Clinical Review

The author reports no financial relationships relevant to this article.

The past year has seen the publication of much useful evidence regarding urinary incontinence, from both epidemiologic studies and clinical trials. Research into the pathophysiology of incontinence continues to move forward, slowly but surely, measured not in breakthroughs but in gradually increasing knowledge of how the urethra and bladder function in the continent person and how that function can break down, leading to incontinence and other urinary symptoms.

Highlighted here are four notable studies from 2007, as well as progress notes on a trial mentioned early this year in Examining the Evidence (January issue).

New data clarify incidence and uncloak the effect of weight gain

Townsend MK, Danforth KN, Liffort KL, et al. Incidence and remission of urinary incontinence in middle-aged women. Am J Obstet Gynecol. 2007;197:167.e1–167.e5.

Townsend MK, Danforth KN, Liffort KL, et al. Body mass index, weight gain, and incident urinary incontinence in middle-aged women. Obstet Gynecol. 2007;110:346–353.

Studies of urinary incontinence in numerous populations have reported its prevalence—i.e., the percentage of people who have the condition at any point in time—but few have attempted to define its incidence—i.e., the rate at which it develops during a defined period.

Incidence is a true rate, described with a unit of time in the denominator. Prevalence is not a rate (although it is commonly referred to as such) and is described as a percentage only, without time in the denominator. With that distinction in mind, it is easy to see why prevalence data greatly outnumber incidence data: Prevalence can be obtained by means of cross-sectional study, with one-time collection of data. In contrast, incidence data require a population that is free of the condition of interest at baseline; that population is then followed to determine how many people who were initially free of the condition go on to develop it.

Lack of a standard definition makes it hard to measure incontinence

Reported prevalence can range from less than 10% to more than 90%, depending on how incontinence is defined:

• Very low prevalence is found when the definition is limited to persons with the greatest severity or frequency of symptoms
• at the other end of the spectrum, very high prevalence—even approaching 100%—can be found using a definition that includes people who have “ever” leaked urine.

The same issues complicate estimates of incidence. Because there is no consensus over what constitutes a clinically significant threshold for incontinence, investigators are forced to develop their own definitions.

In a pair of studies, Townsend and colleagues neatly circumvent this problem. Using data from the Nurses’ Health Study II, they used a series of definitions of incontinence, ranging from less severe to more severe, to describe their findings in ways that are easily transferred to clinical practice. They focused their attention on women aged 36 to 55 years to estimate the incidence of incontinence over a 2-year period. At baseline, women were considered at risk of incident incontinence if they reported never leaking or leaking only a few drops less than once a month. Three categories of incontinence were then defined, based on symptoms 2 years later:

• incident incontinence: any urine loss, defined as leaking 1–3 times a month
• frequent incontinence: urine loss at least once a week
• severe incontinence: urine loss at least once a week of sufficient volume to at least wet underwear.

Incidence rose with BMI, weight gain

In almost 34,000 continent women from 2001 to follow-up in 2003, the overall (average) incidence of urinary incontinence was 6.9 women for every 100 woman-years. Frequent incontinence developed in, on average, 1.8 women for every 100 woman-years; severe incontinence, in 0.6 women for every 100 woman-years.

Using multivariable logistic regression models, the authors analyzed the likelihood of incident incontinence by body mass index (BMI) and estimated weight gain from the age of 18 until 2001. For either variable, odds ratios (OR) showed a highly significant trend (P<.001) for an increased risk of incident incontinence.

For example, at a BMI greater than 35 kg/m², the likelihood of:

• any incontinence increased by a factor of about 2 (OR, 2.11; 95% confidence interval [CI], 1.84–2.42)
• frequent incontinence increased by a factor of almost 4 (OR, 3.85; 95% CI, 3.05–4.85)
• severe incontinence increased by a factor of more than 5 (OR, 5.52; 95% CI, 3.72–8.18).

The trend for weight gain was similar, with a gain of more than 30 kg showing odds ratios and 95% confidence intervals of similar magnitude to those seen with a BMI greater than 35.

But one third of incontinent women improved after 2 years

Although urinary incontinence is usually understood as a chronic condition, albeit under the influence of other factors, such as weight gain, data on remission are even scarcer than data on incidence. Using the same dataset, the authors determined that almost 31,000 women were incontinent at baseline in 2001, with incontinence occurring at least monthly. Complete remission, defined as no leaking in 2003, occurred in almost 14% of women. One third reported improvement, defined as either complete remission or a decrease in leaking frequency from 2001 to 2003.

It’s interesting that complete remission was more common in younger women. It also was more common in women who experienced frequent incontinence than in those who reported occasional incontinence. The remaining percentage of women—almost 60%—reported a similar or increased frequency of incontinence over the 2 years of follow-up.

The authors did not collect data on treatment. Estimates of persistence, improvement, and remission could be affected, therefore, if women received effective treatment between 2001 and 2003. However, only about one third of women reported mentioning their symptoms to a physician, and only 13% reported receiving treatment for incontinence. The magnitude of the effect of treatment on remission or improvement of urinary incontinence symptoms therefore seems limited.

Women remain reticent about incontinence

Several points underline the clinical importance of these data, including the relatively high incidence of incontinence symptoms and the strong influence of BMI and weight gain on that incidence. Also notable, and described in previous studies, is the vast underreporting and undertreatment of incontinence in women—an observation that should motivate all clinicians to include screening for urinary incontinence as part of regular well-woman care. Clinicians should also be prepared to refer women with incontinence or to initiate evaluation and management.

Some reports have suggested that the stigma of urinary incontinence has diminished slightly in light of widespread direct-to-consumer advertising for products related to the care (e.g., pads) or treatment (e.g., pharmaceuticals) of incontinence. The data from Townsend and colleagues are relatively recent, yet the majority of women failed to report their symptoms, and an even higher percentage received no treatment. The authors recommend that health-care providers initiate a discussion of urinary symptoms even in middle-aged women, who may be targeted for screening less frequently than older women.

In fascial sling vs Burch, sling prevails but is linked to more adverse effects

Albo ME, Richter HE, Brubaker L, et al, for the Urinary Incontinence Treatment Network. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med. 2007;356:2143–2155; comment: 2198–2200.

Eagerly anticipated results of the Urinary Incontinence Treatment Network’s first surgical trial, which compared the fascial sling procedure with Burch colposuspension for stress incontinence, were published in May in the New England Journal of Medicine. The Urinary Incontinence Treatment Network is a multicenter clinical trials group that was established in 2000 and is sponsored by the National Institutes of Health (specifically, by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Child Health and Human Development).

Women were eligible for the trial if they experienced symptoms of stress incontinence; symptoms of mixed incontinence were allowed as long as stress symptoms predominated. Of 655 women in the trial, 326 were randomly assigned to undergo placement of an autologous rectus fascia pubovaginal sling, and 329 were randomized to Burch colposuspension.

Overall success was defined as:

• negative pad test
• no urinary incontinence reported in a 3-day diary
• negative stress test to cough and Valsalva maneuver
• no self-reported symptoms of stress incontinence
• no retreatment for stress incontinence.

“Stress success,” or stress continence, was defined using the last three criteria.

At 2 years after the index surgery, 520 women (79%) were available for follow-up. Overall success and stress success were slightly higher in women who underwent sling placement than in those treated by Burch: overall success, 47% versus 38%, and stress success, 66% versus 49%, respectively. However, women who had slings experienced more adverse outcomes, including urinary tract infection, difficulty voiding, and postoperative urge incontinence.

Success rates were much lower than previously reported

These findings are particularly striking because the success rates are lower than in previous reports—and lower than the figures commonly used by surgeons to counsel women about likely results. “Success” for either procedure has been commonly quoted in the 80% to 90% range, not the 30% to 40% range found here. The authors are to be commended for the stringent definition of “success,” which included elements that invariably result in a lower success rate. It is these numbers that women are most interested in when they are considering this type of surgery.

The difference between sling and Burch procedures was particularly remarkable in regard to stress success (17 percentage points). The smaller difference seen for overall success (9 percentage points) can be attributed to the increase in postoperative urge incontinence among women undergoing the sling procedure.

If the other adverse events associated with the sling procedure (i.e., urinary tract infection and voiding difficulty) had been included in the composite measure of success, it seems possible, if not likely, that a smaller difference—or no difference at all—would have been seen between the sling and Burch groups.

Additional data still to come

Follow-up of women in this trial has been extended for up to 5 years and should provide much-needed information on longer-term results after these surgeries.

Transobturator mid-urethral sling linked to fewer complications

Sung VW, Schleinitz MD, Rardin CR, Ward RM, Myers DL. Comparison of retropubic versus transobturator approach to mid-urethral slings: a systematic review and meta-analysis. Am J Obstet Gynecol. 2007;197:3–11.

In this Update 1 year ago, I remarked on the need for more comparative information about the various mid-urethral slings currently on the market, particularly in regard to complications—information necessary to make recommendations and guide clinical decision-making.

Originally, the procedure for mid-urethral sling placement was modified from the retropubic approach to the obturator approach with the aim of reducing the risk of major bladder and urethral injury and vascular complications (FIGURE 1). Recent data suggest that that goal has been achieved. In a systematic review and meta-analysis of 17 studies that compared retropubic and transobturator approaches, Sung and colleagues found the transobturator route to be associated with fewer complications.

FIGURE 1 Transobturator approach lives up to promise

The retropubic approach (A) was modified to create the transobturator approach (B), with the aim of protecting the bladder, urethra, and vascular structures. A recent meta-analysis indicates that this goal was achieved.

Subjective and objective outcomes were similar for the two approaches

Overall, 492 women in six trials were randomly assigned to receive either a retropubic or transobturator mid-urethral sling for treatment of stress incontinence. Although some trials specified exactly which device was used, others did not. Follow-up ranged from 1 to 15 months.

Because the studies used different definitions of objective success as outcomes, it was not possible to obtain a pooled estimate for objective outcomes. However, the authors were able to calculate a pooled estimate for subjective outcomes by defining subjective success as a woman reporting either continence or improved status after surgery, and by defining failure as a woman reporting unchanged or deteriorating incontinence status.

The pooled odds ratio for subjective failure after transobturator placement of a mid-urethral sling was 0.85, compared with the retropubic approach (95% CI, 0.38–1.92). Results were relatively stable despite changes in definitions of success and failure and restriction to studies with more than 1 year of follow-up. Sung and colleagues concluded that evidence was insufficient to support one or the other approach in regard to subjective or objective outcomes.

Bladder perforation was most common complication

Findings regarding complications were more conclusive. Again drawing on data from six randomized trials, the authors estimated a pooled odds ratio for complications from transobturator placement of 0.40, compared with the retropubic approach (95% CI, 0.19–0.83). Using data from both randomized trials and cohort studies, the most common complications were:

• bladder perforation: 3.5% for retropubic placement, 0.2% for the transobturator route
• hematoma: 1.5% for retropubic placement, 0.08% for the transobturator route.

More definitive data are in the works

As noted here last year, the Urinary Incontinence Treatment Network is enrolling women with stress or stress-predominant mixed incontinence in a randomized trial to compare the retropubic and transobturator approaches for mid-urethral slings. With a sample size of 655 women and 2-year follow-up planned, this trial should be adequately powered to detect clinically important differences, if they exist, in both continence outcomes and complications. Enrollment is projected to close in 2008, with results to follow 2 years later.

Botox injection for detrusor overactivity is no quick fix after all

Interest continues to rise in treating detrusor overactivity—with or without incontinence—with botulinum toxin A. Only one commercial product is available in the United States, sold by Allergan under the trade name Botox. Last year, the Pelvic Floor Disorders Network, sponsored by the National Institute of Child Health and Human Development and the Office of Research in Women’s Health, began a placebo-controlled trial of cystoscopic detrusor injection of 200 U of Botox versus placebo, randomized in a 2:1 ratio, for women with incontinence caused by refractory idiopathic detrusor overactivity (FIGURE 2).

Although a sample size of 210 subjects was planned, enrollment was halted after 43 women received injections (28 with Botox, 15 with placebo). The reason: A higher-than-expected rate of urinary retention.

The trial had defined urinary retention as:

• use of catheterization for more than 4 weeks after the date of injection, or
• postvoid residual (PVR) urine of 200 mL or more at the 4-week visit. (The protocol mandated that a patient with this degree of retention be catheterized or that catheterization be considered by the clinician.)

FIGURE 2 Botox relieves detrusor overactivity—but only temporarily

A trial intended to encompass 210 women was halted early because the rate of urinary retention was significantly higher than expected. Twenty-eight women underwent injection of 200 U of Botox, and almost half were classified as having urinary retention 4 weeks after the procedure.

Rate of urinary retention proved to be much higher than anticipated

At the time the study protocol was finalized, most existing studies had focused on patients with neurogenic detrusor overactivity incontinence, many of whom already had impaired bladder emptying treated with self-catheterization. Communication with clinicians using Botox off-label for idiopathic detrusor overactivity incontinence suggested that the occurrence of urinary retention requiring intervention was less than 5%. However, of the 28 women who received Botox, 12 experienced urinary retention; most of these women (9 of 12) had elevated PVR at 4 weeks after injection. Although this elevation was temporary, some women required catheterization for months.

Of the 43 women included in the trial, 12 (28%) experienced urinary retention. However, counting only subjects who received Botox, the proportion with retention was 12 of 28 (43%). None of the women who received placebo experienced urinary retention.

There was also a higher incidence of urinary tract infection in women who developed retention after Botox injection and performed self-catheterization.

Follow-up continues for all 43 subjects, as the protocol provided for monitoring up to 1 year after injection. A full report on the safety and effectiveness of Botox for idiopathic detrusor overactivity in this trial is pending (manuscript submitted for publication).

Catheterization may raise risk of infection without providing a benefit

Ideal management of women who experience elevated PVR after Botox injection is unclear. Many clinicians wonder whether treatment—i.e., catheterization—is necessary for the type of impaired bladder emptying that occurs after Botox injection. It is even possible that catheterization increases the risk of urinary tract infection (or colonization) without providing a benefit to balance that risk.

Botox may still be an option, provided the patient is counseled about risks

Our understanding, albeit incomplete, of the mechanism of action when Botox is used to treat detrusor overactivity does not suggest an increased risk of elevated intravesical pressure leading to ureteral reflux and kidney damage; in fact, normal bladder pressure has been observed in the few studies in which it was measured after Botox injection. However, until we have further information about the short- and long-term risks, if any, of elevated PVR after Botox injection, clinicians should counsel patients about this possibility before proceeding with off-label use of Botox for detrusor overactivity.

Patients unlikely to tolerate repeated Botox injection over several years

Whether or not Botox in its current form will prove to be a useful treatment for women who have detrusor overactivity incontinence remains to be proven conclusively. Even if Botox relieves symptoms, especially in women who have not obtained relief from other treatments, current evidence suggests that the effect is time-limited, probably on the order of several months—although occasional patients obtain relief of greater duration, suggesting an effect that lasts beyond direct Botox action.

Given that most women experience these symptoms on a chronic basis—perhaps especially those who are refractory to usual treatment—it seems unlikely that repeated injections at intervals of only several months can be sustained for years. Ideally, development of second-generation products and further research will produce longer-lasting effects without the need for repeated injections at regular intervals.

The author reports no financial relationships relevant to this article.

The past year has seen the publication of much useful evidence regarding urinary incontinence, from both epidemiologic studies and clinical trials. Research into the pathophysiology of incontinence continues to move forward, slowly but surely, measured not in breakthroughs but in gradually increasing knowledge of how the urethra and bladder function in the continent person and how that function can break down, leading to incontinence and other urinary symptoms.

Highlighted here are four notable studies from 2007, as well as progress notes on a trial mentioned early this year in Examining the Evidence (January issue).

New data clarify incidence and uncloak the effect of weight gain

Townsend MK, Danforth KN, Liffort KL, et al. Incidence and remission of urinary incontinence in middle-aged women. Am J Obstet Gynecol. 2007;197:167.e1–167.e5.

Townsend MK, Danforth KN, Liffort KL, et al. Body mass index, weight gain, and incident urinary incontinence in middle-aged women. Obstet Gynecol. 2007;110:346–353.

Studies of urinary incontinence in numerous populations have reported its prevalence—i.e., the percentage of people who have the condition at any point in time—but few have attempted to define its incidence—i.e., the rate at which it develops during a defined period.

Incidence is a true rate, described with a unit of time in the denominator. Prevalence is not a rate (although it is commonly referred to as such) and is described as a percentage only, without time in the denominator. With that distinction in mind, it is easy to see why prevalence data greatly outnumber incidence data: Prevalence can be obtained by means of cross-sectional study, with one-time collection of data. In contrast, incidence data require a population that is free of the condition of interest at baseline; that population is then followed to determine how many people who were initially free of the condition go on to develop it.

Lack of a standard definition makes it hard to measure incontinence

Reported prevalence can range from less than 10% to more than 90%, depending on how incontinence is defined:

• Very low prevalence is found when the definition is limited to persons with the greatest severity or frequency of symptoms
• at the other end of the spectrum, very high prevalence—even approaching 100%—can be found using a definition that includes people who have “ever” leaked urine.

The same issues complicate estimates of incidence. Because there is no consensus over what constitutes a clinically significant threshold for incontinence, investigators are forced to develop their own definitions.

In a pair of studies, Townsend and colleagues neatly circumvent this problem. Using data from the Nurses’ Health Study II, they used a series of definitions of incontinence, ranging from less severe to more severe, to describe their findings in ways that are easily transferred to clinical practice. They focused their attention on women aged 36 to 55 years to estimate the incidence of incontinence over a 2-year period. At baseline, women were considered at risk of incident incontinence if they reported never leaking or leaking only a few drops less than once a month. Three categories of incontinence were then defined, based on symptoms 2 years later:

• incident incontinence: any urine loss, defined as leaking 1–3 times a month
• frequent incontinence: urine loss at least once a week
• severe incontinence: urine loss at least once a week of sufficient volume to at least wet underwear.

Incidence rose with BMI, weight gain

In almost 34,000 continent women from 2001 to follow-up in 2003, the overall (average) incidence of urinary incontinence was 6.9 women for every 100 woman-years. Frequent incontinence developed in, on average, 1.8 women for every 100 woman-years; severe incontinence, in 0.6 women for every 100 woman-years.

Using multivariable logistic regression models, the authors analyzed the likelihood of incident incontinence by body mass index (BMI) and estimated weight gain from the age of 18 until 2001. For either variable, odds ratios (OR) showed a highly significant trend (P<.001) for an increased risk of incident incontinence.

For example, at a BMI greater than 35 kg/m², the likelihood of:

• any incontinence increased by a factor of about 2 (OR, 2.11; 95% confidence interval [CI], 1.84–2.42)
• frequent incontinence increased by a factor of almost 4 (OR, 3.85; 95% CI, 3.05–4.85)
• severe incontinence increased by a factor of more than 5 (OR, 5.52; 95% CI, 3.72–8.18).

The trend for weight gain was similar, with a gain of more than 30 kg showing odds ratios and 95% confidence intervals of similar magnitude to those seen with a BMI greater than 35.

But one third of incontinent women improved after 2 years

Although urinary incontinence is usually understood as a chronic condition, albeit under the influence of other factors, such as weight gain, data on remission are even scarcer than data on incidence. Using the same dataset, the authors determined that almost 31,000 women were incontinent at baseline in 2001, with incontinence occurring at least monthly. Complete remission, defined as no leaking in 2003, occurred in almost 14% of women. One third reported improvement, defined as either complete remission or a decrease in leaking frequency from 2001 to 2003.

It’s interesting that complete remission was more common in younger women. It also was more common in women who experienced frequent incontinence than in those who reported occasional incontinence. The remaining percentage of women—almost 60%—reported a similar or increased frequency of incontinence over the 2 years of follow-up.

The authors did not collect data on treatment. Estimates of persistence, improvement, and remission could be affected, therefore, if women received effective treatment between 2001 and 2003. However, only about one third of women reported mentioning their symptoms to a physician, and only 13% reported receiving treatment for incontinence. The magnitude of the effect of treatment on remission or improvement of urinary incontinence symptoms therefore seems limited.

Women remain reticent about incontinence

Several points underline the clinical importance of these data, including the relatively high incidence of incontinence symptoms and the strong influence of BMI and weight gain on that incidence. Also notable, and described in previous studies, is the vast underreporting and undertreatment of incontinence in women—an observation that should motivate all clinicians to include screening for urinary incontinence as part of regular well-woman care. Clinicians should also be prepared to refer women with incontinence or to initiate evaluation and management.

Some reports have suggested that the stigma of urinary incontinence has diminished slightly in light of widespread direct-to-consumer advertising for products related to the care (e.g., pads) or treatment (e.g., pharmaceuticals) of incontinence. The data from Townsend and colleagues are relatively recent, yet the majority of women failed to report their symptoms, and an even higher percentage received no treatment. The authors recommend that health-care providers initiate a discussion of urinary symptoms even in middle-aged women, who may be targeted for screening less frequently than older women.

In fascial sling vs Burch, sling prevails but is linked to more adverse effects

Albo ME, Richter HE, Brubaker L, et al, for the Urinary Incontinence Treatment Network. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med. 2007;356:2143–2155; comment: 2198–2200.

Eagerly anticipated results of the Urinary Incontinence Treatment Network’s first surgical trial, which compared the fascial sling procedure with Burch colposuspension for stress incontinence, were published in May in the New England Journal of Medicine. The Urinary Incontinence Treatment Network is a multicenter clinical trials group that was established in 2000 and is sponsored by the National Institutes of Health (specifically, by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Child Health and Human Development).

Women were eligible for the trial if they experienced symptoms of stress incontinence; symptoms of mixed incontinence were allowed as long as stress symptoms predominated. Of 655 women in the trial, 326 were randomly assigned to undergo placement of an autologous rectus fascia pubovaginal sling, and 329 were randomized to Burch colposuspension.

Overall success was defined as:

• negative pad test
• no urinary incontinence reported in a 3-day diary
• negative stress test to cough and Valsalva maneuver
• no self-reported symptoms of stress incontinence
• no retreatment for stress incontinence.

“Stress success,” or stress continence, was defined using the last three criteria.

At 2 years after the index surgery, 520 women (79%) were available for follow-up. Overall success and stress success were slightly higher in women who underwent sling placement than in those treated by Burch: overall success, 47% versus 38%, and stress success, 66% versus 49%, respectively. However, women who had slings experienced more adverse outcomes, including urinary tract infection, difficulty voiding, and postoperative urge incontinence.

Success rates were much lower than previously reported

These findings are particularly striking because the success rates are lower than in previous reports—and lower than the figures commonly used by surgeons to counsel women about likely results. “Success” for either procedure has been commonly quoted in the 80% to 90% range, not the 30% to 40% range found here. The authors are to be commended for the stringent definition of “success,” which included elements that invariably result in a lower success rate. It is these numbers that women are most interested in when they are considering this type of surgery.

The difference between sling and Burch procedures was particularly remarkable in regard to stress success (17 percentage points). The smaller difference seen for overall success (9 percentage points) can be attributed to the increase in postoperative urge incontinence among women undergoing the sling procedure.

If the other adverse events associated with the sling procedure (i.e., urinary tract infection and voiding difficulty) had been included in the composite measure of success, it seems possible, if not likely, that a smaller difference—or no difference at all—would have been seen between the sling and Burch groups.

Additional data still to come

Follow-up of women in this trial has been extended for up to 5 years and should provide much-needed information on longer-term results after these surgeries.

Transobturator mid-urethral sling linked to fewer complications

Sung VW, Schleinitz MD, Rardin CR, Ward RM, Myers DL. Comparison of retropubic versus transobturator approach to mid-urethral slings: a systematic review and meta-analysis. Am J Obstet Gynecol. 2007;197:3–11.

In this Update 1 year ago, I remarked on the need for more comparative information about the various mid-urethral slings currently on the market, particularly in regard to complications—information necessary to make recommendations and guide clinical decision-making.

Originally, the procedure for mid-urethral sling placement was modified from the retropubic approach to the obturator approach with the aim of reducing the risk of major bladder and urethral injury and vascular complications (FIGURE 1). Recent data suggest that that goal has been achieved. In a systematic review and meta-analysis of 17 studies that compared retropubic and transobturator approaches, Sung and colleagues found the transobturator route to be associated with fewer complications.

FIGURE 1 Transobturator approach lives up to promise

The retropubic approach (A) was modified to create the transobturator approach (B), with the aim of protecting the bladder, urethra, and vascular structures. A recent meta-analysis indicates that this goal was achieved.

Subjective and objective outcomes were similar for the two approaches

Overall, 492 women in six trials were randomly assigned to receive either a retropubic or transobturator mid-urethral sling for treatment of stress incontinence. Although some trials specified exactly which device was used, others did not. Follow-up ranged from 1 to 15 months.

Because the studies used different definitions of objective success as outcomes, it was not possible to obtain a pooled estimate for objective outcomes. However, the authors were able to calculate a pooled estimate for subjective outcomes by defining subjective success as a woman reporting either continence or improved status after surgery, and by defining failure as a woman reporting unchanged or deteriorating incontinence status.

The pooled odds ratio for subjective failure after transobturator placement of a mid-urethral sling was 0.85, compared with the retropubic approach (95% CI, 0.38–1.92). Results were relatively stable despite changes in definitions of success and failure and restriction to studies with more than 1 year of follow-up. Sung and colleagues concluded that evidence was insufficient to support one or the other approach in regard to subjective or objective outcomes.

Bladder perforation was most common complication

Findings regarding complications were more conclusive. Again drawing on data from six randomized trials, the authors estimated a pooled odds ratio for complications from transobturator placement of 0.40, compared with the retropubic approach (95% CI, 0.19–0.83). Using data from both randomized trials and cohort studies, the most common complications were:

• bladder perforation: 3.5% for retropubic placement, 0.2% for the transobturator route
• hematoma: 1.5% for retropubic placement, 0.08% for the transobturator route.

More definitive data are in the works

As noted here last year, the Urinary Incontinence Treatment Network is enrolling women with stress or stress-predominant mixed incontinence in a randomized trial to compare the retropubic and transobturator approaches for mid-urethral slings. With a sample size of 655 women and 2-year follow-up planned, this trial should be adequately powered to detect clinically important differences, if they exist, in both continence outcomes and complications. Enrollment is projected to close in 2008, with results to follow 2 years later.

Botox injection for detrusor overactivity is no quick fix after all

Interest continues to rise in treating detrusor overactivity—with or without incontinence—with botulinum toxin A. Only one commercial product is available in the United States, sold by Allergan under the trade name Botox. Last year, the Pelvic Floor Disorders Network, sponsored by the National Institute of Child Health and Human Development and the Office of Research in Women’s Health, began a placebo-controlled trial of cystoscopic detrusor injection of 200 U of Botox versus placebo, randomized in a 2:1 ratio, for women with incontinence caused by refractory idiopathic detrusor overactivity (FIGURE 2).

Although a sample size of 210 subjects was planned, enrollment was halted after 43 women received injections (28 with Botox, 15 with placebo). The reason: A higher-than-expected rate of urinary retention.

The trial had defined urinary retention as:

• use of catheterization for more than 4 weeks after the date of injection, or
• postvoid residual (PVR) urine of 200 mL or more at the 4-week visit. (The protocol mandated that a patient with this degree of retention be catheterized or that catheterization be considered by the clinician.)

FIGURE 2 Botox relieves detrusor overactivity—but only temporarily

A trial intended to encompass 210 women was halted early because the rate of urinary retention was significantly higher than expected. Twenty-eight women underwent injection of 200 U of Botox, and almost half were classified as having urinary retention 4 weeks after the procedure.

Rate of urinary retention proved to be much higher than anticipated

At the time the study protocol was finalized, most existing studies had focused on patients with neurogenic detrusor overactivity incontinence, many of whom already had impaired bladder emptying treated with self-catheterization. Communication with clinicians using Botox off-label for idiopathic detrusor overactivity incontinence suggested that the occurrence of urinary retention requiring intervention was less than 5%. However, of the 28 women who received Botox, 12 experienced urinary retention; most of these women (9 of 12) had elevated PVR at 4 weeks after injection. Although this elevation was temporary, some women required catheterization for months.

Of the 43 women included in the trial, 12 (28%) experienced urinary retention. However, counting only subjects who received Botox, the proportion with retention was 12 of 28 (43%). None of the women who received placebo experienced urinary retention.

There was also a higher incidence of urinary tract infection in women who developed retention after Botox injection and performed self-catheterization.

Follow-up continues for all 43 subjects, as the protocol provided for monitoring up to 1 year after injection. A full report on the safety and effectiveness of Botox for idiopathic detrusor overactivity in this trial is pending (manuscript submitted for publication).

Catheterization may raise risk of infection without providing a benefit

Ideal management of women who experience elevated PVR after Botox injection is unclear. Many clinicians wonder whether treatment—i.e., catheterization—is necessary for the type of impaired bladder emptying that occurs after Botox injection. It is even possible that catheterization increases the risk of urinary tract infection (or colonization) without providing a benefit to balance that risk.

Botox may still be an option, provided the patient is counseled about risks

Our understanding, albeit incomplete, of the mechanism of action when Botox is used to treat detrusor overactivity does not suggest an increased risk of elevated intravesical pressure leading to ureteral reflux and kidney damage; in fact, normal bladder pressure has been observed in the few studies in which it was measured after Botox injection. However, until we have further information about the short- and long-term risks, if any, of elevated PVR after Botox injection, clinicians should counsel patients about this possibility before proceeding with off-label use of Botox for detrusor overactivity.

Patients unlikely to tolerate repeated Botox injection over several years

Whether or not Botox in its current form will prove to be a useful treatment for women who have detrusor overactivity incontinence remains to be proven conclusively. Even if Botox relieves symptoms, especially in women who have not obtained relief from other treatments, current evidence suggests that the effect is time-limited, probably on the order of several months—although occasional patients obtain relief of greater duration, suggesting an effect that lasts beyond direct Botox action.

Given that most women experience these symptoms on a chronic basis—perhaps especially those who are refractory to usual treatment—it seems unlikely that repeated injections at intervals of only several months can be sustained for years. Ideally, development of second-generation products and further research will produce longer-lasting effects without the need for repeated injections at regular intervals.

The author reports no financial relationships relevant to this article.

The past year has seen the publication of much useful evidence regarding urinary incontinence, from both epidemiologic studies and clinical trials. Research into the pathophysiology of incontinence continues to move forward, slowly but surely, measured not in breakthroughs but in gradually increasing knowledge of how the urethra and bladder function in the continent person and how that function can break down, leading to incontinence and other urinary symptoms.

Highlighted here are four notable studies from 2007, as well as progress notes on a trial mentioned early this year in Examining the Evidence (January issue).

New data clarify incidence and uncloak the effect of weight gain

Townsend MK, Danforth KN, Liffort KL, et al. Incidence and remission of urinary incontinence in middle-aged women. Am J Obstet Gynecol. 2007;197:167.e1–167.e5.

Townsend MK, Danforth KN, Liffort KL, et al. Body mass index, weight gain, and incident urinary incontinence in middle-aged women. Obstet Gynecol. 2007;110:346–353.

Studies of urinary incontinence in numerous populations have reported its prevalence—i.e., the percentage of people who have the condition at any point in time—but few have attempted to define its incidence—i.e., the rate at which it develops during a defined period.

Incidence is a true rate, described with a unit of time in the denominator. Prevalence is not a rate (although it is commonly referred to as such) and is described as a percentage only, without time in the denominator. With that distinction in mind, it is easy to see why prevalence data greatly outnumber incidence data: Prevalence can be obtained by means of cross-sectional study, with one-time collection of data. In contrast, incidence data require a population that is free of the condition of interest at baseline; that population is then followed to determine how many people who were initially free of the condition go on to develop it.

Lack of a standard definition makes it hard to measure incontinence

Reported prevalence can range from less than 10% to more than 90%, depending on how incontinence is defined:

• Very low prevalence is found when the definition is limited to persons with the greatest severity or frequency of symptoms
• at the other end of the spectrum, very high prevalence—even approaching 100%—can be found using a definition that includes people who have “ever” leaked urine.

The same issues complicate estimates of incidence. Because there is no consensus over what constitutes a clinically significant threshold for incontinence, investigators are forced to develop their own definitions.

In a pair of studies, Townsend and colleagues neatly circumvent this problem. Using data from the Nurses’ Health Study II, they used a series of definitions of incontinence, ranging from less severe to more severe, to describe their findings in ways that are easily transferred to clinical practice. They focused their attention on women aged 36 to 55 years to estimate the incidence of incontinence over a 2-year period. At baseline, women were considered at risk of incident incontinence if they reported never leaking or leaking only a few drops less than once a month. Three categories of incontinence were then defined, based on symptoms 2 years later:

• incident incontinence: any urine loss, defined as leaking 1–3 times a month
• frequent incontinence: urine loss at least once a week
• severe incontinence: urine loss at least once a week of sufficient volume to at least wet underwear.

Incidence rose with BMI, weight gain

In almost 34,000 continent women from 2001 to follow-up in 2003, the overall (average) incidence of urinary incontinence was 6.9 women for every 100 woman-years. Frequent incontinence developed in, on average, 1.8 women for every 100 woman-years; severe incontinence, in 0.6 women for every 100 woman-years.

Using multivariable logistic regression models, the authors analyzed the likelihood of incident incontinence by body mass index (BMI) and estimated weight gain from the age of 18 until 2001. For either variable, odds ratios (OR) showed a highly significant trend (P<.001) for an increased risk of incident incontinence.

For example, at a BMI greater than 35 kg/m², the likelihood of:

• any incontinence increased by a factor of about 2 (OR, 2.11; 95% confidence interval [CI], 1.84–2.42)
• frequent incontinence increased by a factor of almost 4 (OR, 3.85; 95% CI, 3.05–4.85)
• severe incontinence increased by a factor of more than 5 (OR, 5.52; 95% CI, 3.72–8.18).

The trend for weight gain was similar, with a gain of more than 30 kg showing odds ratios and 95% confidence intervals of similar magnitude to those seen with a BMI greater than 35.

But one third of incontinent women improved after 2 years

Although urinary incontinence is usually understood as a chronic condition, albeit under the influence of other factors, such as weight gain, data on remission are even scarcer than data on incidence. Using the same dataset, the authors determined that almost 31,000 women were incontinent at baseline in 2001, with incontinence occurring at least monthly. Complete remission, defined as no leaking in 2003, occurred in almost 14% of women. One third reported improvement, defined as either complete remission or a decrease in leaking frequency from 2001 to 2003.

It’s interesting that complete remission was more common in younger women. It also was more common in women who experienced frequent incontinence than in those who reported occasional incontinence. The remaining percentage of women—almost 60%—reported a similar or increased frequency of incontinence over the 2 years of follow-up.

The authors did not collect data on treatment. Estimates of persistence, improvement, and remission could be affected, therefore, if women received effective treatment between 2001 and 2003. However, only about one third of women reported mentioning their symptoms to a physician, and only 13% reported receiving treatment for incontinence. The magnitude of the effect of treatment on remission or improvement of urinary incontinence symptoms therefore seems limited.

Women remain reticent about incontinence

Several points underline the clinical importance of these data, including the relatively high incidence of incontinence symptoms and the strong influence of BMI and weight gain on that incidence. Also notable, and described in previous studies, is the vast underreporting and undertreatment of incontinence in women—an observation that should motivate all clinicians to include screening for urinary incontinence as part of regular well-woman care. Clinicians should also be prepared to refer women with incontinence or to initiate evaluation and management.

Some reports have suggested that the stigma of urinary incontinence has diminished slightly in light of widespread direct-to-consumer advertising for products related to the care (e.g., pads) or treatment (e.g., pharmaceuticals) of incontinence. The data from Townsend and colleagues are relatively recent, yet the majority of women failed to report their symptoms, and an even higher percentage received no treatment. The authors recommend that health-care providers initiate a discussion of urinary symptoms even in middle-aged women, who may be targeted for screening less frequently than older women.

In fascial sling vs Burch, sling prevails but is linked to more adverse effects

Albo ME, Richter HE, Brubaker L, et al, for the Urinary Incontinence Treatment Network. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med. 2007;356:2143–2155; comment: 2198–2200.

Eagerly anticipated results of the Urinary Incontinence Treatment Network’s first surgical trial, which compared the fascial sling procedure with Burch colposuspension for stress incontinence, were published in May in the New England Journal of Medicine. The Urinary Incontinence Treatment Network is a multicenter clinical trials group that was established in 2000 and is sponsored by the National Institutes of Health (specifically, by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Child Health and Human Development).

Women were eligible for the trial if they experienced symptoms of stress incontinence; symptoms of mixed incontinence were allowed as long as stress symptoms predominated. Of 655 women in the trial, 326 were randomly assigned to undergo placement of an autologous rectus fascia pubovaginal sling, and 329 were randomized to Burch colposuspension.

Overall success was defined as:

• negative pad test
• no urinary incontinence reported in a 3-day diary
• negative stress test to cough and Valsalva maneuver
• no self-reported symptoms of stress incontinence
• no retreatment for stress incontinence.

“Stress success,” or stress continence, was defined using the last three criteria.

At 2 years after the index surgery, 520 women (79%) were available for follow-up. Overall success and stress success were slightly higher in women who underwent sling placement than in those treated by Burch: overall success, 47% versus 38%, and stress success, 66% versus 49%, respectively. However, women who had slings experienced more adverse outcomes, including urinary tract infection, difficulty voiding, and postoperative urge incontinence.

Success rates were much lower than previously reported

These findings are particularly striking because the success rates are lower than in previous reports—and lower than the figures commonly used by surgeons to counsel women about likely results. “Success” for either procedure has been commonly quoted in the 80% to 90% range, not the 30% to 40% range found here. The authors are to be commended for the stringent definition of “success,” which included elements that invariably result in a lower success rate. It is these numbers that women are most interested in when they are considering this type of surgery.

The difference between sling and Burch procedures was particularly remarkable in regard to stress success (17 percentage points). The smaller difference seen for overall success (9 percentage points) can be attributed to the increase in postoperative urge incontinence among women undergoing the sling procedure.

If the other adverse events associated with the sling procedure (i.e., urinary tract infection and voiding difficulty) had been included in the composite measure of success, it seems possible, if not likely, that a smaller difference—or no difference at all—would have been seen between the sling and Burch groups.

Additional data still to come

Follow-up of women in this trial has been extended for up to 5 years and should provide much-needed information on longer-term results after these surgeries.

Transobturator mid-urethral sling linked to fewer complications

Sung VW, Schleinitz MD, Rardin CR, Ward RM, Myers DL. Comparison of retropubic versus transobturator approach to mid-urethral slings: a systematic review and meta-analysis. Am J Obstet Gynecol. 2007;197:3–11.

In this Update 1 year ago, I remarked on the need for more comparative information about the various mid-urethral slings currently on the market, particularly in regard to complications—information necessary to make recommendations and guide clinical decision-making.

Originally, the procedure for mid-urethral sling placement was modified from the retropubic approach to the obturator approach with the aim of reducing the risk of major bladder and urethral injury and vascular complications (FIGURE 1). Recent data suggest that that goal has been achieved. In a systematic review and meta-analysis of 17 studies that compared retropubic and transobturator approaches, Sung and colleagues found the transobturator route to be associated with fewer complications.

FIGURE 1 Transobturator approach lives up to promise

The retropubic approach (A) was modified to create the transobturator approach (B), with the aim of protecting the bladder, urethra, and vascular structures. A recent meta-analysis indicates that this goal was achieved.

Subjective and objective outcomes were similar for the two approaches

Overall, 492 women in six trials were randomly assigned to receive either a retropubic or transobturator mid-urethral sling for treatment of stress incontinence. Although some trials specified exactly which device was used, others did not. Follow-up ranged from 1 to 15 months.

Because the studies used different definitions of objective success as outcomes, it was not possible to obtain a pooled estimate for objective outcomes. However, the authors were able to calculate a pooled estimate for subjective outcomes by defining subjective success as a woman reporting either continence or improved status after surgery, and by defining failure as a woman reporting unchanged or deteriorating incontinence status.

The pooled odds ratio for subjective failure after transobturator placement of a mid-urethral sling was 0.85, compared with the retropubic approach (95% CI, 0.38–1.92). Results were relatively stable despite changes in definitions of success and failure and restriction to studies with more than 1 year of follow-up. Sung and colleagues concluded that evidence was insufficient to support one or the other approach in regard to subjective or objective outcomes.

Bladder perforation was most common complication

Findings regarding complications were more conclusive. Again drawing on data from six randomized trials, the authors estimated a pooled odds ratio for complications from transobturator placement of 0.40, compared with the retropubic approach (95% CI, 0.19–0.83). Using data from both randomized trials and cohort studies, the most common complications were:

• bladder perforation: 3.5% for retropubic placement, 0.2% for the transobturator route
• hematoma: 1.5% for retropubic placement, 0.08% for the transobturator route.

More definitive data are in the works

As noted here last year, the Urinary Incontinence Treatment Network is enrolling women with stress or stress-predominant mixed incontinence in a randomized trial to compare the retropubic and transobturator approaches for mid-urethral slings. With a sample size of 655 women and 2-year follow-up planned, this trial should be adequately powered to detect clinically important differences, if they exist, in both continence outcomes and complications. Enrollment is projected to close in 2008, with results to follow 2 years later.

Botox injection for detrusor overactivity is no quick fix after all

Interest continues to rise in treating detrusor overactivity—with or without incontinence—with botulinum toxin A. Only one commercial product is available in the United States, sold by Allergan under the trade name Botox. Last year, the Pelvic Floor Disorders Network, sponsored by the National Institute of Child Health and Human Development and the Office of Research in Women’s Health, began a placebo-controlled trial of cystoscopic detrusor injection of 200 U of Botox versus placebo, randomized in a 2:1 ratio, for women with incontinence caused by refractory idiopathic detrusor overactivity (FIGURE 2).

Although a sample size of 210 subjects was planned, enrollment was halted after 43 women received injections (28 with Botox, 15 with placebo). The reason: A higher-than-expected rate of urinary retention.

The trial had defined urinary retention as:

• use of catheterization for more than 4 weeks after the date of injection, or
• postvoid residual (PVR) urine of 200 mL or more at the 4-week visit. (The protocol mandated that a patient with this degree of retention be catheterized or that catheterization be considered by the clinician.)

FIGURE 2 Botox relieves detrusor overactivity—but only temporarily

A trial intended to encompass 210 women was halted early because the rate of urinary retention was significantly higher than expected. Twenty-eight women underwent injection of 200 U of Botox, and almost half were classified as having urinary retention 4 weeks after the procedure.

Rate of urinary retention proved to be much higher than anticipated

At the time the study protocol was finalized, most existing studies had focused on patients with neurogenic detrusor overactivity incontinence, many of whom already had impaired bladder emptying treated with self-catheterization. Communication with clinicians using Botox off-label for idiopathic detrusor overactivity incontinence suggested that the occurrence of urinary retention requiring intervention was less than 5%. However, of the 28 women who received Botox, 12 experienced urinary retention; most of these women (9 of 12) had elevated PVR at 4 weeks after injection. Although this elevation was temporary, some women required catheterization for months.

Of the 43 women included in the trial, 12 (28%) experienced urinary retention. However, counting only subjects who received Botox, the proportion with retention was 12 of 28 (43%). None of the women who received placebo experienced urinary retention.

There was also a higher incidence of urinary tract infection in women who developed retention after Botox injection and performed self-catheterization.

Follow-up continues for all 43 subjects, as the protocol provided for monitoring up to 1 year after injection. A full report on the safety and effectiveness of Botox for idiopathic detrusor overactivity in this trial is pending (manuscript submitted for publication).

Catheterization may raise risk of infection without providing a benefit

Ideal management of women who experience elevated PVR after Botox injection is unclear. Many clinicians wonder whether treatment—i.e., catheterization—is necessary for the type of impaired bladder emptying that occurs after Botox injection. It is even possible that catheterization increases the risk of urinary tract infection (or colonization) without providing a benefit to balance that risk.

Botox may still be an option, provided the patient is counseled about risks

Our understanding, albeit incomplete, of the mechanism of action when Botox is used to treat detrusor overactivity does not suggest an increased risk of elevated intravesical pressure leading to ureteral reflux and kidney damage; in fact, normal bladder pressure has been observed in the few studies in which it was measured after Botox injection. However, until we have further information about the short- and long-term risks, if any, of elevated PVR after Botox injection, clinicians should counsel patients about this possibility before proceeding with off-label use of Botox for detrusor overactivity.

Patients unlikely to tolerate repeated Botox injection over several years

Whether or not Botox in its current form will prove to be a useful treatment for women who have detrusor overactivity incontinence remains to be proven conclusively. Even if Botox relieves symptoms, especially in women who have not obtained relief from other treatments, current evidence suggests that the effect is time-limited, probably on the order of several months—although occasional patients obtain relief of greater duration, suggesting an effect that lasts beyond direct Botox action.

Given that most women experience these symptoms on a chronic basis—perhaps especially those who are refractory to usual treatment—it seems unlikely that repeated injections at intervals of only several months can be sustained for years. Ideally, development of second-generation products and further research will produce longer-lasting effects without the need for repeated injections at regular intervals.

The authors report no financial relationships relevant to this article.

CASE 1 Ovarian mass in a perimenopausal patient

A.R. is a 50-year-old gravida 3 para 3 who complains to her primary gynecologist of perimenopausal bleeding. A pelvic examination suggests an ovarian mass, and ultrasonography (US) reveals a myomatous uterus, thickened endometrium (34 mm), and a left ovarian cyst, with debris, that is 3.5×3.4×3.9 cm in size. The mass is thought to be a hemorrhagic cyst. Endometrial biopsy is benign.

Five weeks later, repeat US reveals that the mass has increased in size to 5.6×5.3×4.3 cm. It now appears complex in nature, with smooth walls and a single solid projection. The patient’s CA-125 level is 15 U/mL, which is in the normal range.

How should the mass be managed?

This scenario isn’t uncommon: Approximately one in every 10 women undergoes surgery for an adnexal mass, and an even higher percentage develop a mass that ultimately resolves or requires no surgery.¹ Most of these lesions occur in women of reproductive age and are benign, often functional. The two groups at highest risk of malignancy are prepubescent and postmenopausal females.^2,3 The rate of malignancy among prepubescent girls who have an adnexal mass is 35%; in postmenopausal women who have an adnexal mass, 30%.^2,3

In this article, we describe how to evaluate and manage an adnexal mass in perimenopausal and postmenopausal women, as well as in the pregnant population, and outline the fundamentals of excision and surgical staging. Whenever possible, we base our observations on comprehensive guidelines and reliable data.

In the case just described, the increasing size of the mass and the complex appearance on follow-up imaging justify a surgical approach. Conservative management and definitive surgical treatment are the two treatment options for any adnexal mass.

Multipronged assessment is vital

Pelvic examination alone is insufficient to accurately assess ovarian size and internal characteristics of the mass, especially in postmenopausal and obese women.⁴ Nevertheless, the pelvic exam is a critical component of evaluation and often detects pathology. Pelvic examination also can assist in determining the best route of removal, depending on the mobility and size of the mass.

US yields the most information

US is the most effective tool for evaluating pelvic structures. It helps characterize masses and differentiates uterine, ovarian, and extraovarian tissues (FIGURE). If there is a high suspicion of malignancy, the next step is computed tomography (CT) to rule out metastatic disease.

US findings that suggest a malignant process are:

• solid component, not hyperechoic; usually nodular or papillary
• thick septations (2–3 mm)
• bilaterality
• positive flow to the solid component of the mass
• ascites.⁵

If a pregnant patient requires further evaluation for an adnexal mass, she should undergo magnetic resonance imaging (MRI) without contrast, not CT, to avoid radiation exposure. Although we lack studies of the safety of contrast agents in pregnant women, animal studies have demonstrated an increased rate of miscarriage, skeletal dysplasia, and visceral abnormalities with the use of contrast.⁶

FIGURE The complex nature of a mass comes to light via ultrasonography

This complex mass of the right ovary, seen from different vantage points in A and B, contains multiple cysts and septations. Minimal blood flow is apparent in C.

An incidental mass may not require immediate surgery

A small (<5 cm in diameter), simple, asymptomatic mass may be followed conservatively (TABLE).⁷ Follow-up consists of repeat US, beginning within 4 to 6 weeks after detection.

Any postmenopausal woman who has a complex mass identified by US should undergo CA-125 testing and surgical excision. A mass in a premenopausal woman should also be removed if it has these characteristics—provided the mass is not functional and the complexity does not arise from hemorrhage associated with ovulation.

A program at the University of Kentucky enrolled 15,106 women older than 50 years to undergo annual transvaginal US for ovarian cancer screening.⁸ Of these, 18% were given a diagnosis of unilocular ovarian cysts, with an initial mean diameter of 2.7 cm; 69.4% of the cysts resolved spontaneously. No woman with an isolated unilocular cystic ovarian tumor developed ovarian cancer during the 6.3-year follow-up; the risk of malignancy was less than 0.1% with a 95% confidence interval. It therefore appears safe to follow small simple cysts in women of any age.

TABLE

When an adnexal mass is detected, possibilities are many

Medical therapy might facilitate regression of the mass

Conservative management might also include medical therapy. Follicular cysts are very common in menarchal and perimenopausal women, and a trial of hormones, in the form of an oral contraceptive (OC) for 4 to 6 weeks, is a common strategy to prevent new cysts by suppressing ovulation. Such a trial is appropriate only for a premenopausal woman who has a simple cyst, however. A complex mass should generally not be observed unless the complexity is thought to be the result of a physiologic process. Six weeks of OC use is long enough to cause physiologic cysts to regress and to reveal which patients should proceed to surgery.⁹

Surgical treatment, staging

A mass that is suspicious for malignancy should be removed as soon as possible. If frozen section histology confirms the diagnosis, total abdominal hysterectomy with bilateral salpingo-oophorectomy is appropriate. If the patient desires childbearing and the cancer is of low grade and confined to the ovary, unilateral oophorectomy with ipsilateral nodes and staging is appropriate.

Surgical staging of ovarian malignancy should be carried out by a gynecologic oncologist. It involves removal of all mullerian structures, bilateral pelvic and periaortic lymph node sampling, peritoneal biopsies, and cytology or biopsy of the diaphragm. If there is no evidence of gross tumor, comprehensive staging with peritoneal biopsies, lymph node dissection, and cytology of the diaphragm is crucial.

Pathologic findings may necessitate upstaging of the patient and indicate the need for chemotherapy. Approximately 20% of patients who appear to have stage I or II localized disease have occult dissemination within the abdomen.¹⁰

If there is gross disease within the abdomen, the goal of surgery is to remove it.

When should you refer?

According to guidelines from the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists, a postmenopausal woman with an adnexal mass should be referred to a gynecologic oncologist when she has one or more of the following:

• nodular or fixed mass
• elevated CA-125 level (>35 U/mL)
• ascites
• evidence of metastasis on imaging
• strong family history of breast or ovarian cancer.¹¹

A premenopausal woman should be referred if she has an adnexal mass and one or more of the following:

• elevated CA-125 (>200 U/mL)
• evidence of metastatic disease
• ascites.

Referral may also be appropriate if there is a first-degree relative with breast or ovarian cancer.¹¹

CASE 1 Resolved

After the patient is counseled about the likelihood of malignancy, she undergoes exploratory laparotomy with frozen section. The ovary ruptures, and analysis of a frozen section is consistent with mullerian adenocarcinoma.

She then undergoes total abdominal hysterectomy and bilateral salpingooophorectomy. Gynecologic oncology is consulted, and complete staging follows, including omentectomy, peritoneal biopsies, and pelvic and periaortic lymph node dissection. Pathology reveals stage IC poorly differentiated adenocarcinoma, endometrioid type. Combination chemotherapy with carboplatin and a taxane is recommended.

Selecting a surgical approach

CASE 2 Elderly patient with a complex mass

P.W., an 86-year-old gravida 9 para 4043, has an incidental adnexal mass detected during CT imaging. The left ovarian mass is complex and 7 cm in diameter at its largest point. The CA-125 level is 23 U/mL, and the carcinoembryonic antigen level is 4.5 ng/mL—both within normal range. A colonoscopy—performed as routine screening, not as part of the workup for the mass—is normal.

Because the mass is complex, surgery is indicated, and the physician prefers the laparoscopic approach—but is it reasonable?

In cases such as this, the decision is best left to the discretion of the surgeon. If the mass is mobile and small enough to fit into a bag (to prevent spillage if it ruptures), laparoscopic removal is appropriate. As in other settings, laparoscopy speeds recovery and shortens hospitalization.

Laparoscopic removal of an adnexal mass is technically similar to an open procedure. After washings are obtained and the ureter is identified, the infundibulopelvic ligament is ligated or cauterized. The broad ligament anterior to the ureter is separated from the peritoneum. The utero-ovarian ligament is then cauterized, as is the fallopian tube, and the specimen is placed in a sealed bag. The bag is then generally removed through a 10-mm port, and the specimen is sent for pathologic evaluation.

If frozen section analysis indicates that a mass is malignant, a gynecologic oncologist can stage the patient during the same procedure. This staging can be performed laparoscopically if it is technically feasible and if the surgeon feels comfortable using this approach. If it is not possible to stage the patient at the initial surgery, staging should occur within 6 weeks after the original diagnosis.

For a discussion of the advisability of laparoscopy in a pregnant patient, see below.

CASE 2 Resolved

The patient undergoes bilateral salpingo-oophorectomy via a laparoscopic approach. During the procedure, the left ovary is placed into an endoscopic specimen bag and drained to allow adequate removal through the abdominal port site; no rupture occurs. Frozen section is benign, and the final pathology report shows the mass to be a serous cystadenoma.

The pregnant patient

CASE 3 Suspicious mass with abnormal vascularity

B.E. is a 25-year-old gravida 2 para 1001 who has a pelvic mass identified during a 20-week anomaly scan. The mass involves the left ovary and is 7.1 cm in size, well circumscribed, and solid, with multiple cystic spaces and increased flow apparent on color Doppler imaging. The mass is characterized by a large degree of abnormal vascularity, and an experienced ultrasonographer describes it as “worrisome for malignancy.” MRI is performed, and the findings are consistent with those of ultrasonography but without evidence of malignant spread. Tumor markers are within normal limits, except for ß-human chorionic gonadotropin, which is elevated for the obvious reason.

Is surgery appropriate?

Gravidas develop pelvic masses at a significant rate, with a prevalence of approximately 2.3%, according to a study of 18,391 pregnant women who underwent US imaging at Washington University between 1988 and 1993.¹² The majority of patients who had an adnexal mass—76%, or 320 women—had a simple cyst that was less than 5 cm in diameter and associated with no adverse events. The other 24%, or 102 women, had a mass larger than 5 cm, either simple or complex in nature. Most masses resolved spontaneously, and only 25 required surgical removal.¹² No invasive carcinomas were found.

Despite the long odds of malignancy, an adnexal mass in pregnancy warrants close evaluation and follow-up and, occasionally, surgical management.

When is surgery justified?

Cholecystitis, appendicitis, and ovarian torsion are common diagnoses that require operative intervention regardless of gestational age.

Otherwise, when a complex adnexal mass is identified during pregnancy and is symptomatic or large enough to require removal, the gynecologist should proceed with surgery, whenever possible, in the second trimester—the most opportune time for removal. In some women, the ideal time for surgical removal of a mass detected during pregnancy is around 18 weeks’ gestation, but certainly before 24 weeks. Given the position of the gravid uterus, exploratory laparotomy is preferred over laparoscopy at this stage of gestation.

Intraoperative evaluation of the mass by pathology with frozen section is recommended. Even though immediate staging may not be feasible, owing to the pregnancy, pathology results can reassure the patient and her family and also facilitate planning of the optimal time and route of delivery.

If the mass is determined to be malignant, the patient should undergo surgical staging after completion of the pregnancy. At 37 weeks, labor should be induced, with staging performed within the next 2 to 4 weeks, or a cesarean section should be performed, with staging carried out at that time.

Laparoscopy may be feasible in the first trimester

Because laparoscopy can be difficult to perform during pregnancy, it should be used judiciously; uterine size can limit visibility and hinder safe placement of trocars. The first trimester is the least problematic period for laparoscopy.

A large study in Sweden compared laparoscopy with laparotomy between 4 and 20 weeks’ gestation and assessed fetal outcomes.¹³ In the study, 2,181 women underwent laparoscopy and 1,522 underwent laparotomy. Low birth weight (<2,500 g), intrauterine growth restriction, and delivery before 37 weeks’ gestation increased among all surgical patients, with no differences attributed to the route of the procedure. Nor were there significant differences between surgical and nonsurgical patients in either infant survival at 1 year or the incidence of fetal malformation.

As long as the anesthesiologist is aware of the pregnancy, a general surgeon can safely perform either laparoscopy or laparotomy during the first or second trimester. Care should be taken not to remove a corpus luteum before the 14th week of gestation. Pregnancy should not alter the surgeon’s preferred treatment approach at this time, unless uterine size is the limiting factor.

CASE 3 Resolved

B.E. safely undergoes exploratory laparotomy and left oophorectomy at 23-4/7 weeks’ gestation. Frozen section indicates that the mass is a malignant neoplasm. The final pathology report describes a highly unusual constellation of histologic findings, including juvenile granulosa cell tumor, dysgerminoma, and gonadoblastoma. A cesarean delivery with completion of cancer staging is planned when the fetus achieves lung maturity, with preservation of the contralateral ovary and uterus nodal sampling, peritoneal biopsies, and omentectomy.

The authors report no financial relationships relevant to this article.

CASE 1 Ovarian mass in a perimenopausal patient

A.R. is a 50-year-old gravida 3 para 3 who complains to her primary gynecologist of perimenopausal bleeding. A pelvic examination suggests an ovarian mass, and ultrasonography (US) reveals a myomatous uterus, thickened endometrium (34 mm), and a left ovarian cyst, with debris, that is 3.5×3.4×3.9 cm in size. The mass is thought to be a hemorrhagic cyst. Endometrial biopsy is benign.

Five weeks later, repeat US reveals that the mass has increased in size to 5.6×5.3×4.3 cm. It now appears complex in nature, with smooth walls and a single solid projection. The patient’s CA-125 level is 15 U/mL, which is in the normal range.

How should the mass be managed?

This scenario isn’t uncommon: Approximately one in every 10 women undergoes surgery for an adnexal mass, and an even higher percentage develop a mass that ultimately resolves or requires no surgery.¹ Most of these lesions occur in women of reproductive age and are benign, often functional. The two groups at highest risk of malignancy are prepubescent and postmenopausal females.^2,3 The rate of malignancy among prepubescent girls who have an adnexal mass is 35%; in postmenopausal women who have an adnexal mass, 30%.^2,3

In this article, we describe how to evaluate and manage an adnexal mass in perimenopausal and postmenopausal women, as well as in the pregnant population, and outline the fundamentals of excision and surgical staging. Whenever possible, we base our observations on comprehensive guidelines and reliable data.

In the case just described, the increasing size of the mass and the complex appearance on follow-up imaging justify a surgical approach. Conservative management and definitive surgical treatment are the two treatment options for any adnexal mass.

Multipronged assessment is vital

Pelvic examination alone is insufficient to accurately assess ovarian size and internal characteristics of the mass, especially in postmenopausal and obese women.⁴ Nevertheless, the pelvic exam is a critical component of evaluation and often detects pathology. Pelvic examination also can assist in determining the best route of removal, depending on the mobility and size of the mass.

US yields the most information

US is the most effective tool for evaluating pelvic structures. It helps characterize masses and differentiates uterine, ovarian, and extraovarian tissues (FIGURE). If there is a high suspicion of malignancy, the next step is computed tomography (CT) to rule out metastatic disease.

US findings that suggest a malignant process are:

• solid component, not hyperechoic; usually nodular or papillary
• thick septations (2–3 mm)
• bilaterality
• positive flow to the solid component of the mass
• ascites.⁵

If a pregnant patient requires further evaluation for an adnexal mass, she should undergo magnetic resonance imaging (MRI) without contrast, not CT, to avoid radiation exposure. Although we lack studies of the safety of contrast agents in pregnant women, animal studies have demonstrated an increased rate of miscarriage, skeletal dysplasia, and visceral abnormalities with the use of contrast.⁶

FIGURE The complex nature of a mass comes to light via ultrasonography

This complex mass of the right ovary, seen from different vantage points in A and B, contains multiple cysts and septations. Minimal blood flow is apparent in C.

An incidental mass may not require immediate surgery

A small (<5 cm in diameter), simple, asymptomatic mass may be followed conservatively (TABLE).⁷ Follow-up consists of repeat US, beginning within 4 to 6 weeks after detection.

Any postmenopausal woman who has a complex mass identified by US should undergo CA-125 testing and surgical excision. A mass in a premenopausal woman should also be removed if it has these characteristics—provided the mass is not functional and the complexity does not arise from hemorrhage associated with ovulation.

A program at the University of Kentucky enrolled 15,106 women older than 50 years to undergo annual transvaginal US for ovarian cancer screening.⁸ Of these, 18% were given a diagnosis of unilocular ovarian cysts, with an initial mean diameter of 2.7 cm; 69.4% of the cysts resolved spontaneously. No woman with an isolated unilocular cystic ovarian tumor developed ovarian cancer during the 6.3-year follow-up; the risk of malignancy was less than 0.1% with a 95% confidence interval. It therefore appears safe to follow small simple cysts in women of any age.

TABLE

When an adnexal mass is detected, possibilities are many

Medical therapy might facilitate regression of the mass

Conservative management might also include medical therapy. Follicular cysts are very common in menarchal and perimenopausal women, and a trial of hormones, in the form of an oral contraceptive (OC) for 4 to 6 weeks, is a common strategy to prevent new cysts by suppressing ovulation. Such a trial is appropriate only for a premenopausal woman who has a simple cyst, however. A complex mass should generally not be observed unless the complexity is thought to be the result of a physiologic process. Six weeks of OC use is long enough to cause physiologic cysts to regress and to reveal which patients should proceed to surgery.⁹

Surgical treatment, staging

A mass that is suspicious for malignancy should be removed as soon as possible. If frozen section histology confirms the diagnosis, total abdominal hysterectomy with bilateral salpingo-oophorectomy is appropriate. If the patient desires childbearing and the cancer is of low grade and confined to the ovary, unilateral oophorectomy with ipsilateral nodes and staging is appropriate.

Surgical staging of ovarian malignancy should be carried out by a gynecologic oncologist. It involves removal of all mullerian structures, bilateral pelvic and periaortic lymph node sampling, peritoneal biopsies, and cytology or biopsy of the diaphragm. If there is no evidence of gross tumor, comprehensive staging with peritoneal biopsies, lymph node dissection, and cytology of the diaphragm is crucial.

Pathologic findings may necessitate upstaging of the patient and indicate the need for chemotherapy. Approximately 20% of patients who appear to have stage I or II localized disease have occult dissemination within the abdomen.¹⁰

If there is gross disease within the abdomen, the goal of surgery is to remove it.

When should you refer?

According to guidelines from the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists, a postmenopausal woman with an adnexal mass should be referred to a gynecologic oncologist when she has one or more of the following:

• nodular or fixed mass
• elevated CA-125 level (>35 U/mL)
• ascites
• evidence of metastasis on imaging
• strong family history of breast or ovarian cancer.¹¹

A premenopausal woman should be referred if she has an adnexal mass and one or more of the following:

• elevated CA-125 (>200 U/mL)
• evidence of metastatic disease
• ascites.

Referral may also be appropriate if there is a first-degree relative with breast or ovarian cancer.¹¹

CASE 1 Resolved

After the patient is counseled about the likelihood of malignancy, she undergoes exploratory laparotomy with frozen section. The ovary ruptures, and analysis of a frozen section is consistent with mullerian adenocarcinoma.

She then undergoes total abdominal hysterectomy and bilateral salpingooophorectomy. Gynecologic oncology is consulted, and complete staging follows, including omentectomy, peritoneal biopsies, and pelvic and periaortic lymph node dissection. Pathology reveals stage IC poorly differentiated adenocarcinoma, endometrioid type. Combination chemotherapy with carboplatin and a taxane is recommended.

Selecting a surgical approach

CASE 2 Elderly patient with a complex mass

P.W., an 86-year-old gravida 9 para 4043, has an incidental adnexal mass detected during CT imaging. The left ovarian mass is complex and 7 cm in diameter at its largest point. The CA-125 level is 23 U/mL, and the carcinoembryonic antigen level is 4.5 ng/mL—both within normal range. A colonoscopy—performed as routine screening, not as part of the workup for the mass—is normal.

Because the mass is complex, surgery is indicated, and the physician prefers the laparoscopic approach—but is it reasonable?

In cases such as this, the decision is best left to the discretion of the surgeon. If the mass is mobile and small enough to fit into a bag (to prevent spillage if it ruptures), laparoscopic removal is appropriate. As in other settings, laparoscopy speeds recovery and shortens hospitalization.

Laparoscopic removal of an adnexal mass is technically similar to an open procedure. After washings are obtained and the ureter is identified, the infundibulopelvic ligament is ligated or cauterized. The broad ligament anterior to the ureter is separated from the peritoneum. The utero-ovarian ligament is then cauterized, as is the fallopian tube, and the specimen is placed in a sealed bag. The bag is then generally removed through a 10-mm port, and the specimen is sent for pathologic evaluation.

If frozen section analysis indicates that a mass is malignant, a gynecologic oncologist can stage the patient during the same procedure. This staging can be performed laparoscopically if it is technically feasible and if the surgeon feels comfortable using this approach. If it is not possible to stage the patient at the initial surgery, staging should occur within 6 weeks after the original diagnosis.

For a discussion of the advisability of laparoscopy in a pregnant patient, see below.

CASE 2 Resolved

The patient undergoes bilateral salpingo-oophorectomy via a laparoscopic approach. During the procedure, the left ovary is placed into an endoscopic specimen bag and drained to allow adequate removal through the abdominal port site; no rupture occurs. Frozen section is benign, and the final pathology report shows the mass to be a serous cystadenoma.

The pregnant patient

CASE 3 Suspicious mass with abnormal vascularity

B.E. is a 25-year-old gravida 2 para 1001 who has a pelvic mass identified during a 20-week anomaly scan. The mass involves the left ovary and is 7.1 cm in size, well circumscribed, and solid, with multiple cystic spaces and increased flow apparent on color Doppler imaging. The mass is characterized by a large degree of abnormal vascularity, and an experienced ultrasonographer describes it as “worrisome for malignancy.” MRI is performed, and the findings are consistent with those of ultrasonography but without evidence of malignant spread. Tumor markers are within normal limits, except for ß-human chorionic gonadotropin, which is elevated for the obvious reason.

Is surgery appropriate?

Gravidas develop pelvic masses at a significant rate, with a prevalence of approximately 2.3%, according to a study of 18,391 pregnant women who underwent US imaging at Washington University between 1988 and 1993.¹² The majority of patients who had an adnexal mass—76%, or 320 women—had a simple cyst that was less than 5 cm in diameter and associated with no adverse events. The other 24%, or 102 women, had a mass larger than 5 cm, either simple or complex in nature. Most masses resolved spontaneously, and only 25 required surgical removal.¹² No invasive carcinomas were found.

Despite the long odds of malignancy, an adnexal mass in pregnancy warrants close evaluation and follow-up and, occasionally, surgical management.

When is surgery justified?

Cholecystitis, appendicitis, and ovarian torsion are common diagnoses that require operative intervention regardless of gestational age.

Otherwise, when a complex adnexal mass is identified during pregnancy and is symptomatic or large enough to require removal, the gynecologist should proceed with surgery, whenever possible, in the second trimester—the most opportune time for removal. In some women, the ideal time for surgical removal of a mass detected during pregnancy is around 18 weeks’ gestation, but certainly before 24 weeks. Given the position of the gravid uterus, exploratory laparotomy is preferred over laparoscopy at this stage of gestation.

Intraoperative evaluation of the mass by pathology with frozen section is recommended. Even though immediate staging may not be feasible, owing to the pregnancy, pathology results can reassure the patient and her family and also facilitate planning of the optimal time and route of delivery.

If the mass is determined to be malignant, the patient should undergo surgical staging after completion of the pregnancy. At 37 weeks, labor should be induced, with staging performed within the next 2 to 4 weeks, or a cesarean section should be performed, with staging carried out at that time.

Laparoscopy may be feasible in the first trimester

Because laparoscopy can be difficult to perform during pregnancy, it should be used judiciously; uterine size can limit visibility and hinder safe placement of trocars. The first trimester is the least problematic period for laparoscopy.

A large study in Sweden compared laparoscopy with laparotomy between 4 and 20 weeks’ gestation and assessed fetal outcomes.¹³ In the study, 2,181 women underwent laparoscopy and 1,522 underwent laparotomy. Low birth weight (<2,500 g), intrauterine growth restriction, and delivery before 37 weeks’ gestation increased among all surgical patients, with no differences attributed to the route of the procedure. Nor were there significant differences between surgical and nonsurgical patients in either infant survival at 1 year or the incidence of fetal malformation.

As long as the anesthesiologist is aware of the pregnancy, a general surgeon can safely perform either laparoscopy or laparotomy during the first or second trimester. Care should be taken not to remove a corpus luteum before the 14th week of gestation. Pregnancy should not alter the surgeon’s preferred treatment approach at this time, unless uterine size is the limiting factor.

CASE 3 Resolved

B.E. safely undergoes exploratory laparotomy and left oophorectomy at 23-4/7 weeks’ gestation. Frozen section indicates that the mass is a malignant neoplasm. The final pathology report describes a highly unusual constellation of histologic findings, including juvenile granulosa cell tumor, dysgerminoma, and gonadoblastoma. A cesarean delivery with completion of cancer staging is planned when the fetus achieves lung maturity, with preservation of the contralateral ovary and uterus nodal sampling, peritoneal biopsies, and omentectomy.

The authors report no financial relationships relevant to this article.

CASE 1 Ovarian mass in a perimenopausal patient

A.R. is a 50-year-old gravida 3 para 3 who complains to her primary gynecologist of perimenopausal bleeding. A pelvic examination suggests an ovarian mass, and ultrasonography (US) reveals a myomatous uterus, thickened endometrium (34 mm), and a left ovarian cyst, with debris, that is 3.5×3.4×3.9 cm in size. The mass is thought to be a hemorrhagic cyst. Endometrial biopsy is benign.

Five weeks later, repeat US reveals that the mass has increased in size to 5.6×5.3×4.3 cm. It now appears complex in nature, with smooth walls and a single solid projection. The patient’s CA-125 level is 15 U/mL, which is in the normal range.

How should the mass be managed?

This scenario isn’t uncommon: Approximately one in every 10 women undergoes surgery for an adnexal mass, and an even higher percentage develop a mass that ultimately resolves or requires no surgery.¹ Most of these lesions occur in women of reproductive age and are benign, often functional. The two groups at highest risk of malignancy are prepubescent and postmenopausal females.^2,3 The rate of malignancy among prepubescent girls who have an adnexal mass is 35%; in postmenopausal women who have an adnexal mass, 30%.^2,3

In this article, we describe how to evaluate and manage an adnexal mass in perimenopausal and postmenopausal women, as well as in the pregnant population, and outline the fundamentals of excision and surgical staging. Whenever possible, we base our observations on comprehensive guidelines and reliable data.

In the case just described, the increasing size of the mass and the complex appearance on follow-up imaging justify a surgical approach. Conservative management and definitive surgical treatment are the two treatment options for any adnexal mass.

Multipronged assessment is vital

Pelvic examination alone is insufficient to accurately assess ovarian size and internal characteristics of the mass, especially in postmenopausal and obese women.⁴ Nevertheless, the pelvic exam is a critical component of evaluation and often detects pathology. Pelvic examination also can assist in determining the best route of removal, depending on the mobility and size of the mass.

US yields the most information

US is the most effective tool for evaluating pelvic structures. It helps characterize masses and differentiates uterine, ovarian, and extraovarian tissues (FIGURE). If there is a high suspicion of malignancy, the next step is computed tomography (CT) to rule out metastatic disease.

US findings that suggest a malignant process are:

• solid component, not hyperechoic; usually nodular or papillary
• thick septations (2–3 mm)
• bilaterality
• positive flow to the solid component of the mass
• ascites.⁵

If a pregnant patient requires further evaluation for an adnexal mass, she should undergo magnetic resonance imaging (MRI) without contrast, not CT, to avoid radiation exposure. Although we lack studies of the safety of contrast agents in pregnant women, animal studies have demonstrated an increased rate of miscarriage, skeletal dysplasia, and visceral abnormalities with the use of contrast.⁶

FIGURE The complex nature of a mass comes to light via ultrasonography

This complex mass of the right ovary, seen from different vantage points in A and B, contains multiple cysts and septations. Minimal blood flow is apparent in C.

An incidental mass may not require immediate surgery

A small (<5 cm in diameter), simple, asymptomatic mass may be followed conservatively (TABLE).⁷ Follow-up consists of repeat US, beginning within 4 to 6 weeks after detection.

Any postmenopausal woman who has a complex mass identified by US should undergo CA-125 testing and surgical excision. A mass in a premenopausal woman should also be removed if it has these characteristics—provided the mass is not functional and the complexity does not arise from hemorrhage associated with ovulation.

A program at the University of Kentucky enrolled 15,106 women older than 50 years to undergo annual transvaginal US for ovarian cancer screening.⁸ Of these, 18% were given a diagnosis of unilocular ovarian cysts, with an initial mean diameter of 2.7 cm; 69.4% of the cysts resolved spontaneously. No woman with an isolated unilocular cystic ovarian tumor developed ovarian cancer during the 6.3-year follow-up; the risk of malignancy was less than 0.1% with a 95% confidence interval. It therefore appears safe to follow small simple cysts in women of any age.

TABLE

When an adnexal mass is detected, possibilities are many

Medical therapy might facilitate regression of the mass

Conservative management might also include medical therapy. Follicular cysts are very common in menarchal and perimenopausal women, and a trial of hormones, in the form of an oral contraceptive (OC) for 4 to 6 weeks, is a common strategy to prevent new cysts by suppressing ovulation. Such a trial is appropriate only for a premenopausal woman who has a simple cyst, however. A complex mass should generally not be observed unless the complexity is thought to be the result of a physiologic process. Six weeks of OC use is long enough to cause physiologic cysts to regress and to reveal which patients should proceed to surgery.⁹

Surgical treatment, staging

A mass that is suspicious for malignancy should be removed as soon as possible. If frozen section histology confirms the diagnosis, total abdominal hysterectomy with bilateral salpingo-oophorectomy is appropriate. If the patient desires childbearing and the cancer is of low grade and confined to the ovary, unilateral oophorectomy with ipsilateral nodes and staging is appropriate.

Surgical staging of ovarian malignancy should be carried out by a gynecologic oncologist. It involves removal of all mullerian structures, bilateral pelvic and periaortic lymph node sampling, peritoneal biopsies, and cytology or biopsy of the diaphragm. If there is no evidence of gross tumor, comprehensive staging with peritoneal biopsies, lymph node dissection, and cytology of the diaphragm is crucial.

Pathologic findings may necessitate upstaging of the patient and indicate the need for chemotherapy. Approximately 20% of patients who appear to have stage I or II localized disease have occult dissemination within the abdomen.¹⁰

If there is gross disease within the abdomen, the goal of surgery is to remove it.

When should you refer?

According to guidelines from the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists, a postmenopausal woman with an adnexal mass should be referred to a gynecologic oncologist when she has one or more of the following:

• nodular or fixed mass
• elevated CA-125 level (>35 U/mL)
• ascites
• evidence of metastasis on imaging
• strong family history of breast or ovarian cancer.¹¹

A premenopausal woman should be referred if she has an adnexal mass and one or more of the following:

• elevated CA-125 (>200 U/mL)
• evidence of metastatic disease
• ascites.

Referral may also be appropriate if there is a first-degree relative with breast or ovarian cancer.¹¹

CASE 1 Resolved

After the patient is counseled about the likelihood of malignancy, she undergoes exploratory laparotomy with frozen section. The ovary ruptures, and analysis of a frozen section is consistent with mullerian adenocarcinoma.

She then undergoes total abdominal hysterectomy and bilateral salpingooophorectomy. Gynecologic oncology is consulted, and complete staging follows, including omentectomy, peritoneal biopsies, and pelvic and periaortic lymph node dissection. Pathology reveals stage IC poorly differentiated adenocarcinoma, endometrioid type. Combination chemotherapy with carboplatin and a taxane is recommended.

Selecting a surgical approach

CASE 2 Elderly patient with a complex mass

P.W., an 86-year-old gravida 9 para 4043, has an incidental adnexal mass detected during CT imaging. The left ovarian mass is complex and 7 cm in diameter at its largest point. The CA-125 level is 23 U/mL, and the carcinoembryonic antigen level is 4.5 ng/mL—both within normal range. A colonoscopy—performed as routine screening, not as part of the workup for the mass—is normal.

Because the mass is complex, surgery is indicated, and the physician prefers the laparoscopic approach—but is it reasonable?

In cases such as this, the decision is best left to the discretion of the surgeon. If the mass is mobile and small enough to fit into a bag (to prevent spillage if it ruptures), laparoscopic removal is appropriate. As in other settings, laparoscopy speeds recovery and shortens hospitalization.

Laparoscopic removal of an adnexal mass is technically similar to an open procedure. After washings are obtained and the ureter is identified, the infundibulopelvic ligament is ligated or cauterized. The broad ligament anterior to the ureter is separated from the peritoneum. The utero-ovarian ligament is then cauterized, as is the fallopian tube, and the specimen is placed in a sealed bag. The bag is then generally removed through a 10-mm port, and the specimen is sent for pathologic evaluation.

If frozen section analysis indicates that a mass is malignant, a gynecologic oncologist can stage the patient during the same procedure. This staging can be performed laparoscopically if it is technically feasible and if the surgeon feels comfortable using this approach. If it is not possible to stage the patient at the initial surgery, staging should occur within 6 weeks after the original diagnosis.

For a discussion of the advisability of laparoscopy in a pregnant patient, see below.

CASE 2 Resolved

The patient undergoes bilateral salpingo-oophorectomy via a laparoscopic approach. During the procedure, the left ovary is placed into an endoscopic specimen bag and drained to allow adequate removal through the abdominal port site; no rupture occurs. Frozen section is benign, and the final pathology report shows the mass to be a serous cystadenoma.

The pregnant patient

CASE 3 Suspicious mass with abnormal vascularity

B.E. is a 25-year-old gravida 2 para 1001 who has a pelvic mass identified during a 20-week anomaly scan. The mass involves the left ovary and is 7.1 cm in size, well circumscribed, and solid, with multiple cystic spaces and increased flow apparent on color Doppler imaging. The mass is characterized by a large degree of abnormal vascularity, and an experienced ultrasonographer describes it as “worrisome for malignancy.” MRI is performed, and the findings are consistent with those of ultrasonography but without evidence of malignant spread. Tumor markers are within normal limits, except for ß-human chorionic gonadotropin, which is elevated for the obvious reason.

Is surgery appropriate?

Gravidas develop pelvic masses at a significant rate, with a prevalence of approximately 2.3%, according to a study of 18,391 pregnant women who underwent US imaging at Washington University between 1988 and 1993.¹² The majority of patients who had an adnexal mass—76%, or 320 women—had a simple cyst that was less than 5 cm in diameter and associated with no adverse events. The other 24%, or 102 women, had a mass larger than 5 cm, either simple or complex in nature. Most masses resolved spontaneously, and only 25 required surgical removal.¹² No invasive carcinomas were found.

Despite the long odds of malignancy, an adnexal mass in pregnancy warrants close evaluation and follow-up and, occasionally, surgical management.

When is surgery justified?

Cholecystitis, appendicitis, and ovarian torsion are common diagnoses that require operative intervention regardless of gestational age.

Otherwise, when a complex adnexal mass is identified during pregnancy and is symptomatic or large enough to require removal, the gynecologist should proceed with surgery, whenever possible, in the second trimester—the most opportune time for removal. In some women, the ideal time for surgical removal of a mass detected during pregnancy is around 18 weeks’ gestation, but certainly before 24 weeks. Given the position of the gravid uterus, exploratory laparotomy is preferred over laparoscopy at this stage of gestation.

Intraoperative evaluation of the mass by pathology with frozen section is recommended. Even though immediate staging may not be feasible, owing to the pregnancy, pathology results can reassure the patient and her family and also facilitate planning of the optimal time and route of delivery.

If the mass is determined to be malignant, the patient should undergo surgical staging after completion of the pregnancy. At 37 weeks, labor should be induced, with staging performed within the next 2 to 4 weeks, or a cesarean section should be performed, with staging carried out at that time.

Laparoscopy may be feasible in the first trimester

Because laparoscopy can be difficult to perform during pregnancy, it should be used judiciously; uterine size can limit visibility and hinder safe placement of trocars. The first trimester is the least problematic period for laparoscopy.

A large study in Sweden compared laparoscopy with laparotomy between 4 and 20 weeks’ gestation and assessed fetal outcomes.¹³ In the study, 2,181 women underwent laparoscopy and 1,522 underwent laparotomy. Low birth weight (<2,500 g), intrauterine growth restriction, and delivery before 37 weeks’ gestation increased among all surgical patients, with no differences attributed to the route of the procedure. Nor were there significant differences between surgical and nonsurgical patients in either infant survival at 1 year or the incidence of fetal malformation.

As long as the anesthesiologist is aware of the pregnancy, a general surgeon can safely perform either laparoscopy or laparotomy during the first or second trimester. Care should be taken not to remove a corpus luteum before the 14th week of gestation. Pregnancy should not alter the surgeon’s preferred treatment approach at this time, unless uterine size is the limiting factor.

CASE 3 Resolved

B.E. safely undergoes exploratory laparotomy and left oophorectomy at 23-4/7 weeks’ gestation. Frozen section indicates that the mass is a malignant neoplasm. The final pathology report describes a highly unusual constellation of histologic findings, including juvenile granulosa cell tumor, dysgerminoma, and gonadoblastoma. A cesarean delivery with completion of cancer staging is planned when the fetus achieves lung maturity, with preservation of the contralateral ovary and uterus nodal sampling, peritoneal biopsies, and omentectomy.

Why? And is this state of confusion permanent? Most of all, how are your colleagues dealing with that lack of clarity in their practice?

Questions put to your peers

In early September, the Hormone Foundation, public education affiliate of the Endocrine Society, released the results of a national survey of doctors involved in menopause care.² The survey was designed to gauge the effects of the WHI on clinical practice and was conducted on behalf of the Hormone Foundation with financial support from Novogyne Pharmaceuticals. Among the findings:

• Only 15% of the physicians believe their patients’ perceptions of the risks of hormone replacement are accurate
  
• Only 18% of physicians—this includes ObGyns—report that they themselves have “no confusion at all” about the findings of the WHI
  
• 83% of physicians believe their patients are as confused now as when the WHI findings were released in 2002—or more so
  
• 81% of physicians believe the media are as, or more, confused as when the findings were released.²
  

“There’s a lot of noise,” says Nanette Santoro, MD, director of reproductive endocrinology at Albert Einstein College of Medicine, Bronx, New York, and a member of the Hormone Foundation’s Women’s Health Task Force. “And there have been a lot of arguments back and forth.”

What can a physician do to achieve a little clarity?

Staying up-to-date on the clinical practice guidelines is the best way to combat confusion, Dr. Santoro says. A good starting point, she notes, is the Hormone Foundation Web site (Hormone. org), which links to the American College of Obstetricians and Gynecologists, the American Society for Reproductive Medicine (ASRM), and the North American Menopause Society (NAMS), all of which publish reliable guidelines.

“I think that’s probably the best way of keeping abreast of what’s happening now if [physicians] are not really deeply into menopause care,” she says. “But getting filtered information, or getting information from pundits or from the media is, I think, more hazardous because the quality of that information can be variable. And the days of getting your information from pharmaceutical representatives are long gone in this area because, again, it is not sufficiently reliable.”

“Afraid of hormones”

In the years since early WHI findings were published, Anita L. Nelson, MD, has not noticed confusion so much as fear among her patients. Dr. Nelson is professor of obstetrics and gynecology at the David Geffen School of Medicine at UCLA in Los Angeles.

“I think the things that are concerning to patients by and large are breast cancer and, in women who have done more reading on it, some of them are concerned about dementia,” Dr. Nelson says. “But by and large, other than those focused issues, it is hormones that patients are afraid of, and they sort of wave their hands in this global aura of ‘badness’ that they’re afraid of.”

One reason is the WHI. “Obviously that contributed to it,” she says. But a bigger cause of fear among her patients, a large percentage of whom are referred, is the fact that “their physicians have been taking them off of therapy. They’re not offering it,” she says, “or they are putting up a sort of barrier by saying, ‘You have to go see Dr. Nelson before you can start taking those medications.’”

The problem doesn’t end there, she adds. “The sad thing is that they are by and large not offering them alternative medications while they’re waiting for the transition—or if they are, sometimes they are actually giving them hazardous drugs. One of my favorite things is when patients who have high blood pressure are denied estrogen but are given Bellergal [ergotamine, belladonna alkaloids, and phenobarbital], which has a vasoconstrictive medication in it.”

“We do want folks to review the data,” she says, noting that ObGyns are “true believers” and unlikely to quit prescribing hormone therapy (HT). It is the internists and the family medicine physicians “who still have significant misgivings about the safety of these therapies in recently menopausal women.”

Joanna Shulman, MD, agrees. She is associate professor and director of the medical student clerkship in obstetrics and gynecology at Mount Sinai School of Medicine in New York City.

“The internists I work with or that my patients see tend to be terrified of hormone therapy. So I think they tend to discourage their patients.”

Mea culpa, anyone?

Confusion over the WHI is an issue for another prominent ObGyn—Wulf H. Utian, MD, PhD, editor-in-chief of Menopause Management and executive director of NAMS. In an editorial in the September/October issue of Menopause Management, Dr. Utian faults the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) for starting a “firestorm in women’s health” by publicizing the abrupt termination of the estrogen–progestin arm of the WHI study.⁴

Utian notes that he pointed out his dismay over the WHI way back in 2002, when he wrote, again in Menopause Management: “The manner in which the study was terminated was poorly planned, abrupt, and inhumane. Predictably, the media response was enormous, ranging from thoughtful to sensational. Panic was caused, numerous women discontinued therapy, and women and their health providers alike have been thrown into a state of confusion, distrust, and quandary of what to do next.”⁴

Bruce Wineman, DO, concurs. Although he retired from practice as a reproductive endocrinologist at the Marshfield Clinic in Marshfield, Wisconsin, shortly before the WHI findings were first published, he maintains his license and stays active in the ASRM. “The worst part of the WHI is that they got so much press with it,” he says, “and that the group of women that they chose was exactly the group of women that was going to have the maximum amount of negative effect.”

Utian believes a mea culpa is in order. “There are reams of important and pertinent data coming out of all the substudies of the WHI,” he writes. “For these to be accepted with confidence, it is well time for the NIH to bring all their WHI investigators together to develop a transparent and comprehensive summary of their results. It is also time for the WHI investigators to cease their stubborn defense and misrepresentation of their 2002 data, and to return to scientific integrity.”³

Same view in the trenches

Mohamed Mitwally, MD, spends 90% of his day in clinical practice at the Reproductive Medicine and Fertility Center in Colorado Springs, Colorado. He estimates that roughly half of his perimenopausal and menopausal patients troubled by vasomotor and other symptoms are currently on HT. Since the WHI’s initial findings were published, Dr. Mitwally has “absolutely” had to spend considerably more time educating his patients—“and educating physicians,” he says. His patients are reluctant to take HT because of press attention to the WHI. And other physicians are reluctant to give HT because they understand that the WHI is a randomized trial “and so don’t question it.”

Dr. Mitwally blames two entities for this state of affairs. “The credit goes to the WHI,” he says. “They did a wonderful job of screwing people up” with a “very poorly designed study.” There is also “a lot of misinformation,” thanks to the media. “They just want to get any bad news and magnify it.”

In the wake of the WHI, Dr. Mitwally recalls, “it was like chaos” for 3 or 4 years—and there is still a lot of confusion.

Nevertheless, when a patient complains of moderate or severe vasomotor symptoms, Dr. Mitwally usually turns to HT as a first-line therapy. “It is excellent for these patients,” he says, although he emphasizes that “every patient should be managed separately.”

“I think the most important thing in the whole issue of HT is that physicians should leave these patients to subspecialists,” he says, by which he means reproductive endocrinologists and ObGyns with expertise in menopause care.

Plethora of products

One of the more surprising impacts of the WHI is the array of estrogen products now available. Because the WHI was expected to confirm observational data that suggested that estrogen reduced the risk of cardiovascular disease, the number of products in development skyrocketed.

“I think something like 35 compounds got approved while the study was under way, so there is more stuff than ever,” says Dr. Santoro. “But that actually was attractive to some people in the survey and has been found to be attractive to patients because it does give more choices the way things are going, which is toward more of a customized approach to giving hormones.”

Raksha Joshi, MD, chief medical officer and medical director of Monmouth Family Health Center in Long Branch, New Jersey, a federally funded qualified health migrant center (FQHC), says the broader array of estrogen products adds to the time she spends educating patients.

“We do tell them about the other forms of estrogen and their bioeffectiveness and what they would achieve for this particular woman,” she says.

For patients who report moderate to severe menopausal symptoms, Dr. Joshi considers estrogen a first-line therapy, but recommends concurrent lifestyle changes.

“Of course, the WHI has not disappeared,” she says, so concerns about risks remain. “But in the transition, when the symptoms are paramount, I would tailor the treatment to what the woman wants to get out of it. But I think it is important for the woman to understand that this is not a panacea and that it will not cure all her symptoms. Therefore, lifestyle changes and getting hormone replacement therapy should go concurrently.”

As for alternative therapies, women are increasingly likely to ask for or about them.

“We talk about that,” says Dr. Shulman. “If they’re miserable and they don’t think they’re appropriate candidates for estrogen, we talk about other things. Or some people will come in and say, ‘I don’t want to take estrogen. Is there anything else?’”

In these cases, Dr. Shulman recommends a number of options. “Effexor has shown some benefit, apparently, in the literature,” she says. “And I mention black cohosh, which is in a lot of popular over-the-counter type remedies and which, apparently, recently was shown to have possibly some benefit.” Of course, “there’s a tremendous placebo effect with all of these,” she observes.

“And then I suggest things like getting plenty of exercise and eating sensibly, and I take my other patients’ recommendations. One patient told me that she takes a cool shower every night before going to bed and finds it beneficial, so I don’t know—it’s one of those ‘can’t hurt, might help’ things.”

Estrogen got a “bad name”

When she looks back over the past 5 years, Dr. Shulman thinks the WHI’s effects have been destructive in many ways.

“I think the most important thing is that [HT] got an undeservedly bad name when the Women’s Health Initiative was published,” she says. The WHI “really did a disservice for women who could benefit from [HT] enormously and weren’t really at risk—not just for vasomotor symptoms but also emotional lability, depression, increased anxiety, things like that.”

“I have many women for whom I did prescribe estrogen, and they’re still on it and will probably never get off because they think that I saved their lives. So for women to be scared unfairly by the Women’s Health Initiative and to have to suffer with vasomotor and emotional problems is really a disservice.”

Dr. Wineman agrees, and points out that even some professional organizations are beginning to reconsider the initial WHI findings. “They’re beginning to say, ‘I really believe that there are certain women who would probably benefit a great deal more than we once thought, and perhaps we jumped to some wrong conclusions.’”

Why? And is this state of confusion permanent? Most of all, how are your colleagues dealing with that lack of clarity in their practice?

Questions put to your peers

In early September, the Hormone Foundation, public education affiliate of the Endocrine Society, released the results of a national survey of doctors involved in menopause care.² The survey was designed to gauge the effects of the WHI on clinical practice and was conducted on behalf of the Hormone Foundation with financial support from Novogyne Pharmaceuticals. Among the findings:

• Only 15% of the physicians believe their patients’ perceptions of the risks of hormone replacement are accurate
  
• Only 18% of physicians—this includes ObGyns—report that they themselves have “no confusion at all” about the findings of the WHI
  
• 83% of physicians believe their patients are as confused now as when the WHI findings were released in 2002—or more so
  
• 81% of physicians believe the media are as, or more, confused as when the findings were released.²
  

“There’s a lot of noise,” says Nanette Santoro, MD, director of reproductive endocrinology at Albert Einstein College of Medicine, Bronx, New York, and a member of the Hormone Foundation’s Women’s Health Task Force. “And there have been a lot of arguments back and forth.”

What can a physician do to achieve a little clarity?

Staying up-to-date on the clinical practice guidelines is the best way to combat confusion, Dr. Santoro says. A good starting point, she notes, is the Hormone Foundation Web site (Hormone. org), which links to the American College of Obstetricians and Gynecologists, the American Society for Reproductive Medicine (ASRM), and the North American Menopause Society (NAMS), all of which publish reliable guidelines.

“I think that’s probably the best way of keeping abreast of what’s happening now if [physicians] are not really deeply into menopause care,” she says. “But getting filtered information, or getting information from pundits or from the media is, I think, more hazardous because the quality of that information can be variable. And the days of getting your information from pharmaceutical representatives are long gone in this area because, again, it is not sufficiently reliable.”

“Afraid of hormones”

In the years since early WHI findings were published, Anita L. Nelson, MD, has not noticed confusion so much as fear among her patients. Dr. Nelson is professor of obstetrics and gynecology at the David Geffen School of Medicine at UCLA in Los Angeles.

“I think the things that are concerning to patients by and large are breast cancer and, in women who have done more reading on it, some of them are concerned about dementia,” Dr. Nelson says. “But by and large, other than those focused issues, it is hormones that patients are afraid of, and they sort of wave their hands in this global aura of ‘badness’ that they’re afraid of.”

One reason is the WHI. “Obviously that contributed to it,” she says. But a bigger cause of fear among her patients, a large percentage of whom are referred, is the fact that “their physicians have been taking them off of therapy. They’re not offering it,” she says, “or they are putting up a sort of barrier by saying, ‘You have to go see Dr. Nelson before you can start taking those medications.’”

The problem doesn’t end there, she adds. “The sad thing is that they are by and large not offering them alternative medications while they’re waiting for the transition—or if they are, sometimes they are actually giving them hazardous drugs. One of my favorite things is when patients who have high blood pressure are denied estrogen but are given Bellergal [ergotamine, belladonna alkaloids, and phenobarbital], which has a vasoconstrictive medication in it.”

“We do want folks to review the data,” she says, noting that ObGyns are “true believers” and unlikely to quit prescribing hormone therapy (HT). It is the internists and the family medicine physicians “who still have significant misgivings about the safety of these therapies in recently menopausal women.”

Joanna Shulman, MD, agrees. She is associate professor and director of the medical student clerkship in obstetrics and gynecology at Mount Sinai School of Medicine in New York City.

“The internists I work with or that my patients see tend to be terrified of hormone therapy. So I think they tend to discourage their patients.”

Mea culpa, anyone?

Confusion over the WHI is an issue for another prominent ObGyn—Wulf H. Utian, MD, PhD, editor-in-chief of Menopause Management and executive director of NAMS. In an editorial in the September/October issue of Menopause Management, Dr. Utian faults the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) for starting a “firestorm in women’s health” by publicizing the abrupt termination of the estrogen–progestin arm of the WHI study.⁴

Utian notes that he pointed out his dismay over the WHI way back in 2002, when he wrote, again in Menopause Management: “The manner in which the study was terminated was poorly planned, abrupt, and inhumane. Predictably, the media response was enormous, ranging from thoughtful to sensational. Panic was caused, numerous women discontinued therapy, and women and their health providers alike have been thrown into a state of confusion, distrust, and quandary of what to do next.”⁴

Bruce Wineman, DO, concurs. Although he retired from practice as a reproductive endocrinologist at the Marshfield Clinic in Marshfield, Wisconsin, shortly before the WHI findings were first published, he maintains his license and stays active in the ASRM. “The worst part of the WHI is that they got so much press with it,” he says, “and that the group of women that they chose was exactly the group of women that was going to have the maximum amount of negative effect.”

Utian believes a mea culpa is in order. “There are reams of important and pertinent data coming out of all the substudies of the WHI,” he writes. “For these to be accepted with confidence, it is well time for the NIH to bring all their WHI investigators together to develop a transparent and comprehensive summary of their results. It is also time for the WHI investigators to cease their stubborn defense and misrepresentation of their 2002 data, and to return to scientific integrity.”³

Same view in the trenches

Mohamed Mitwally, MD, spends 90% of his day in clinical practice at the Reproductive Medicine and Fertility Center in Colorado Springs, Colorado. He estimates that roughly half of his perimenopausal and menopausal patients troubled by vasomotor and other symptoms are currently on HT. Since the WHI’s initial findings were published, Dr. Mitwally has “absolutely” had to spend considerably more time educating his patients—“and educating physicians,” he says. His patients are reluctant to take HT because of press attention to the WHI. And other physicians are reluctant to give HT because they understand that the WHI is a randomized trial “and so don’t question it.”

Dr. Mitwally blames two entities for this state of affairs. “The credit goes to the WHI,” he says. “They did a wonderful job of screwing people up” with a “very poorly designed study.” There is also “a lot of misinformation,” thanks to the media. “They just want to get any bad news and magnify it.”

In the wake of the WHI, Dr. Mitwally recalls, “it was like chaos” for 3 or 4 years—and there is still a lot of confusion.

Nevertheless, when a patient complains of moderate or severe vasomotor symptoms, Dr. Mitwally usually turns to HT as a first-line therapy. “It is excellent for these patients,” he says, although he emphasizes that “every patient should be managed separately.”

“I think the most important thing in the whole issue of HT is that physicians should leave these patients to subspecialists,” he says, by which he means reproductive endocrinologists and ObGyns with expertise in menopause care.

Plethora of products

One of the more surprising impacts of the WHI is the array of estrogen products now available. Because the WHI was expected to confirm observational data that suggested that estrogen reduced the risk of cardiovascular disease, the number of products in development skyrocketed.

“I think something like 35 compounds got approved while the study was under way, so there is more stuff than ever,” says Dr. Santoro. “But that actually was attractive to some people in the survey and has been found to be attractive to patients because it does give more choices the way things are going, which is toward more of a customized approach to giving hormones.”

Raksha Joshi, MD, chief medical officer and medical director of Monmouth Family Health Center in Long Branch, New Jersey, a federally funded qualified health migrant center (FQHC), says the broader array of estrogen products adds to the time she spends educating patients.

“We do tell them about the other forms of estrogen and their bioeffectiveness and what they would achieve for this particular woman,” she says.

For patients who report moderate to severe menopausal symptoms, Dr. Joshi considers estrogen a first-line therapy, but recommends concurrent lifestyle changes.

“Of course, the WHI has not disappeared,” she says, so concerns about risks remain. “But in the transition, when the symptoms are paramount, I would tailor the treatment to what the woman wants to get out of it. But I think it is important for the woman to understand that this is not a panacea and that it will not cure all her symptoms. Therefore, lifestyle changes and getting hormone replacement therapy should go concurrently.”

As for alternative therapies, women are increasingly likely to ask for or about them.

“We talk about that,” says Dr. Shulman. “If they’re miserable and they don’t think they’re appropriate candidates for estrogen, we talk about other things. Or some people will come in and say, ‘I don’t want to take estrogen. Is there anything else?’”

In these cases, Dr. Shulman recommends a number of options. “Effexor has shown some benefit, apparently, in the literature,” she says. “And I mention black cohosh, which is in a lot of popular over-the-counter type remedies and which, apparently, recently was shown to have possibly some benefit.” Of course, “there’s a tremendous placebo effect with all of these,” she observes.

“And then I suggest things like getting plenty of exercise and eating sensibly, and I take my other patients’ recommendations. One patient told me that she takes a cool shower every night before going to bed and finds it beneficial, so I don’t know—it’s one of those ‘can’t hurt, might help’ things.”

Estrogen got a “bad name”

When she looks back over the past 5 years, Dr. Shulman thinks the WHI’s effects have been destructive in many ways.

“I think the most important thing is that [HT] got an undeservedly bad name when the Women’s Health Initiative was published,” she says. The WHI “really did a disservice for women who could benefit from [HT] enormously and weren’t really at risk—not just for vasomotor symptoms but also emotional lability, depression, increased anxiety, things like that.”

“I have many women for whom I did prescribe estrogen, and they’re still on it and will probably never get off because they think that I saved their lives. So for women to be scared unfairly by the Women’s Health Initiative and to have to suffer with vasomotor and emotional problems is really a disservice.”

Dr. Wineman agrees, and points out that even some professional organizations are beginning to reconsider the initial WHI findings. “They’re beginning to say, ‘I really believe that there are certain women who would probably benefit a great deal more than we once thought, and perhaps we jumped to some wrong conclusions.’”

Why? And is this state of confusion permanent? Most of all, how are your colleagues dealing with that lack of clarity in their practice?

Questions put to your peers

In early September, the Hormone Foundation, public education affiliate of the Endocrine Society, released the results of a national survey of doctors involved in menopause care.² The survey was designed to gauge the effects of the WHI on clinical practice and was conducted on behalf of the Hormone Foundation with financial support from Novogyne Pharmaceuticals. Among the findings:

• Only 15% of the physicians believe their patients’ perceptions of the risks of hormone replacement are accurate
  
• Only 18% of physicians—this includes ObGyns—report that they themselves have “no confusion at all” about the findings of the WHI
  
• 83% of physicians believe their patients are as confused now as when the WHI findings were released in 2002—or more so
  
• 81% of physicians believe the media are as, or more, confused as when the findings were released.²
  

“There’s a lot of noise,” says Nanette Santoro, MD, director of reproductive endocrinology at Albert Einstein College of Medicine, Bronx, New York, and a member of the Hormone Foundation’s Women’s Health Task Force. “And there have been a lot of arguments back and forth.”

What can a physician do to achieve a little clarity?

Staying up-to-date on the clinical practice guidelines is the best way to combat confusion, Dr. Santoro says. A good starting point, she notes, is the Hormone Foundation Web site (Hormone. org), which links to the American College of Obstetricians and Gynecologists, the American Society for Reproductive Medicine (ASRM), and the North American Menopause Society (NAMS), all of which publish reliable guidelines.

“I think that’s probably the best way of keeping abreast of what’s happening now if [physicians] are not really deeply into menopause care,” she says. “But getting filtered information, or getting information from pundits or from the media is, I think, more hazardous because the quality of that information can be variable. And the days of getting your information from pharmaceutical representatives are long gone in this area because, again, it is not sufficiently reliable.”

“Afraid of hormones”

In the years since early WHI findings were published, Anita L. Nelson, MD, has not noticed confusion so much as fear among her patients. Dr. Nelson is professor of obstetrics and gynecology at the David Geffen School of Medicine at UCLA in Los Angeles.

“I think the things that are concerning to patients by and large are breast cancer and, in women who have done more reading on it, some of them are concerned about dementia,” Dr. Nelson says. “But by and large, other than those focused issues, it is hormones that patients are afraid of, and they sort of wave their hands in this global aura of ‘badness’ that they’re afraid of.”

One reason is the WHI. “Obviously that contributed to it,” she says. But a bigger cause of fear among her patients, a large percentage of whom are referred, is the fact that “their physicians have been taking them off of therapy. They’re not offering it,” she says, “or they are putting up a sort of barrier by saying, ‘You have to go see Dr. Nelson before you can start taking those medications.’”

The problem doesn’t end there, she adds. “The sad thing is that they are by and large not offering them alternative medications while they’re waiting for the transition—or if they are, sometimes they are actually giving them hazardous drugs. One of my favorite things is when patients who have high blood pressure are denied estrogen but are given Bellergal [ergotamine, belladonna alkaloids, and phenobarbital], which has a vasoconstrictive medication in it.”

“We do want folks to review the data,” she says, noting that ObGyns are “true believers” and unlikely to quit prescribing hormone therapy (HT). It is the internists and the family medicine physicians “who still have significant misgivings about the safety of these therapies in recently menopausal women.”

Joanna Shulman, MD, agrees. She is associate professor and director of the medical student clerkship in obstetrics and gynecology at Mount Sinai School of Medicine in New York City.

“The internists I work with or that my patients see tend to be terrified of hormone therapy. So I think they tend to discourage their patients.”

Mea culpa, anyone?

Confusion over the WHI is an issue for another prominent ObGyn—Wulf H. Utian, MD, PhD, editor-in-chief of Menopause Management and executive director of NAMS. In an editorial in the September/October issue of Menopause Management, Dr. Utian faults the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) for starting a “firestorm in women’s health” by publicizing the abrupt termination of the estrogen–progestin arm of the WHI study.⁴

Utian notes that he pointed out his dismay over the WHI way back in 2002, when he wrote, again in Menopause Management: “The manner in which the study was terminated was poorly planned, abrupt, and inhumane. Predictably, the media response was enormous, ranging from thoughtful to sensational. Panic was caused, numerous women discontinued therapy, and women and their health providers alike have been thrown into a state of confusion, distrust, and quandary of what to do next.”⁴

Bruce Wineman, DO, concurs. Although he retired from practice as a reproductive endocrinologist at the Marshfield Clinic in Marshfield, Wisconsin, shortly before the WHI findings were first published, he maintains his license and stays active in the ASRM. “The worst part of the WHI is that they got so much press with it,” he says, “and that the group of women that they chose was exactly the group of women that was going to have the maximum amount of negative effect.”

Utian believes a mea culpa is in order. “There are reams of important and pertinent data coming out of all the substudies of the WHI,” he writes. “For these to be accepted with confidence, it is well time for the NIH to bring all their WHI investigators together to develop a transparent and comprehensive summary of their results. It is also time for the WHI investigators to cease their stubborn defense and misrepresentation of their 2002 data, and to return to scientific integrity.”³

Same view in the trenches

Mohamed Mitwally, MD, spends 90% of his day in clinical practice at the Reproductive Medicine and Fertility Center in Colorado Springs, Colorado. He estimates that roughly half of his perimenopausal and menopausal patients troubled by vasomotor and other symptoms are currently on HT. Since the WHI’s initial findings were published, Dr. Mitwally has “absolutely” had to spend considerably more time educating his patients—“and educating physicians,” he says. His patients are reluctant to take HT because of press attention to the WHI. And other physicians are reluctant to give HT because they understand that the WHI is a randomized trial “and so don’t question it.”

Dr. Mitwally blames two entities for this state of affairs. “The credit goes to the WHI,” he says. “They did a wonderful job of screwing people up” with a “very poorly designed study.” There is also “a lot of misinformation,” thanks to the media. “They just want to get any bad news and magnify it.”

In the wake of the WHI, Dr. Mitwally recalls, “it was like chaos” for 3 or 4 years—and there is still a lot of confusion.

Nevertheless, when a patient complains of moderate or severe vasomotor symptoms, Dr. Mitwally usually turns to HT as a first-line therapy. “It is excellent for these patients,” he says, although he emphasizes that “every patient should be managed separately.”

“I think the most important thing in the whole issue of HT is that physicians should leave these patients to subspecialists,” he says, by which he means reproductive endocrinologists and ObGyns with expertise in menopause care.

Plethora of products

One of the more surprising impacts of the WHI is the array of estrogen products now available. Because the WHI was expected to confirm observational data that suggested that estrogen reduced the risk of cardiovascular disease, the number of products in development skyrocketed.

“I think something like 35 compounds got approved while the study was under way, so there is more stuff than ever,” says Dr. Santoro. “But that actually was attractive to some people in the survey and has been found to be attractive to patients because it does give more choices the way things are going, which is toward more of a customized approach to giving hormones.”

Raksha Joshi, MD, chief medical officer and medical director of Monmouth Family Health Center in Long Branch, New Jersey, a federally funded qualified health migrant center (FQHC), says the broader array of estrogen products adds to the time she spends educating patients.

“We do tell them about the other forms of estrogen and their bioeffectiveness and what they would achieve for this particular woman,” she says.

For patients who report moderate to severe menopausal symptoms, Dr. Joshi considers estrogen a first-line therapy, but recommends concurrent lifestyle changes.

“Of course, the WHI has not disappeared,” she says, so concerns about risks remain. “But in the transition, when the symptoms are paramount, I would tailor the treatment to what the woman wants to get out of it. But I think it is important for the woman to understand that this is not a panacea and that it will not cure all her symptoms. Therefore, lifestyle changes and getting hormone replacement therapy should go concurrently.”

As for alternative therapies, women are increasingly likely to ask for or about them.

“We talk about that,” says Dr. Shulman. “If they’re miserable and they don’t think they’re appropriate candidates for estrogen, we talk about other things. Or some people will come in and say, ‘I don’t want to take estrogen. Is there anything else?’”

In these cases, Dr. Shulman recommends a number of options. “Effexor has shown some benefit, apparently, in the literature,” she says. “And I mention black cohosh, which is in a lot of popular over-the-counter type remedies and which, apparently, recently was shown to have possibly some benefit.” Of course, “there’s a tremendous placebo effect with all of these,” she observes.

“And then I suggest things like getting plenty of exercise and eating sensibly, and I take my other patients’ recommendations. One patient told me that she takes a cool shower every night before going to bed and finds it beneficial, so I don’t know—it’s one of those ‘can’t hurt, might help’ things.”

Estrogen got a “bad name”

When she looks back over the past 5 years, Dr. Shulman thinks the WHI’s effects have been destructive in many ways.

“I think the most important thing is that [HT] got an undeservedly bad name when the Women’s Health Initiative was published,” she says. The WHI “really did a disservice for women who could benefit from [HT] enormously and weren’t really at risk—not just for vasomotor symptoms but also emotional lability, depression, increased anxiety, things like that.”

“I have many women for whom I did prescribe estrogen, and they’re still on it and will probably never get off because they think that I saved their lives. So for women to be scared unfairly by the Women’s Health Initiative and to have to suffer with vasomotor and emotional problems is really a disservice.”

Dr. Wineman agrees, and points out that even some professional organizations are beginning to reconsider the initial WHI findings. “They’re beginning to say, ‘I really believe that there are certain women who would probably benefit a great deal more than we once thought, and perhaps we jumped to some wrong conclusions.’”