, the risk of pregnancy is more than 3 times greater for obese women (OR 3.60, 95% CI 1.96–6.53) and 1.5 times greater for overweight women (OR 1.53, 95% CI 0.75–2.95).¹⁶ Of all covariates tested, those that were shown to increase the odds of failure of the emergency contraception were higher body mass index, further unprotected intercourse, and conception probability (based on time of fertility cycle). In fact, among obese women treated with levonorgestrel, the observed pregnancy rate was 5.8%, which is slightly above the overall pregnancy rate expected in the absence of emergency contraception, suggesting that for obese women levonorgestrel-based emergency contraception may even be ineffective.

This is in line with recent reports suggesting that oral contraceptives are less effective in obese women. More effective regimens such as an IUD or ulipristal might be preferred in these women. However, obesity should not be used as a reason not to offer emergency contraception, as this is the last chance these women have to prevent pregnancy.

IS IT ABORTION?

Q: True or false? Emergency contraception does not cause abortion.

A: True, but patients may ask for more details about this. Hormonal emergency contraception works primarily by delaying or inhibiting ovulation and inhibiting fertilization.

Levonorgestrel or combined estrogen-progestin-based methods would be unlikely to have any adverse effects on the endometrium after fertilization, since they would only serve to enhance the progesterone effect. Therefore, they are unlikely to affect the ability of the embryo to attach to the endometrium.

Ulipristal, on the other hand, can have just the opposite effect on the postovulatory endometrium because of its inhibitory action on progesterone. Ulipristal is structurally similar to mifepristone, and its mechanism of action varies depending on the time of administration during the menstrual cycle. When unprotected intercourse occurs during a time when fertility is not possible, ulipristal behaves like a placebo. When intercourse occurs just before ovulation, ulipristal acts by delaying ovulation and thereby preventing fertilization (similar to levonorgestrel). Ulipristal may have an additional action of affecting the ability of the embryo to either attach to the endometrium or maintain its attachment, by a variety of mechanisms of action.^17,18 Because of this, some in the popular press and on the Internet have spoken out against the use of ulipristal.

The ACOG considers pregnancy to begin not with fertilization of the egg but with implantation, as demonstrated by a positive pregnancy test.

Of note, the copper IUD also prevents implantation after fertilization, which likely explains its high efficacy.

Women who have detailed questions about this can be counseled that levonorgestrel works mostly by preventing ovulation, and that ulipristal and the copper IUD might also work via postfertilization mechanisms. However, they are not considered to be abortive, based on standard definitions of pregnancy.

If a woman is pregnant and she takes levonorgestrel-based emergency contraception, this has not been shown to have any adverse effects on the fetus (similar to oral contraceptives).

Ulipristal is classified as pregnancy category X, and therefore its use during pregnancy is contraindicated. Based on information provided by the manufacturer, there are no adequate, well-controlled studies of ulipristal use in pregnant women. Although fetal loss was observed in animal studies after ulipristal administration (during the period of organogenesis), no malformations or adverse events were present in the surviving fetuses. Ulipristal is not indicated for termination of an existing pregnancy.

DO THE USUAL CONTRAINDICATIONS TO HORMONAL CONTRACEPTIVES APPLY?

Q: True or false? Because emergency contraception has such a short duration of exposure, the usual medical contraindications to hormonal therapies do not apply to it.

A: True. The usual contraindications to the use of hormonal contraceptives (eg, migraine with aura, hypertension, history of venous thromboembolism) do not apply to emergency contraception because of the short time of exposure.¹⁹ Furthermore, the risks associated with pregnancy in these women would likely outweigh any risks associated with emergency contraception.

However, one must be cognizant of potential drug interactions. According to the manufacturer, the use of ulipristal did not inhibit or induce cytochrome P 450 enzymes in vitro; therefore, in vivo studies were not performed. But because ulipristal is metabolized primarily via CYP3A4, an interaction between agents that induce or inhibit CYP3A4 could occur.²⁰ Thus, concomitant use of drugs such as barbiturates, rifampin (Rifadin), St. John’s wort, or antiseizure drugs such as topiramate (Topamax) may lower ulipristal concentrations. These medications may also affect levonorgestrel levels, similar to their effects on combined hormonal contraception. However, it is not known whether this translates to decreased efficacy.

When a woman is taking medications that can potentially decrease the effectiveness of hormonal emergency contraception, a more effective method such as a copper IUD might be more strongly considered. If a woman is not interested in an IUD, oral emergency contraception should still be offered, given that this is one of the last chances to prevent pregnancy, especially if she is on a potential teratogen.

Oral contraceptive pills have not been studied in combination with ulipristal. However, because ulipristal binds with high affinity to progesterone receptors (thus competing with the contraceptive), use of additional barrier contraceptives is recommended for the remainder of the menstrual cycle.

EMERGENCY CONTRACEPTION AND BREASTFEEDING

Q: True of false? Emergency contraceptives can be used if a woman is breastfeeding.

A: That depends on which method is used. Both the ACOG and the World Health Organization state that it is safe for breastfeeding women to use emergency contraception, but these are older guidelines addressing progestin-only regimens (ie, levonorgestrel).^19,21 It is unknown whether ulipristal is secreted into human breast milk, although excretion was seen in animal studies. Therefore, ulipristal is not recommended for use by women who are breastfeeding.^20,22 To minimize the infant’s exposure to levonorgestrel, mothers should consider not nursing for at least 8 hours after ingestion, but no more than 24 hours is needed.²³

People have been marking the skin with pigments for at least 4,000 years.¹ Tattoos have been found on Egyptian mummies, and Roman gladiators are known to have used tattoos for identification.² Tattooing was considered fashionable among royalty in the first half of the 20th century.³ And today it is perhaps more popular than ever.

But tattooing is not confined to popular culture and decoration. It has established uses in medicine, as well as other medically related uses that represent more recent trends. In this review, we explore the range of medical tattooing.

MEDICAL ALERT TATTOOING

Medical alert tattooing is a form of medical identification similar to medical alert jewelry, ie, bracelets and necklaces, to alert first-responders to a medical condition or to specific desires for care, such as do-not-resuscitate (DNR) directives.

Some people choose to have their medical condition tattooed rather than wear medical alert jewelry, which can break or be misplaced. ^4–6

This practice is currently unregulated by the medical community, and the few reports of its use published to date include two people with diabetes who had the word “diabetic” tattooed on their bodies,^4,5 and a woman with a tattoo warning of a past severe reaction to succinylcholine during anesthesia.⁶ She had been advised to wear medical alert jewelry, but she instead chose a tattoo.

Blood-type tattooing was briefly used in a few communities in the United States in the early 1950s as part of a program to provide a “walking blood bank.”⁷ However, the practice fell out of favor as physicians questioned the reliability of tattoos for medical information.⁷

This type of tattooing could also benefit patients with adrenal insufficiency, O-negative blood type, and allergies, and patients taking an anticoagulant drug (after discussing the risks of bleeding with their primary physician).

Emergency medical technicians are trained to search unresponsive patients for health-related items, including medical alert necklaces and bracelets. Since tattooing for disease identification purposes is not an officially recognized procedure, these personnel need to be aware that this practice is increasing among the general public. Identifying medical alert tattoos in emergency situations is much more difficult in people with extensive decorative tattooing.

Tattoos indicating health directives

Reports of people with tattoos indicating health directives (DNR, do-not-defibrillate) have prompted debate over the validity of tattoos as a type of advance directive.^8–13 These types of tattoos pose practical and ethical problems: they may not reflect a person’s current wishes, and they may have even been applied as a joke.¹³ Furthermore, they are not recognized as meeting any of the legal requirements for advance directives, so they cannot be considered as valid health directives, but only as a way to guide treatment decisions.¹⁴

The same is true for the other ways of notifying first-responders to one’s treatment wishes, ie, wallet cards and medical alert bracelets and necklaces. One manufacturer of medical alert bracelets and necklaces offers to engrave that the wearer has a living will and to keep on file a copy of the document, which they can fax or read out loud to paramedics if they are contacted.¹¹

Organ donor tattoo

In the case of a man who had his consent to be an organ donor tattooed on his chest,¹⁵ the tattoo was viewed as not equivalent to signed documentation; however, such tattoos can be used to help guide management.¹⁵

DIABETIC PATIENTS AND MEDICAL ALERT TATTOOS

Medical alert tattooing is increasingly common in people with diabetes. Discussions on social-networking sites on the Internet indicate that diabetic patients often do this on their own without consulting their physician.

The photograph at left is reprinted with the permission of the American Academy of Family Physicians, from reference 5.

In our clinic, we have encountered patients with tattoos on the wrist (Figure 1), similar to those seen on the Internet, typically displaying a six-pointed star of life, a caduceus (physician’s staff), and the word “diabetic.” Patients we have encountered in the past 3 to 4 years have cited the same rationale for resorting to medical tattooing—ie, the cost of repeatedly replacing broken and lost medical alert jewelry.

We believe there is a convincing rationale for diabetic patients to undergo medical tattooing, and we believe that diabetes organizations need to evaluate this and provide education to patients and clinicians about it, so that patients can discuss it with their care providers before taking action on their own.

Risks of tattooing in diabetic patients

Diabetic patients who ask their physician about getting a diabetes-alert tattoo should be informed about the dangers of tattooing in diabetes. The diabetes should be optimally controlled, as gauged by both hemoglobin A_1c and mean blood glucose profile at the time of tattooing, in order to promote healing of the tattooed area and to prevent wound infection.

Also helpful is to advise diabetic patients to avoid tattooing of the feet or lower legs in view of the risk of diabetes-related neurovascular disease that may impair healing or incite infection.

RECONSTRUCTIVE AND COSMETIC TATTOOING

Areolar reconstruction

Breast reconstruction after mastectomy is fundamental to the psychosocial health of the patient and helps her regain a positive body image.^16,17 Tattooing of the nipple-areola complex¹⁶ is usually the final step of the breast reconstruction process.

Complications of areolar tattooing are rare but can include local erythema and infection. ¹⁸ And patients should be informed that the tattoos will likely fade over time and require re-tattooing.¹⁸

Tattooing as camouflage

Tattooing is used to repigment the skin in conditions that cause hypopigmentation or hyperpigmentation, ² including burns.¹⁹ It is also used as an alternative to laser treatment in port-wine stain and in cosmetic surgery of the scalp.²⁰

Tattooing is used for micropigmentation of the lips and fingertips in patients who have vitiligo. However, this should be reserved for those with stable vitiligo, since tattooing may trigger another patch of vitiligo at tattoo sites.²¹

Although medical management exists for vitiligo, it is often ineffective for lip vitiligo since the success of medical therapy depends on the pigment-cell reservoir at the site of depigmentation. The lips lack such a reservoir of melanocytes, so tattooing may be an option.²²

Corneal scarring

Perforating injury, measles keratitis, and other conditions can result in cosmetically disfiguring discoloration of the cornea. When microsurgical reconstruction is ineffective or is not an option, corneal tattooing has been reported to provide satisfactory results at up to 4 years.²³ Reopacification, increased opacity, fading of the tattoo pigment, and epithelial growth have been reported, and in one series, most patients required reoperation.²⁴

Tattooing to hide surgical scars

Spyropoulou and Fatah²⁵ reported three patients in a plastic surgery practice who underwent decorative tattooing to camouflage cosmetically undesirable scars. The authors suggested this as a valid option, especially in younger patients, among whom tattooing is common and acceptable.²⁵

‘Permanent makeup’

Tattooing is also used to simulate makeup (“permanent makeup”) and may be beneficial to people allergic to conventional makeup or people with disabilities that make applying makeup difficult.²⁶ Complications of this procedure include bleeding, crusting, swelling, infection, allergic reactions, hypertrophic scars, keloid, loss of eyelashes, eyelid necrosis, and ectropion, as well as complications related to magnetic resonance imaging (described further below).

Most pigments used for this purpose do not have an established history of safe use, and patients may experience severe allergic reactions. A recent report described severe allergic reactions resistant to topical or systemic therapy with steroids in combination with topical tacrolimus (Prograf), especially after exposure to red dye 181.²⁷ Researchers have recommended the regulation and control of colorants in permanent makeup.²⁷

RADIATION ONCOLOGY

Tattooing is used in radiation oncology to ensure accurate targeting of radiation therapy. Typically, several small, black marks 1 to 2 mm in size are applied by a medical professional using an 18- or 19-gauge hypodermic needle and india ink.² The marks are permanent.

Although these markings are clearly helpful during radiation treatment, they can be psychologically upsetting to patients, as they are a constant reminder of the disease and the treatment, both during the treatment course and long after it is finished.

An alternative is to use temporary marks for the 6 to 7 weeks that patients typically need them. However, temporary tattooing is prone to fading, and this is a key limitation.

ENDOSCOPIC TATTOOING

In laparoscopic gastrointestinal surgery, lesions are often difficult to visualize and localize since the surgeon is unable to palpate the bowel directly to identify the diseased segment; this increases the risk of resecting the wrong segment of bowel.²⁸ Endoscopic tattooing of the segment to be resected greatly improves the accuracy of laparoscopic procedures. Endoscopic tattooing is also used to facilitate identification of subtle mucosal lesions or endoscopic resection sites at the time of subsequent endoscopy.^29,30

India ink or a similar presterilized commercial preparation is commonly used.³¹ Complications are rare but include mild chronic inflammation, hyperplastic changes, inflammatory bowel disease, abdominal abscess, inflammatory pseudotumor, focal peritonitis, peritoneal staining, and, very rarely, seeding of tumor via the tattooing needle.³⁰

FORENSIC MEDICINE

Specialists in forensic medicine use primary markers such as fingerprints and dental records and secondary markers such as birthmarks, scarring, and tattoos to identify victims.³² Tattoos are useful for identification when finger-prints or dental records are unavailable,³³ as in the tsunami of December 2004 in Southeast Asia³⁴ and the London Paddington train crash of October 1999.³⁵ However, as the body decomposes, tattoos can discolor and fade, making them hard to identify. Application of 3% hydrogen peroxide to the tattoo site has been reported to aid in identification, and infrared imaging has shown promise.³²

GENERAL RISKS AND COMPLICATIONS OF TATTOOING

Improper sterilization of tattooing needles and tattoo ink in public tattoo parlors can cause a wide range of diseases and skin reactions.^36–44

Infection

Pyodermal infections can include temporary inflammation at the sites of needle punctures, superficial infections such as impetigo and ecthyma, and deeper infections such as cellulitis, erysipelas, and furunculosis.

Other transmissible infections include hepatitis, syphilis, leprosy, tuberculosis cutis, rubella, chancroid, tetanus, and molluscum contagiosum. An outbreak of infection with Mycobacterium chelonae from premixed tattoo ink has also been reported.⁴⁴

Hepatitis C has been shown in epidemiologic studies to be transmissible via nonsterile needles. Human immunodeficiency virus is also theoretically transmissible this way, but this is difficult to confirm because the virus has a long incubation period.³⁶

Cutaneous reactions

Skin reactions to tattooing include aseptic inflammation and acquired sensitivity to tattoo dyes, especially red dyes, but also to chromium in green dyes, cadmium in yellow dyes, and cobalt in blue dyes.³⁸ The reaction can manifest as either allergic contact dermatitis or photoallergic dermatitis.

Cutaneous conditions that localize in tattooed areas include vaccinia, verruca vulgaris, herpes simplex, herpes zoster, psoriasis, lichen planus, keratosis follicularis (Darier disease), chronic discoid lupus erythematosus, and keratoacanthoma.

Other possible conditions include keloid, sarcoidal granuloma, erythema multiforme, localized scleroderma, and lymphadenopathy.^36,37

Malignancy

Malignancies reported to arise within tattoos include squamous cell carcinoma, basal cell carcinoma, malignant melanoma, leiomyosarcoma, primary non-Hodgkin lymphoma, and dermatofibrosarcoma protuberans.³⁹ These malignancies may be considered coincidental, but carcinogenicity of the tattooing colorants is a concern to be addressed. Nevertheless, a malignancy within a tattoo is more difficult to identify on skin examination.

Burns during magnetic resonance imaging

The metallic ferric acid pigments used in tattoos can conduct heat on the skin during magnetic resonance imaging,⁴⁰ resulting in traumatic burns. This has also been reported to occur with tattoos with nonferrous pigments. ⁴¹ Patients should be asked before this procedure if they have tattooing so that this complication can be avoided.

Two other complications

Two interesting complications of tattooing have been described. First, tattoo pigments have been noted within lymph nodes in patients with melanoma.⁴² This finding during surgery could cause the surgeon to mistake tattoo pigment for disease and to complete a regional lymph node dissection if biopsy of the sentinel node is not performed.

The other involved disseminated hyperalgesia after volar wrist tattooing. The authors speculated that the pain associated with volar tattooing may have been related to the proximity of the tattoo to the palmar cutaneous branch of the median nerve.⁴³
 

Acknowledgment: The authors would like to acknowledge the patients in Figure 1 for their permission to use their photos and Nicolas Kluger, MD, Departments of Dermatology, Allergology, and Venereology, University of Helsinki, Finland, for his input into an early draft of this manuscript.