Andrew M. Kaunitz, MD

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

In February 2013, the FDA approved ospemifeme (Osphena 60 mg tablets, Shionogi Inc, Florham Park, NJ), an orally administered tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women.¹ As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in other tissues.

In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.² Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia and active or prior venous thromboembolism (VTE), stroke, or myocardial infarction.³ Although ospemifene has an estrogen-agonist impact on the endometrium, no cases of endometrial cancer were noted in clinical trials (the longest of which was 12 months).⁴ Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%, respectively), and muscle spasms (3.2% vs 0.9%, respectively).²

Women today have greater expectations regarding sexuality during their menopausal years. However, fewer menopausal women are using hormone therapy, leading to an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women. Ospemifene may be of particular appeal for symptomatic women who prefer not to use estrogen vaginal cream, tablets, or the vaginal ring. However, in contrast to vaginal estrogen therapy, ospemifene increases hot flushes and may (like tamoxifen and raloxifene) increase the risk of VTE. As with vaginal estrogen, package labeling does not specifically recommend the use of progestin with ospemifene to prevent endometrial neoplasia in women with an intact uterus. However, and again, as with vaginal estrogen, endometrial monitoring should be considered in long-term users, and any vaginal bleeding occurring in users should be evaluated.

Use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the package labeling indicates, “Osphena [ospemifene] 60 mg has not been adequately studied in women with breast cancer…”³ Accordingly, the FDA’s guidance is that, as with vaginal estrogen, ospemifene “…should not be used in women with known or suspected breast cancer or with a history of breast cancer.”¹

In February 2013, the FDA approved ospemifeme (Osphena 60 mg tablets, Shionogi Inc, Florham Park, NJ), an orally administered tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women.¹ As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in other tissues.

In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.² Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia and active or prior venous thromboembolism (VTE), stroke, or myocardial infarction.³ Although ospemifene has an estrogen-agonist impact on the endometrium, no cases of endometrial cancer were noted in clinical trials (the longest of which was 12 months).⁴ Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%, respectively), and muscle spasms (3.2% vs 0.9%, respectively).²

Women today have greater expectations regarding sexuality during their menopausal years. However, fewer menopausal women are using hormone therapy, leading to an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women. Ospemifene may be of particular appeal for symptomatic women who prefer not to use estrogen vaginal cream, tablets, or the vaginal ring. However, in contrast to vaginal estrogen therapy, ospemifene increases hot flushes and may (like tamoxifen and raloxifene) increase the risk of VTE. As with vaginal estrogen, package labeling does not specifically recommend the use of progestin with ospemifene to prevent endometrial neoplasia in women with an intact uterus. However, and again, as with vaginal estrogen, endometrial monitoring should be considered in long-term users, and any vaginal bleeding occurring in users should be evaluated.

Use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the package labeling indicates, “Osphena [ospemifene] 60 mg has not been adequately studied in women with breast cancer…”³ Accordingly, the FDA’s guidance is that, as with vaginal estrogen, ospemifene “…should not be used in women with known or suspected breast cancer or with a history of breast cancer.”¹

In February 2013, the FDA approved ospemifeme (Osphena 60 mg tablets, Shionogi Inc, Florham Park, NJ), an orally administered tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women.¹ As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in other tissues.

In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.² Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia and active or prior venous thromboembolism (VTE), stroke, or myocardial infarction.³ Although ospemifene has an estrogen-agonist impact on the endometrium, no cases of endometrial cancer were noted in clinical trials (the longest of which was 12 months).⁴ Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%, respectively), and muscle spasms (3.2% vs 0.9%, respectively).²

Women today have greater expectations regarding sexuality during their menopausal years. However, fewer menopausal women are using hormone therapy, leading to an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women. Ospemifene may be of particular appeal for symptomatic women who prefer not to use estrogen vaginal cream, tablets, or the vaginal ring. However, in contrast to vaginal estrogen therapy, ospemifene increases hot flushes and may (like tamoxifen and raloxifene) increase the risk of VTE. As with vaginal estrogen, package labeling does not specifically recommend the use of progestin with ospemifene to prevent endometrial neoplasia in women with an intact uterus. However, and again, as with vaginal estrogen, endometrial monitoring should be considered in long-term users, and any vaginal bleeding occurring in users should be evaluated.

Use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the package labeling indicates, “Osphena [ospemifene] 60 mg has not been adequately studied in women with breast cancer…”³ Accordingly, the FDA’s guidance is that, as with vaginal estrogen, ospemifene “…should not be used in women with known or suspected breast cancer or with a history of breast cancer.”¹

Read Examining the Evidence: Is “overdiagnosis” of breast cancer common among women screened by mammography? by Dr. Kaunitz (January 2013)

Read Examining the Evidence: Is “overdiagnosis” of breast cancer common among women screened by mammography? by Dr. Kaunitz (January 2013)

Read Examining the Evidence: Is “overdiagnosis” of breast cancer common among women screened by mammography? by Dr. Kaunitz (January 2013)

To reduce deaths from cancer, screening should achieve two goals:

• It should lead to earlier detection of tumors likely to be fatal
• It should lead to better outcomes after treatment of these tumors.

In other words, effective screening increases the incidence of cancers identified at an early stage (when they have a better prognosis) as it reduces the incidence of malignancies detected at a late stage.

This study found that although screening does indeed increase the rate of detection of early-stage cancers, it reduces the diagnosis of late-stage malignancies only marginally.

Details of the trial

Using SEER data from 1976 through 2008, Bleyer and Welch looked for trends in the incidence of breast cancer—both early-stage malignancies (ductal carcinoma in situ and localized disease) and late-stage disease (regional and distant cancers)—among women aged 40 years or older. They also calculated the baseline incidence of breast cancer before screening using data from 1973, the first year that the rate of breast cancer was recorded. Because the incidence of breast cancer that year was “almost certainly spuriously low,” they also incorporated data from 1974 and 1975, when the rate of breast cancer was higher than average following the diagnosis of breast cancer in First Lady Betty Ford.

Bleyer and Welch also took measures to adjust for the higher incidence of breast cancer associated with the use of menopausal hormone therapy. To do so, they estimated the current incidence of breast cancer using data from 2006 through 2008, and they adjusted data for each year that the rate of breast cancer exceeded that figure from 1990 through 2005.

From 1976 through 2008, the rate of detection of early-stage disease more than doubled, increasing from 112 to 234 cancers per 100,000 women, while the detection of late-stage disease incrementally decreased, from 102 to 94 cancers per 100,000 women. Assuming a “constant underlying disease burden,” Bleyer and Welch estimated that only eight of the 122 additional early-stage cancers identified through screening were destined to progress to advanced disease. That means that 114 excess cases of breast cancer were detected per 100,000 women.

The number of women affected by overdiagnosis: an estimated 1.3 million, including more than 70,000 women in 2008 alone.

During the 30 years covered by this study, breast cancer deaths declined 28% among women aged 40 years and older (a population in which screening mammography was prevalent); among women younger than age 40 (a population in which screening was not prevalent), breast cancer mortality declined 42%. These declines are thought to be the result, largely, of advances in treatment.

Harms versus benefits of early detection

There is no question that screening mammography saves lives by promoting early diagnosis of breast cancer. However, as I stated above, the decline in breast cancer deaths identified in this study may be attributable more to improvements in treatment than to early diagnosis of breast cancer. This study also suggests that the benefits of screening mammography are overshadowed by the harms (including unnecessary diagnostic imaging, biopsies, surgery, chemotherapy, and radiation therapy) associated with overdiagnosis. From this perspective, a screening strategy for average-risk women in which mammography is initiated later, and is performed less frequently, would appear prudent. Accordingly, rather than adhere to guidelines from ACOG and other groups that recommend that screening be initiated earlier and performed annually, it makes more sense in average-risk women to follow the 2009 guidelines from the US Preventive Services Task Force, which recommend:

• biennial screening mammography for women aged 50 to 74 years
• biennial screening mammography before the age of 50 years only if, after counseling about the potential benefits and risks, the patient chooses this option.¹

How these findings compare with other data

Three studies shed light on the efficacy of screening mammography in other populations. In an investigation from Norway, Kalager and colleagues examined the breast cancer mortality rate in four groups of women:

• those who lived in counties where screening mammography was performed during the years 1996 through 2005
• those who lived in counties where screening mammography was not performed (1996–2005)
• two historical comparison groups (1986–1995) that mirrored the first two groups.²

Their analysis of 40,075 women with breast cancer suggested that one-third of the reduction in breast cancer deaths during the time periods studied was the direct result of screening, whereas the bulk of the observed reduction in breast cancer mortality was attributed to greater breast cancer awareness, improved diagnostic (as opposed to screening) techniques, and enhancements in treatment.

In a look at breast cancer mortality within three pairs of European countries, Autier and colleagues concluded that screening did not directly contribute to the observed reduction in mortality.³ The country pairs were:

• Northern Ireland and the Republic of Ireland
• the Netherlands and Belgium/Flanders
• Sweden and Norway.

Each pair of countries offered comparable health-care services, had a similar prevalence of risk factors for breast cancer mortality, and experienced a similar reduction in breast cancer mortality from 1989 to 2006. However, implementation of mammography screening in these paired countries differed by approximately 10 to 15 years.

Last, in a meta-analysis from the United Kingdom, where women 50 to 70 years old are invited to be screened every 3 years, an independent panel concluded that mammography reduced breast cancer deaths but also led to overdiagnosis.⁴ Although the analysis included studies “with many limitations,” its findings suggest that one breast cancer death would be prevented for every three cases of overdiagnosis.

Improvements are expected

Thanks to a recent analysis of the breast cancer genome, in the future it may become possible to identify which breast tumors are likely to progress. Such an advance would allow clinicians to recommend treatment strategies in a highly selective fashion.⁵

We want to hear from you! Tell us what you think.

To reduce deaths from cancer, screening should achieve two goals:

• It should lead to earlier detection of tumors likely to be fatal
• It should lead to better outcomes after treatment of these tumors.

In other words, effective screening increases the incidence of cancers identified at an early stage (when they have a better prognosis) as it reduces the incidence of malignancies detected at a late stage.

This study found that although screening does indeed increase the rate of detection of early-stage cancers, it reduces the diagnosis of late-stage malignancies only marginally.

Details of the trial

Using SEER data from 1976 through 2008, Bleyer and Welch looked for trends in the incidence of breast cancer—both early-stage malignancies (ductal carcinoma in situ and localized disease) and late-stage disease (regional and distant cancers)—among women aged 40 years or older. They also calculated the baseline incidence of breast cancer before screening using data from 1973, the first year that the rate of breast cancer was recorded. Because the incidence of breast cancer that year was “almost certainly spuriously low,” they also incorporated data from 1974 and 1975, when the rate of breast cancer was higher than average following the diagnosis of breast cancer in First Lady Betty Ford.

Bleyer and Welch also took measures to adjust for the higher incidence of breast cancer associated with the use of menopausal hormone therapy. To do so, they estimated the current incidence of breast cancer using data from 2006 through 2008, and they adjusted data for each year that the rate of breast cancer exceeded that figure from 1990 through 2005.

From 1976 through 2008, the rate of detection of early-stage disease more than doubled, increasing from 112 to 234 cancers per 100,000 women, while the detection of late-stage disease incrementally decreased, from 102 to 94 cancers per 100,000 women. Assuming a “constant underlying disease burden,” Bleyer and Welch estimated that only eight of the 122 additional early-stage cancers identified through screening were destined to progress to advanced disease. That means that 114 excess cases of breast cancer were detected per 100,000 women.

The number of women affected by overdiagnosis: an estimated 1.3 million, including more than 70,000 women in 2008 alone.

During the 30 years covered by this study, breast cancer deaths declined 28% among women aged 40 years and older (a population in which screening mammography was prevalent); among women younger than age 40 (a population in which screening was not prevalent), breast cancer mortality declined 42%. These declines are thought to be the result, largely, of advances in treatment.

Harms versus benefits of early detection

There is no question that screening mammography saves lives by promoting early diagnosis of breast cancer. However, as I stated above, the decline in breast cancer deaths identified in this study may be attributable more to improvements in treatment than to early diagnosis of breast cancer. This study also suggests that the benefits of screening mammography are overshadowed by the harms (including unnecessary diagnostic imaging, biopsies, surgery, chemotherapy, and radiation therapy) associated with overdiagnosis. From this perspective, a screening strategy for average-risk women in which mammography is initiated later, and is performed less frequently, would appear prudent. Accordingly, rather than adhere to guidelines from ACOG and other groups that recommend that screening be initiated earlier and performed annually, it makes more sense in average-risk women to follow the 2009 guidelines from the US Preventive Services Task Force, which recommend:

• biennial screening mammography for women aged 50 to 74 years
• biennial screening mammography before the age of 50 years only if, after counseling about the potential benefits and risks, the patient chooses this option.¹

How these findings compare with other data

Three studies shed light on the efficacy of screening mammography in other populations. In an investigation from Norway, Kalager and colleagues examined the breast cancer mortality rate in four groups of women:

• those who lived in counties where screening mammography was performed during the years 1996 through 2005
• those who lived in counties where screening mammography was not performed (1996–2005)
• two historical comparison groups (1986–1995) that mirrored the first two groups.²

Their analysis of 40,075 women with breast cancer suggested that one-third of the reduction in breast cancer deaths during the time periods studied was the direct result of screening, whereas the bulk of the observed reduction in breast cancer mortality was attributed to greater breast cancer awareness, improved diagnostic (as opposed to screening) techniques, and enhancements in treatment.

In a look at breast cancer mortality within three pairs of European countries, Autier and colleagues concluded that screening did not directly contribute to the observed reduction in mortality.³ The country pairs were:

• Northern Ireland and the Republic of Ireland
• the Netherlands and Belgium/Flanders
• Sweden and Norway.

Each pair of countries offered comparable health-care services, had a similar prevalence of risk factors for breast cancer mortality, and experienced a similar reduction in breast cancer mortality from 1989 to 2006. However, implementation of mammography screening in these paired countries differed by approximately 10 to 15 years.

Last, in a meta-analysis from the United Kingdom, where women 50 to 70 years old are invited to be screened every 3 years, an independent panel concluded that mammography reduced breast cancer deaths but also led to overdiagnosis.⁴ Although the analysis included studies “with many limitations,” its findings suggest that one breast cancer death would be prevented for every three cases of overdiagnosis.

Improvements are expected

Thanks to a recent analysis of the breast cancer genome, in the future it may become possible to identify which breast tumors are likely to progress. Such an advance would allow clinicians to recommend treatment strategies in a highly selective fashion.⁵

We want to hear from you! Tell us what you think.

To reduce deaths from cancer, screening should achieve two goals:

• It should lead to earlier detection of tumors likely to be fatal
• It should lead to better outcomes after treatment of these tumors.

In other words, effective screening increases the incidence of cancers identified at an early stage (when they have a better prognosis) as it reduces the incidence of malignancies detected at a late stage.

This study found that although screening does indeed increase the rate of detection of early-stage cancers, it reduces the diagnosis of late-stage malignancies only marginally.

Details of the trial

Using SEER data from 1976 through 2008, Bleyer and Welch looked for trends in the incidence of breast cancer—both early-stage malignancies (ductal carcinoma in situ and localized disease) and late-stage disease (regional and distant cancers)—among women aged 40 years or older. They also calculated the baseline incidence of breast cancer before screening using data from 1973, the first year that the rate of breast cancer was recorded. Because the incidence of breast cancer that year was “almost certainly spuriously low,” they also incorporated data from 1974 and 1975, when the rate of breast cancer was higher than average following the diagnosis of breast cancer in First Lady Betty Ford.

Bleyer and Welch also took measures to adjust for the higher incidence of breast cancer associated with the use of menopausal hormone therapy. To do so, they estimated the current incidence of breast cancer using data from 2006 through 2008, and they adjusted data for each year that the rate of breast cancer exceeded that figure from 1990 through 2005.

From 1976 through 2008, the rate of detection of early-stage disease more than doubled, increasing from 112 to 234 cancers per 100,000 women, while the detection of late-stage disease incrementally decreased, from 102 to 94 cancers per 100,000 women. Assuming a “constant underlying disease burden,” Bleyer and Welch estimated that only eight of the 122 additional early-stage cancers identified through screening were destined to progress to advanced disease. That means that 114 excess cases of breast cancer were detected per 100,000 women.

The number of women affected by overdiagnosis: an estimated 1.3 million, including more than 70,000 women in 2008 alone.

During the 30 years covered by this study, breast cancer deaths declined 28% among women aged 40 years and older (a population in which screening mammography was prevalent); among women younger than age 40 (a population in which screening was not prevalent), breast cancer mortality declined 42%. These declines are thought to be the result, largely, of advances in treatment.

Harms versus benefits of early detection

There is no question that screening mammography saves lives by promoting early diagnosis of breast cancer. However, as I stated above, the decline in breast cancer deaths identified in this study may be attributable more to improvements in treatment than to early diagnosis of breast cancer. This study also suggests that the benefits of screening mammography are overshadowed by the harms (including unnecessary diagnostic imaging, biopsies, surgery, chemotherapy, and radiation therapy) associated with overdiagnosis. From this perspective, a screening strategy for average-risk women in which mammography is initiated later, and is performed less frequently, would appear prudent. Accordingly, rather than adhere to guidelines from ACOG and other groups that recommend that screening be initiated earlier and performed annually, it makes more sense in average-risk women to follow the 2009 guidelines from the US Preventive Services Task Force, which recommend:

• biennial screening mammography for women aged 50 to 74 years
• biennial screening mammography before the age of 50 years only if, after counseling about the potential benefits and risks, the patient chooses this option.¹

How these findings compare with other data

Three studies shed light on the efficacy of screening mammography in other populations. In an investigation from Norway, Kalager and colleagues examined the breast cancer mortality rate in four groups of women:

• those who lived in counties where screening mammography was performed during the years 1996 through 2005
• those who lived in counties where screening mammography was not performed (1996–2005)
• two historical comparison groups (1986–1995) that mirrored the first two groups.²

Their analysis of 40,075 women with breast cancer suggested that one-third of the reduction in breast cancer deaths during the time periods studied was the direct result of screening, whereas the bulk of the observed reduction in breast cancer mortality was attributed to greater breast cancer awareness, improved diagnostic (as opposed to screening) techniques, and enhancements in treatment.

In a look at breast cancer mortality within three pairs of European countries, Autier and colleagues concluded that screening did not directly contribute to the observed reduction in mortality.³ The country pairs were:

• Northern Ireland and the Republic of Ireland
• the Netherlands and Belgium/Flanders
• Sweden and Norway.

Each pair of countries offered comparable health-care services, had a similar prevalence of risk factors for breast cancer mortality, and experienced a similar reduction in breast cancer mortality from 1989 to 2006. However, implementation of mammography screening in these paired countries differed by approximately 10 to 15 years.

Last, in a meta-analysis from the United Kingdom, where women 50 to 70 years old are invited to be screened every 3 years, an independent panel concluded that mammography reduced breast cancer deaths but also led to overdiagnosis.⁴ Although the analysis included studies “with many limitations,” its findings suggest that one breast cancer death would be prevented for every three cases of overdiagnosis.

Improvements are expected

Thanks to a recent analysis of the breast cancer genome, in the future it may become possible to identify which breast tumors are likely to progress. Such an advance would allow clinicians to recommend treatment strategies in a highly selective fashion.⁵

We want to hear from you! Tell us what you think.

Although robotic gynecologic surgery has been approved by the US Food and Drug Administration, evidence of its effectiveness is limited. Of the studies that have been conducted, many found no benefit or only slight benefit for the robot, compared with laparoscopic surgery. Nevertheless, the use of the robot in gynecologic surgery has spread rapidly, accounting for more than 200,000 operations in 2009.

In the United States, many patients derive information on the robot from hospital Web sites. In this study, Schiavone and colleagues analyzed the content of these sites for quality and accuracy of information.

Details of the study

Investigators focused on hospitals that had more than 200 beds, settling on 432 institutions in New York, Pennsylvania, Illinois, Georgia, and California. Of these hospitals, 192 (44.4%) featured information about robotic gynecologic surgery on their Web sites.

Manufacturer-based images and text and robot brand names were found in 64.1%, 24.0%, and 32.3% of Web sites, respectively. Of the 192 hospitals with information about the robot on their Web sites, more than 75% reported that robotic surgery is associated with less pain (88.0% of Web sites), a shorter recovery (91.2%), and less blood loss (76.0%). A reduced incidence of scarring (75.0% of Web sites) and infection (58.3%) were also mentioned frequently.

Robotic surgery was described as better overall or as the most effective surgical approach in 41.2% and 26.0% of Web sites, respectively. However, fewer than 50% of Web sites identified the comparison group (laparoscopic or open surgery). The percentage of sites that featured evidence-based data, the cost of the robotic approach, and operative times was 14.6%, 3.7%, and 2.7%, respectively.

Randomized trials paint a different picture

Results from randomized trials of gynecologic surgery have indicated that the benefits of the robotic approach are limited, whereas cost and operative times are increased. For example, in a single-center, blinded, randomized trial of 78 patients undergoing sacrocolpopexy for vaginal prolapse, Paraiso and colleagues found a longer operating time for robotic surgery (a difference of 67 minutes between robotic and laparoscopic sacrocolpopexy; 95% confidence interval [CI], 43–89; P <.001), as well as greater postoperative pain (necessitating use of nonsteroidal anti-inflammatory drugs for a median of 20 days vs 11 days; P <.005) and higher cost (a difference of $1,936; 95% CI, $417–$3,454; P = .008). The groups had equivalent outcomes 1 year after surgery.¹

In a randomized, controlled trial of 95 women undergoing hysterectomy, the robotic approach was associated with a longer mean operative time than the laparoscopic approach (106 vs 75 minutes), but produced similar results in other measures (blood loss, complications, analgesic use, and return to activity).²

Although most patients trust the health information provided by hospitals, this study indicates that much of the Web-based information on robotic gynecologic surgery is not backed by sound evidence and is influenced by the manufacturer. This approach to promoting the robot drives up the cost of health care and misleads patients.

We want to hear from you! Tell us what you think.

Although robotic gynecologic surgery has been approved by the US Food and Drug Administration, evidence of its effectiveness is limited. Of the studies that have been conducted, many found no benefit or only slight benefit for the robot, compared with laparoscopic surgery. Nevertheless, the use of the robot in gynecologic surgery has spread rapidly, accounting for more than 200,000 operations in 2009.

In the United States, many patients derive information on the robot from hospital Web sites. In this study, Schiavone and colleagues analyzed the content of these sites for quality and accuracy of information.

Details of the study

Investigators focused on hospitals that had more than 200 beds, settling on 432 institutions in New York, Pennsylvania, Illinois, Georgia, and California. Of these hospitals, 192 (44.4%) featured information about robotic gynecologic surgery on their Web sites.

Manufacturer-based images and text and robot brand names were found in 64.1%, 24.0%, and 32.3% of Web sites, respectively. Of the 192 hospitals with information about the robot on their Web sites, more than 75% reported that robotic surgery is associated with less pain (88.0% of Web sites), a shorter recovery (91.2%), and less blood loss (76.0%). A reduced incidence of scarring (75.0% of Web sites) and infection (58.3%) were also mentioned frequently.

Robotic surgery was described as better overall or as the most effective surgical approach in 41.2% and 26.0% of Web sites, respectively. However, fewer than 50% of Web sites identified the comparison group (laparoscopic or open surgery). The percentage of sites that featured evidence-based data, the cost of the robotic approach, and operative times was 14.6%, 3.7%, and 2.7%, respectively.

Randomized trials paint a different picture

Results from randomized trials of gynecologic surgery have indicated that the benefits of the robotic approach are limited, whereas cost and operative times are increased. For example, in a single-center, blinded, randomized trial of 78 patients undergoing sacrocolpopexy for vaginal prolapse, Paraiso and colleagues found a longer operating time for robotic surgery (a difference of 67 minutes between robotic and laparoscopic sacrocolpopexy; 95% confidence interval [CI], 43–89; P <.001), as well as greater postoperative pain (necessitating use of nonsteroidal anti-inflammatory drugs for a median of 20 days vs 11 days; P <.005) and higher cost (a difference of $1,936; 95% CI, $417–$3,454; P = .008). The groups had equivalent outcomes 1 year after surgery.¹

In a randomized, controlled trial of 95 women undergoing hysterectomy, the robotic approach was associated with a longer mean operative time than the laparoscopic approach (106 vs 75 minutes), but produced similar results in other measures (blood loss, complications, analgesic use, and return to activity).²

Although most patients trust the health information provided by hospitals, this study indicates that much of the Web-based information on robotic gynecologic surgery is not backed by sound evidence and is influenced by the manufacturer. This approach to promoting the robot drives up the cost of health care and misleads patients.

We want to hear from you! Tell us what you think.

Although robotic gynecologic surgery has been approved by the US Food and Drug Administration, evidence of its effectiveness is limited. Of the studies that have been conducted, many found no benefit or only slight benefit for the robot, compared with laparoscopic surgery. Nevertheless, the use of the robot in gynecologic surgery has spread rapidly, accounting for more than 200,000 operations in 2009.

In the United States, many patients derive information on the robot from hospital Web sites. In this study, Schiavone and colleagues analyzed the content of these sites for quality and accuracy of information.

Details of the study

Investigators focused on hospitals that had more than 200 beds, settling on 432 institutions in New York, Pennsylvania, Illinois, Georgia, and California. Of these hospitals, 192 (44.4%) featured information about robotic gynecologic surgery on their Web sites.

Manufacturer-based images and text and robot brand names were found in 64.1%, 24.0%, and 32.3% of Web sites, respectively. Of the 192 hospitals with information about the robot on their Web sites, more than 75% reported that robotic surgery is associated with less pain (88.0% of Web sites), a shorter recovery (91.2%), and less blood loss (76.0%). A reduced incidence of scarring (75.0% of Web sites) and infection (58.3%) were also mentioned frequently.

Robotic surgery was described as better overall or as the most effective surgical approach in 41.2% and 26.0% of Web sites, respectively. However, fewer than 50% of Web sites identified the comparison group (laparoscopic or open surgery). The percentage of sites that featured evidence-based data, the cost of the robotic approach, and operative times was 14.6%, 3.7%, and 2.7%, respectively.

Randomized trials paint a different picture

Results from randomized trials of gynecologic surgery have indicated that the benefits of the robotic approach are limited, whereas cost and operative times are increased. For example, in a single-center, blinded, randomized trial of 78 patients undergoing sacrocolpopexy for vaginal prolapse, Paraiso and colleagues found a longer operating time for robotic surgery (a difference of 67 minutes between robotic and laparoscopic sacrocolpopexy; 95% confidence interval [CI], 43–89; P <.001), as well as greater postoperative pain (necessitating use of nonsteroidal anti-inflammatory drugs for a median of 20 days vs 11 days; P <.005) and higher cost (a difference of $1,936; 95% CI, $417–$3,454; P = .008). The groups had equivalent outcomes 1 year after surgery.¹

In a randomized, controlled trial of 95 women undergoing hysterectomy, the robotic approach was associated with a longer mean operative time than the laparoscopic approach (106 vs 75 minutes), but produced similar results in other measures (blood loss, complications, analgesic use, and return to activity).²

Although most patients trust the health information provided by hospitals, this study indicates that much of the Web-based information on robotic gynecologic surgery is not backed by sound evidence and is influenced by the manufacturer. This approach to promoting the robot drives up the cost of health care and misleads patients.

We want to hear from you! Tell us what you think.

Several studies have suggested that the risk of preterm birth increases after treatment for CIN. For example, a meta-analysis of 27 studies found a relative risk (RR) of preterm delivery of 1.70 after treatment for CIN (95% confidence interval [CI], 1.24–2.35).¹ Later studies from Nordic countries estimated the RR at 1.8 to 2.8.^2,3

In the United Kingdom, women who have abnormal findings at the time of cervical cancer screening are referred to clinics that specialize in the assessment and management of CIN. At these clinics, colposcopy and punch cervical biopsy are used to evaluate patients. When treatment is warranted, loop electrosurgical excision procedures (LEEP) are the most common intervention.

Details of the study

Investigators focused on two groups of women referred to large colposcopy clinics (more than 550 new patients annually) between 1987 and 2009:

• untreated group: those who underwent punch biopsy only
• treatment group: those who had an excisional procedure.

Women were followed both retrospectively (previous births) and prospectively (subsequent births) to assess gestational age at delivery. The risk of preterm birth (<37 weeks) was compared between groups.

Among women who delivered after colposcopy, the risk of preterm birth was significantly higher in the treatment group than in the untreated group (adjusted RR, 1.19; P<.05). However, when investigators focused on births prior to colposcopy, the risk of preterm delivery was significantly higher in women who were subsequently treated than in those who were untreated (RR, 1.31; P<.05).

Among untreated women who had a birth prior to evaluation for CIN, the risk of preterm delivery in the subsequent pregnancy was marginally, though significantly, higher than the risk associated with the delivery prior to biopsy (RR, 1.14; P<.05). However, among treated women, the risk of preterm delivery was marginally lower after treatment, compared with their risk in the pregnancy before treatment (RR, 0.94; P>.05).

Expertise of the physician may play a role
in the risk of preterm birth

This study’s finding of a higher risk of preterm birth after treatment, compared with before treatment, would seem to support earlier studies that show an increased risk of preterm birth after LEEP. However, the finding that women destined to undergo treatment of CIN had a higher rate of preterm delivery before that treatment is surprising. And the fact that women who gave birth both before and after treatment had no elevated risk of preterm delivery in the later pregnancy is even more startling.

So what are we to make of these data? They suggest that, at least among women receiving care at high-volume specialty clinics in England, the treatment of CIN does not increase the risk of preterm delivery. Castanon and colleagues hypothesize that the clinicians who work in these clinics may remove less tissue during treatment than other clinicians do, minimizing the risk of later preterm delivery.

A cervical cancer screening expert weighs in

Tom Cox, MD, is past president of ASCCP, the Society for Lower Genital Tract Disease, and a widely published expert on cervical cancer screening. He is also an OBG Management Contributing Editor. When asked for his take on the conclusions of Castanon and colleagues, he agreed that the data are highly credible.

“The findings are different than most of the world literature on this subject,” he continued, “and it may be indeed, as the authors suggest, due to less tissue being removed during surgical excision procedures in England, compared with other countries. If that is true, it may be because colposcopists in the United Kingdom receive a higher level of training and are subject to more rigorous quality control than we have in the United States and in other countries—although most of the studies demonstrating odds ratios of 2 to 3 for preterm birth following treatment have been conducted in Scandinavian countries known for their high-quality medical care.”

Castanon and colleagues are at work on Phase 2 of this study, and Dr. Cox anticipates that its findings will help determine why CIN treatment did not increase the risk of preterm delivery.

“Although colposcopy training is far less rigorous in the United States, and quality control is virtually lacking, it has been thought that, in general, the size of cervical excisions in the United States are likely to have been smaller than in the United Kingdom, where large loop excision of the T-zone (LLETZ), using larger loops than with LEEP, has been common. So it will be interesting to see the authors’ promised Phase 2 article, which compares the size of the excision with outcomes.

We want to hear from you! Tell us what you think.

Several studies have suggested that the risk of preterm birth increases after treatment for CIN. For example, a meta-analysis of 27 studies found a relative risk (RR) of preterm delivery of 1.70 after treatment for CIN (95% confidence interval [CI], 1.24–2.35).¹ Later studies from Nordic countries estimated the RR at 1.8 to 2.8.^2,3

In the United Kingdom, women who have abnormal findings at the time of cervical cancer screening are referred to clinics that specialize in the assessment and management of CIN. At these clinics, colposcopy and punch cervical biopsy are used to evaluate patients. When treatment is warranted, loop electrosurgical excision procedures (LEEP) are the most common intervention.

Details of the study

Investigators focused on two groups of women referred to large colposcopy clinics (more than 550 new patients annually) between 1987 and 2009:

• untreated group: those who underwent punch biopsy only
• treatment group: those who had an excisional procedure.

Women were followed both retrospectively (previous births) and prospectively (subsequent births) to assess gestational age at delivery. The risk of preterm birth (<37 weeks) was compared between groups.

Among women who delivered after colposcopy, the risk of preterm birth was significantly higher in the treatment group than in the untreated group (adjusted RR, 1.19; P<.05). However, when investigators focused on births prior to colposcopy, the risk of preterm delivery was significantly higher in women who were subsequently treated than in those who were untreated (RR, 1.31; P<.05).

Among untreated women who had a birth prior to evaluation for CIN, the risk of preterm delivery in the subsequent pregnancy was marginally, though significantly, higher than the risk associated with the delivery prior to biopsy (RR, 1.14; P<.05). However, among treated women, the risk of preterm delivery was marginally lower after treatment, compared with their risk in the pregnancy before treatment (RR, 0.94; P>.05).

Expertise of the physician may play a role
in the risk of preterm birth

This study’s finding of a higher risk of preterm birth after treatment, compared with before treatment, would seem to support earlier studies that show an increased risk of preterm birth after LEEP. However, the finding that women destined to undergo treatment of CIN had a higher rate of preterm delivery before that treatment is surprising. And the fact that women who gave birth both before and after treatment had no elevated risk of preterm delivery in the later pregnancy is even more startling.

So what are we to make of these data? They suggest that, at least among women receiving care at high-volume specialty clinics in England, the treatment of CIN does not increase the risk of preterm delivery. Castanon and colleagues hypothesize that the clinicians who work in these clinics may remove less tissue during treatment than other clinicians do, minimizing the risk of later preterm delivery.

A cervical cancer screening expert weighs in

Tom Cox, MD, is past president of ASCCP, the Society for Lower Genital Tract Disease, and a widely published expert on cervical cancer screening. He is also an OBG Management Contributing Editor. When asked for his take on the conclusions of Castanon and colleagues, he agreed that the data are highly credible.

“The findings are different than most of the world literature on this subject,” he continued, “and it may be indeed, as the authors suggest, due to less tissue being removed during surgical excision procedures in England, compared with other countries. If that is true, it may be because colposcopists in the United Kingdom receive a higher level of training and are subject to more rigorous quality control than we have in the United States and in other countries—although most of the studies demonstrating odds ratios of 2 to 3 for preterm birth following treatment have been conducted in Scandinavian countries known for their high-quality medical care.”

Castanon and colleagues are at work on Phase 2 of this study, and Dr. Cox anticipates that its findings will help determine why CIN treatment did not increase the risk of preterm delivery.

“Although colposcopy training is far less rigorous in the United States, and quality control is virtually lacking, it has been thought that, in general, the size of cervical excisions in the United States are likely to have been smaller than in the United Kingdom, where large loop excision of the T-zone (LLETZ), using larger loops than with LEEP, has been common. So it will be interesting to see the authors’ promised Phase 2 article, which compares the size of the excision with outcomes.

We want to hear from you! Tell us what you think.

Several studies have suggested that the risk of preterm birth increases after treatment for CIN. For example, a meta-analysis of 27 studies found a relative risk (RR) of preterm delivery of 1.70 after treatment for CIN (95% confidence interval [CI], 1.24–2.35).¹ Later studies from Nordic countries estimated the RR at 1.8 to 2.8.^2,3

In the United Kingdom, women who have abnormal findings at the time of cervical cancer screening are referred to clinics that specialize in the assessment and management of CIN. At these clinics, colposcopy and punch cervical biopsy are used to evaluate patients. When treatment is warranted, loop electrosurgical excision procedures (LEEP) are the most common intervention.

Details of the study

Investigators focused on two groups of women referred to large colposcopy clinics (more than 550 new patients annually) between 1987 and 2009:

• untreated group: those who underwent punch biopsy only
• treatment group: those who had an excisional procedure.

Women were followed both retrospectively (previous births) and prospectively (subsequent births) to assess gestational age at delivery. The risk of preterm birth (<37 weeks) was compared between groups.

Among women who delivered after colposcopy, the risk of preterm birth was significantly higher in the treatment group than in the untreated group (adjusted RR, 1.19; P<.05). However, when investigators focused on births prior to colposcopy, the risk of preterm delivery was significantly higher in women who were subsequently treated than in those who were untreated (RR, 1.31; P<.05).

Among untreated women who had a birth prior to evaluation for CIN, the risk of preterm delivery in the subsequent pregnancy was marginally, though significantly, higher than the risk associated with the delivery prior to biopsy (RR, 1.14; P<.05). However, among treated women, the risk of preterm delivery was marginally lower after treatment, compared with their risk in the pregnancy before treatment (RR, 0.94; P>.05).

Expertise of the physician may play a role
in the risk of preterm birth

This study’s finding of a higher risk of preterm birth after treatment, compared with before treatment, would seem to support earlier studies that show an increased risk of preterm birth after LEEP. However, the finding that women destined to undergo treatment of CIN had a higher rate of preterm delivery before that treatment is surprising. And the fact that women who gave birth both before and after treatment had no elevated risk of preterm delivery in the later pregnancy is even more startling.

So what are we to make of these data? They suggest that, at least among women receiving care at high-volume specialty clinics in England, the treatment of CIN does not increase the risk of preterm delivery. Castanon and colleagues hypothesize that the clinicians who work in these clinics may remove less tissue during treatment than other clinicians do, minimizing the risk of later preterm delivery.

A cervical cancer screening expert weighs in

Tom Cox, MD, is past president of ASCCP, the Society for Lower Genital Tract Disease, and a widely published expert on cervical cancer screening. He is also an OBG Management Contributing Editor. When asked for his take on the conclusions of Castanon and colleagues, he agreed that the data are highly credible.

“The findings are different than most of the world literature on this subject,” he continued, “and it may be indeed, as the authors suggest, due to less tissue being removed during surgical excision procedures in England, compared with other countries. If that is true, it may be because colposcopists in the United Kingdom receive a higher level of training and are subject to more rigorous quality control than we have in the United States and in other countries—although most of the studies demonstrating odds ratios of 2 to 3 for preterm birth following treatment have been conducted in Scandinavian countries known for their high-quality medical care.”

Castanon and colleagues are at work on Phase 2 of this study, and Dr. Cox anticipates that its findings will help determine why CIN treatment did not increase the risk of preterm delivery.

“Although colposcopy training is far less rigorous in the United States, and quality control is virtually lacking, it has been thought that, in general, the size of cervical excisions in the United States are likely to have been smaller than in the United Kingdom, where large loop excision of the T-zone (LLETZ), using larger loops than with LEEP, has been common. So it will be interesting to see the authors’ promised Phase 2 article, which compares the size of the excision with outcomes.

We want to hear from you! Tell us what you think.

Because half of US pregnancies continue to be unintended, rates of induced abortion in our patients remain high. In addition, unintended pregnancies lead to negative health and social consequences for women and infants. This recent report from the Contraceptive Choice Project, spearheaded by Dr. Jeffrey Peipert from the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, and published in New England Journal of Medicine underscores the high efficacy of long-acting reversible contraceptives, a term referring to IUDs and the contraceptive implant, in preventing unintended pregnancy in a US population.

Details of the study

Eligibility in the Project included age 14 to 45 years, residence in the St. Louis, Missouri, area, and the need for contraception. The woman’s contraceptive of choice was made available at no charge, with most women choosing a long-acting method. The published study includes outcomes for 7,486 women who used OCs, the patch, the ring, an IUD, implant, or depot medroxyprogesterone acetate (DMPA) injections.

Among women using OCs, the patch, or the ring, the pregnancy rate was 4.55 per 100 participant-years. This rate was nearly 22-fold higher than that observed in women using IUDs or the implant (hazard ratio, 21.8; 95% confidence interval, 13.7–34.9): that rate was 0.27 per 100 participant-years. A similar low rate of pregnancy was noted among women who chose DMPA and returned every 3 months for follow-up injections.

Among women younger than 21 years who used OCs, the patch, or the ring, the rate of unintended pregnancy was twice as high as in older women using these same methods. By contrast, regardless of age, pregnancy rates were uniformly low among women using long-acting methods.

Study limitations

The authors point out that their study design was not randomized—participants were at high risk for unintended pregnancy and willing to begin using a new contraceptive method, which could have resulted in higher adherence rates and lower failure rates.

Access is ongoing barrier to use

These important data from the Contraceptive Choice Project clarify that long-acting reversible contraceptives represent powerful tools to help women minimize unintended pregnancy and induced abortion, and that women will choose these methods if they are accessible.

The findings in this report also make it clear that rates of unintended pregnancy are particularly high among adolescents using shorter-acting hormonal contraceptives (OCs, patch, or ring) and that longer-acting contraceptives are particularly useful in our younger patients. Other recent reports have provided clear evidence that immediately providing long-acting contraceptives after childbirth or induced abortion reduces unintended pregnancy in these settings.^1,2

In the United States, inadequate access to long-acting reversible contraceptives continues to constrain use. Accordingly, insurance policies that fully cover longer-acting contraceptives could go a long way toward reducing the rate of unintended pregnancies and induced abortions in our patients.

If long-acting reversible contraceptives become more available in the United States, I look forward to a time when the great majority of our patients’ pregnancies are planned and when far fewer women will face the troubling prospect of an induced abortion.

We want to hear from you! Tell us what you think.

Because half of US pregnancies continue to be unintended, rates of induced abortion in our patients remain high. In addition, unintended pregnancies lead to negative health and social consequences for women and infants. This recent report from the Contraceptive Choice Project, spearheaded by Dr. Jeffrey Peipert from the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, and published in New England Journal of Medicine underscores the high efficacy of long-acting reversible contraceptives, a term referring to IUDs and the contraceptive implant, in preventing unintended pregnancy in a US population.

Details of the study

Eligibility in the Project included age 14 to 45 years, residence in the St. Louis, Missouri, area, and the need for contraception. The woman’s contraceptive of choice was made available at no charge, with most women choosing a long-acting method. The published study includes outcomes for 7,486 women who used OCs, the patch, the ring, an IUD, implant, or depot medroxyprogesterone acetate (DMPA) injections.

Among women using OCs, the patch, or the ring, the pregnancy rate was 4.55 per 100 participant-years. This rate was nearly 22-fold higher than that observed in women using IUDs or the implant (hazard ratio, 21.8; 95% confidence interval, 13.7–34.9): that rate was 0.27 per 100 participant-years. A similar low rate of pregnancy was noted among women who chose DMPA and returned every 3 months for follow-up injections.

Among women younger than 21 years who used OCs, the patch, or the ring, the rate of unintended pregnancy was twice as high as in older women using these same methods. By contrast, regardless of age, pregnancy rates were uniformly low among women using long-acting methods.

Study limitations

The authors point out that their study design was not randomized—participants were at high risk for unintended pregnancy and willing to begin using a new contraceptive method, which could have resulted in higher adherence rates and lower failure rates.

Access is ongoing barrier to use

These important data from the Contraceptive Choice Project clarify that long-acting reversible contraceptives represent powerful tools to help women minimize unintended pregnancy and induced abortion, and that women will choose these methods if they are accessible.

The findings in this report also make it clear that rates of unintended pregnancy are particularly high among adolescents using shorter-acting hormonal contraceptives (OCs, patch, or ring) and that longer-acting contraceptives are particularly useful in our younger patients. Other recent reports have provided clear evidence that immediately providing long-acting contraceptives after childbirth or induced abortion reduces unintended pregnancy in these settings.^1,2

In the United States, inadequate access to long-acting reversible contraceptives continues to constrain use. Accordingly, insurance policies that fully cover longer-acting contraceptives could go a long way toward reducing the rate of unintended pregnancies and induced abortions in our patients.

If long-acting reversible contraceptives become more available in the United States, I look forward to a time when the great majority of our patients’ pregnancies are planned and when far fewer women will face the troubling prospect of an induced abortion.

We want to hear from you! Tell us what you think.

Because half of US pregnancies continue to be unintended, rates of induced abortion in our patients remain high. In addition, unintended pregnancies lead to negative health and social consequences for women and infants. This recent report from the Contraceptive Choice Project, spearheaded by Dr. Jeffrey Peipert from the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, and published in New England Journal of Medicine underscores the high efficacy of long-acting reversible contraceptives, a term referring to IUDs and the contraceptive implant, in preventing unintended pregnancy in a US population.

Details of the study

Eligibility in the Project included age 14 to 45 years, residence in the St. Louis, Missouri, area, and the need for contraception. The woman’s contraceptive of choice was made available at no charge, with most women choosing a long-acting method. The published study includes outcomes for 7,486 women who used OCs, the patch, the ring, an IUD, implant, or depot medroxyprogesterone acetate (DMPA) injections.

Among women using OCs, the patch, or the ring, the pregnancy rate was 4.55 per 100 participant-years. This rate was nearly 22-fold higher than that observed in women using IUDs or the implant (hazard ratio, 21.8; 95% confidence interval, 13.7–34.9): that rate was 0.27 per 100 participant-years. A similar low rate of pregnancy was noted among women who chose DMPA and returned every 3 months for follow-up injections.

Among women younger than 21 years who used OCs, the patch, or the ring, the rate of unintended pregnancy was twice as high as in older women using these same methods. By contrast, regardless of age, pregnancy rates were uniformly low among women using long-acting methods.

Study limitations

The authors point out that their study design was not randomized—participants were at high risk for unintended pregnancy and willing to begin using a new contraceptive method, which could have resulted in higher adherence rates and lower failure rates.

Access is ongoing barrier to use

These important data from the Contraceptive Choice Project clarify that long-acting reversible contraceptives represent powerful tools to help women minimize unintended pregnancy and induced abortion, and that women will choose these methods if they are accessible.

The findings in this report also make it clear that rates of unintended pregnancy are particularly high among adolescents using shorter-acting hormonal contraceptives (OCs, patch, or ring) and that longer-acting contraceptives are particularly useful in our younger patients. Other recent reports have provided clear evidence that immediately providing long-acting contraceptives after childbirth or induced abortion reduces unintended pregnancy in these settings.^1,2

In the United States, inadequate access to long-acting reversible contraceptives continues to constrain use. Accordingly, insurance policies that fully cover longer-acting contraceptives could go a long way toward reducing the rate of unintended pregnancies and induced abortions in our patients.

If long-acting reversible contraceptives become more available in the United States, I look forward to a time when the great majority of our patients’ pregnancies are planned and when far fewer women will face the troubling prospect of an induced abortion.

We want to hear from you! Tell us what you think.

Important developments in the care of menopausal women in the past 12 months include:

• new evidence about the duration, and nonhormonal management, of hot flushes
• new data on the risk of venous thromboembolism when oral and transdermal hormone therapy (HT) are compared
• trends in thinking regarding ovarian conservation at the time of hysterectomy, as well as a new report on the impact of hysterectomy on subsequent ovarian function
• a new Position Statement on HT from the North American Menopause Society.

Hot flushes can last 10 years or longer

Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol. 2011;117(5):1095–1104.

Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Arch Intern Med. 2011;171(15):1363–1369.

Hot flushes are more persistent than has been recognized

Previous reports have suggested that hot flushes, the most prevalent menopausal symptom, persist from 6 months to longer than 5 years. Freeman and colleagues carried out a prospective, population-based study in the Northeastern United States that enrolled more than 250 women (age range at enrollment, 35 to 47 years) who did not use HT. Subjects in this cohort were followed for 13 years as they progressed through menopause.

Surprisingly, the researchers found that the median duration of moderate-to-severe hot flushes was 10.2 years. Hot flushes persisted longer in black women than in white women (P = .02) and longer in non-obese women than in obese women (P = .003). Duration of symptoms was similar in smokers and nonsmokers.

Once again, soy fails to relieve menopausal symptoms

A number of clinical trials performed since the 2002 publication of the initial findings of the Women’s Health Initiative (WHI) have failed to demonstrate that soy is efficacious for treating menopausal symptoms. Nevertheless, many women remain intrigued by the potential for obtaining symptom relief with over-the-counter supplements.

Investigators in Florida randomized women who had been menopausal for at least 5 years to receive daily soy isoflavones (equivalent to about twice the amount ingested in a typical Asian diet) or placebo for 2 years. Outcomes assessed at baseline and again at 12 and at 24 months included spine and hip bone-mineral density (BMD), menopausal symptoms, and vaginal epithelial maturation. Almost 250 women (mean age, 52 years) were randomized.

At 2 years, researchers found that:

• BMD had declined at all sites by about 2% in both groups
• approximately one half of subjects in the soy group and approximately one third who were randomized to the placebo group reported experiencing hot flushes (P = .02)
• vaginal epithelial maturation did not change appreciably from baseline in either group
• constipation was reported by 31% of women in the soy group and 21% in the placebo group—a difference that only marginally achieved statistical significance.

Hormone therapy and risk of venous thromboembolism

Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause. 2011;18(10):1052–1059.

Olié V, Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause. 2011;18(5):488–493.

Transdermal HT appears to be safer than oral therapy

Yet another observational study adds evidence that venous thromboembolism (VTE) is less of a risk in women using transdermal estrogen therapy than it is in women taking oral therapy.

To compare oral and transdermal estrogen formulations in regard to the risk of VTE that they pose, Laliberte and colleagues conducted a retrospective cohort study of US and Canadian women, using health insurance claims data from women who were starting transdermal or oral estrogen. In all, 27,018 users of transdermal estrogen were matched with an equal number of oral users.

VTE was diagnosed in 115 women using transdermal estradiol and 164 women using oral estrogen. Compared with the rate in women initiating oral estrogen, women using transdermal estradiol had a significantly lower incidence of VTE than oral estrogen users (adjusted incidence rate ratio, 0.67).

Is HT safe for women who have a history of VTE?

The US Food and Drug Administration has designated a personal history of VTE as a contraindication to all estrogen and estrogen-progestin HT formulations in the package labeling for these products. Because accumulating evidence is reassuring in regard to the risk of VTE with transdermal HT, however, it seems reasonable to consider using HT in selected women who have a history of VTE.

In a retrospective cohort study, French investigators assessed the impact of oral and transdermal estrogen on the risk of recurrent VTE in 1,023 postmenopausal women who had an earlier diagnosis of VTE. During follow-up, most of the subjects did not use HT, although 103 used transdermal estrogen and 10 used oral estrogen.

Seventy-seven women experienced recurrent VTE during a mean of 79 months after discontinuing anticoagulation. Compared with non-use of estrogen therapy, use of transdermal estrogen was not significantly associated with recurrent VTE (hazard ratio [HR], 1.0); oral estrogen, however, was associated with a substantial and significantly increased risk of recurrent VTE (HR, 6.4).

Hysterectomy may accelerate the onset of menopause

Moorman PG, Myers ER, Schildkraut JM, Iversen ES, Wang F, Warren N. Effect of hysterectomy with ovarian preservation on ovarian function. Obstet Gynecol. 2011;118(6):1271–1279.

Novetsky AP, Boyd LR, Curtin JP. Trends in bilateral oophorectomy at the time of hysterectomy for benign disease. Obstet Gynecol. 2011;118(6):1280–1286.

Does hysterectomy hasten ovarian failure?

In a prospective cohort study from North Carolina, Moorman and colleagues followed 1) 406 women who did not have malignancy who underwent hysterectomy, with conservation of at least one ovary and 2) 465 women who had an intact uterus (overall age range, 30 to 47 years). Within 5 years of follow-up, ovarian failure had occurred in 60 women who had undergone a hysterectomy and in 46 women who had an intact uterus (adjusted HR, 1.9).

Ovarian failure occurred almost 2 years earlier in women who had undergone a hysterectomy than it did in those whose uterus was intact. The likelihood of ovarian failure was higher in the setting of unilateral oophorectomy than when both ovaries had been conserved.

Hysterectomy for benign disease: Are we performing fewer oophorectomies?

Investigators in New York State followed trends in concomitant bilateral oophorectomy among women undergoing hysterectomy for benign disease, from 2000 to 2006. Overall, the rate of concomitant oophorectomy declined by 8% during this period; among women younger than 55 years, the rate of oophorectomy declined by more than 10%. The rate of concomitant bilateral oophorectomy was higher among women who had a family history of breast or ovarian cancer and among those who had a personal history of breast cancer, ovarian cysts, or endometriosis.

Breaking news: NAMS updates guidance on hormone therapy

North American Menopause Society. The 2012 hormone therapy position statement of The North American Menopause Society. Menopause. 2012;19(3):257–271.

Position Statement emphasizes differences in the benefit-risk profile of estrogen–only HT and estrogen-progestin HT

Periodically, NAMS assembles a multidisciplinary panel of clinicians and researchers to evaluate new evidence about HT and reach consensus on guidance about using hormones, and then publishes a Position Statement on the subject. In March, NAMS published its updated (2012) position on HT.

Two recent, and important, analyses of data from the Women’s Health Initiative (WHI)^6,7 made an impact on the current revision to an earlier (2010) Position Statement; I had summarized those studies in the 2011 OBG Management Update on Menopause. One focused on breast cancer characteristics and mortality associated with use of combination estrogen-progestin HT; the other, outcomes after use of estrogen-only HT. Recap. Initial findings in the estrogen– progestin arm of the WHI, published in 2002,⁸ found that, after participants had used study medications (HT or placebo) for a mean of 5.2 years, their risk of invasive breast cancer was increased (HR, 1.26). This modestly elevated risk was only marginally significant (95% confidence limit, 1.00–1.59).

In 2010, investigators reported on breast cancer characteristics and mortality in WHI participants at a mean follow-up of 11 years. They found that combination HT users had breast cancer histology similar to that of subjects assigned to placebo, but that the tumors were more likely to be node-positive in combination HT users (23.7%, compared with 16.2% among placebo users). In addition, breast cancer mortality was slightly higher among users of HT (2.6 deaths, compared with 1.3 deaths, for every 10,000 woman-years of use) (HR, 1.96; 95% confidence interval [CI], 1.00–4.04); again, this elevated risk reached only marginal statistical significance.

Then, in 2011, WHI investigators reported their findings from the estrogen-alone arm of the study, in which post-menopausal, hysterectomized women were randomized to oral estrogen or placebo and took study medications for a mean of 6.8 years. (Recall that initial findings from the estrogen-only arm of WHI, published in 2004, found that the risk of invasive cancer was lower in women randomized to estrogen [HR, 0.77]—a reduction in risk that approached, but did not achieve, statistical significance [95% CI, 0.59–1.01].⁹) In the 2011 report, the lower risk of breast cancer in the estrogen group persisted; with almost 11 years mean follow-up, this prevention was found to be robust and statistically significant (HR, 0.77; 95% CI, 0.62–0.95).

The sobering increased risk of advanced-stage tumors and the marginally higher likelihood of fatal breast cancer associated with use of estrogen–progestin HT stands in stark contrast with the significant reduction in breast cancer associated with estrogen- only HT.

Accordingly, NAMS has modified its guidance. To step back for a moment, in the abstract of its 2010 Position Statement, NAMS had concluded that:

• Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable for women who initiate HT close to menopause but decreases in older women and with time since menopause in previously untreated women.

Contrast that with the conclusion in the abstract of the Society’s 2012 Position Statement:

• Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms and to prevent osteoporosis in women at high risk of fracture. The more favorable benefit-risk ratio for ET allows more flexibility in extending duration of use compared to EPT where the earlier appearance of increased breast cancer risk precludes a recommendation for use beyond 3 to 5 years.

We want to hear from you! Tell us what you think.

Important developments in the care of menopausal women in the past 12 months include:

• new evidence about the duration, and nonhormonal management, of hot flushes
• new data on the risk of venous thromboembolism when oral and transdermal hormone therapy (HT) are compared
• trends in thinking regarding ovarian conservation at the time of hysterectomy, as well as a new report on the impact of hysterectomy on subsequent ovarian function
• a new Position Statement on HT from the North American Menopause Society.

Hot flushes can last 10 years or longer

Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol. 2011;117(5):1095–1104.

Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Arch Intern Med. 2011;171(15):1363–1369.

Hot flushes are more persistent than has been recognized

Previous reports have suggested that hot flushes, the most prevalent menopausal symptom, persist from 6 months to longer than 5 years. Freeman and colleagues carried out a prospective, population-based study in the Northeastern United States that enrolled more than 250 women (age range at enrollment, 35 to 47 years) who did not use HT. Subjects in this cohort were followed for 13 years as they progressed through menopause.

Surprisingly, the researchers found that the median duration of moderate-to-severe hot flushes was 10.2 years. Hot flushes persisted longer in black women than in white women (P = .02) and longer in non-obese women than in obese women (P = .003). Duration of symptoms was similar in smokers and nonsmokers.

Once again, soy fails to relieve menopausal symptoms

A number of clinical trials performed since the 2002 publication of the initial findings of the Women’s Health Initiative (WHI) have failed to demonstrate that soy is efficacious for treating menopausal symptoms. Nevertheless, many women remain intrigued by the potential for obtaining symptom relief with over-the-counter supplements.

Investigators in Florida randomized women who had been menopausal for at least 5 years to receive daily soy isoflavones (equivalent to about twice the amount ingested in a typical Asian diet) or placebo for 2 years. Outcomes assessed at baseline and again at 12 and at 24 months included spine and hip bone-mineral density (BMD), menopausal symptoms, and vaginal epithelial maturation. Almost 250 women (mean age, 52 years) were randomized.

At 2 years, researchers found that:

• BMD had declined at all sites by about 2% in both groups
• approximately one half of subjects in the soy group and approximately one third who were randomized to the placebo group reported experiencing hot flushes (P = .02)
• vaginal epithelial maturation did not change appreciably from baseline in either group
• constipation was reported by 31% of women in the soy group and 21% in the placebo group—a difference that only marginally achieved statistical significance.

Hormone therapy and risk of venous thromboembolism

Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause. 2011;18(10):1052–1059.

Olié V, Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause. 2011;18(5):488–493.

Transdermal HT appears to be safer than oral therapy

Yet another observational study adds evidence that venous thromboembolism (VTE) is less of a risk in women using transdermal estrogen therapy than it is in women taking oral therapy.

To compare oral and transdermal estrogen formulations in regard to the risk of VTE that they pose, Laliberte and colleagues conducted a retrospective cohort study of US and Canadian women, using health insurance claims data from women who were starting transdermal or oral estrogen. In all, 27,018 users of transdermal estrogen were matched with an equal number of oral users.

VTE was diagnosed in 115 women using transdermal estradiol and 164 women using oral estrogen. Compared with the rate in women initiating oral estrogen, women using transdermal estradiol had a significantly lower incidence of VTE than oral estrogen users (adjusted incidence rate ratio, 0.67).

Is HT safe for women who have a history of VTE?

The US Food and Drug Administration has designated a personal history of VTE as a contraindication to all estrogen and estrogen-progestin HT formulations in the package labeling for these products. Because accumulating evidence is reassuring in regard to the risk of VTE with transdermal HT, however, it seems reasonable to consider using HT in selected women who have a history of VTE.

In a retrospective cohort study, French investigators assessed the impact of oral and transdermal estrogen on the risk of recurrent VTE in 1,023 postmenopausal women who had an earlier diagnosis of VTE. During follow-up, most of the subjects did not use HT, although 103 used transdermal estrogen and 10 used oral estrogen.

Seventy-seven women experienced recurrent VTE during a mean of 79 months after discontinuing anticoagulation. Compared with non-use of estrogen therapy, use of transdermal estrogen was not significantly associated with recurrent VTE (hazard ratio [HR], 1.0); oral estrogen, however, was associated with a substantial and significantly increased risk of recurrent VTE (HR, 6.4).

Hysterectomy may accelerate the onset of menopause

Moorman PG, Myers ER, Schildkraut JM, Iversen ES, Wang F, Warren N. Effect of hysterectomy with ovarian preservation on ovarian function. Obstet Gynecol. 2011;118(6):1271–1279.

Novetsky AP, Boyd LR, Curtin JP. Trends in bilateral oophorectomy at the time of hysterectomy for benign disease. Obstet Gynecol. 2011;118(6):1280–1286.

Does hysterectomy hasten ovarian failure?

In a prospective cohort study from North Carolina, Moorman and colleagues followed 1) 406 women who did not have malignancy who underwent hysterectomy, with conservation of at least one ovary and 2) 465 women who had an intact uterus (overall age range, 30 to 47 years). Within 5 years of follow-up, ovarian failure had occurred in 60 women who had undergone a hysterectomy and in 46 women who had an intact uterus (adjusted HR, 1.9).

Ovarian failure occurred almost 2 years earlier in women who had undergone a hysterectomy than it did in those whose uterus was intact. The likelihood of ovarian failure was higher in the setting of unilateral oophorectomy than when both ovaries had been conserved.

Hysterectomy for benign disease: Are we performing fewer oophorectomies?

Investigators in New York State followed trends in concomitant bilateral oophorectomy among women undergoing hysterectomy for benign disease, from 2000 to 2006. Overall, the rate of concomitant oophorectomy declined by 8% during this period; among women younger than 55 years, the rate of oophorectomy declined by more than 10%. The rate of concomitant bilateral oophorectomy was higher among women who had a family history of breast or ovarian cancer and among those who had a personal history of breast cancer, ovarian cysts, or endometriosis.

Breaking news: NAMS updates guidance on hormone therapy

North American Menopause Society. The 2012 hormone therapy position statement of The North American Menopause Society. Menopause. 2012;19(3):257–271.

Position Statement emphasizes differences in the benefit-risk profile of estrogen–only HT and estrogen-progestin HT

Periodically, NAMS assembles a multidisciplinary panel of clinicians and researchers to evaluate new evidence about HT and reach consensus on guidance about using hormones, and then publishes a Position Statement on the subject. In March, NAMS published its updated (2012) position on HT.

Two recent, and important, analyses of data from the Women’s Health Initiative (WHI)^6,7 made an impact on the current revision to an earlier (2010) Position Statement; I had summarized those studies in the 2011 OBG Management Update on Menopause. One focused on breast cancer characteristics and mortality associated with use of combination estrogen-progestin HT; the other, outcomes after use of estrogen-only HT. Recap. Initial findings in the estrogen– progestin arm of the WHI, published in 2002,⁸ found that, after participants had used study medications (HT or placebo) for a mean of 5.2 years, their risk of invasive breast cancer was increased (HR, 1.26). This modestly elevated risk was only marginally significant (95% confidence limit, 1.00–1.59).

In 2010, investigators reported on breast cancer characteristics and mortality in WHI participants at a mean follow-up of 11 years. They found that combination HT users had breast cancer histology similar to that of subjects assigned to placebo, but that the tumors were more likely to be node-positive in combination HT users (23.7%, compared with 16.2% among placebo users). In addition, breast cancer mortality was slightly higher among users of HT (2.6 deaths, compared with 1.3 deaths, for every 10,000 woman-years of use) (HR, 1.96; 95% confidence interval [CI], 1.00–4.04); again, this elevated risk reached only marginal statistical significance.

Then, in 2011, WHI investigators reported their findings from the estrogen-alone arm of the study, in which post-menopausal, hysterectomized women were randomized to oral estrogen or placebo and took study medications for a mean of 6.8 years. (Recall that initial findings from the estrogen-only arm of WHI, published in 2004, found that the risk of invasive cancer was lower in women randomized to estrogen [HR, 0.77]—a reduction in risk that approached, but did not achieve, statistical significance [95% CI, 0.59–1.01].⁹) In the 2011 report, the lower risk of breast cancer in the estrogen group persisted; with almost 11 years mean follow-up, this prevention was found to be robust and statistically significant (HR, 0.77; 95% CI, 0.62–0.95).

The sobering increased risk of advanced-stage tumors and the marginally higher likelihood of fatal breast cancer associated with use of estrogen–progestin HT stands in stark contrast with the significant reduction in breast cancer associated with estrogen- only HT.

Accordingly, NAMS has modified its guidance. To step back for a moment, in the abstract of its 2010 Position Statement, NAMS had concluded that:

• Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable for women who initiate HT close to menopause but decreases in older women and with time since menopause in previously untreated women.

Contrast that with the conclusion in the abstract of the Society’s 2012 Position Statement:

• Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms and to prevent osteoporosis in women at high risk of fracture. The more favorable benefit-risk ratio for ET allows more flexibility in extending duration of use compared to EPT where the earlier appearance of increased breast cancer risk precludes a recommendation for use beyond 3 to 5 years.

We want to hear from you! Tell us what you think.

Important developments in the care of menopausal women in the past 12 months include:

• new evidence about the duration, and nonhormonal management, of hot flushes
• new data on the risk of venous thromboembolism when oral and transdermal hormone therapy (HT) are compared
• trends in thinking regarding ovarian conservation at the time of hysterectomy, as well as a new report on the impact of hysterectomy on subsequent ovarian function
• a new Position Statement on HT from the North American Menopause Society.

Hot flushes can last 10 years or longer

Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol. 2011;117(5):1095–1104.

Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Arch Intern Med. 2011;171(15):1363–1369.

Hot flushes are more persistent than has been recognized

Previous reports have suggested that hot flushes, the most prevalent menopausal symptom, persist from 6 months to longer than 5 years. Freeman and colleagues carried out a prospective, population-based study in the Northeastern United States that enrolled more than 250 women (age range at enrollment, 35 to 47 years) who did not use HT. Subjects in this cohort were followed for 13 years as they progressed through menopause.

Surprisingly, the researchers found that the median duration of moderate-to-severe hot flushes was 10.2 years. Hot flushes persisted longer in black women than in white women (P = .02) and longer in non-obese women than in obese women (P = .003). Duration of symptoms was similar in smokers and nonsmokers.

Once again, soy fails to relieve menopausal symptoms

A number of clinical trials performed since the 2002 publication of the initial findings of the Women’s Health Initiative (WHI) have failed to demonstrate that soy is efficacious for treating menopausal symptoms. Nevertheless, many women remain intrigued by the potential for obtaining symptom relief with over-the-counter supplements.

Investigators in Florida randomized women who had been menopausal for at least 5 years to receive daily soy isoflavones (equivalent to about twice the amount ingested in a typical Asian diet) or placebo for 2 years. Outcomes assessed at baseline and again at 12 and at 24 months included spine and hip bone-mineral density (BMD), menopausal symptoms, and vaginal epithelial maturation. Almost 250 women (mean age, 52 years) were randomized.

At 2 years, researchers found that:

• BMD had declined at all sites by about 2% in both groups
• approximately one half of subjects in the soy group and approximately one third who were randomized to the placebo group reported experiencing hot flushes (P = .02)
• vaginal epithelial maturation did not change appreciably from baseline in either group
• constipation was reported by 31% of women in the soy group and 21% in the placebo group—a difference that only marginally achieved statistical significance.

Hormone therapy and risk of venous thromboembolism

Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause. 2011;18(10):1052–1059.

Olié V, Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause. 2011;18(5):488–493.

Transdermal HT appears to be safer than oral therapy

Yet another observational study adds evidence that venous thromboembolism (VTE) is less of a risk in women using transdermal estrogen therapy than it is in women taking oral therapy.

To compare oral and transdermal estrogen formulations in regard to the risk of VTE that they pose, Laliberte and colleagues conducted a retrospective cohort study of US and Canadian women, using health insurance claims data from women who were starting transdermal or oral estrogen. In all, 27,018 users of transdermal estrogen were matched with an equal number of oral users.

VTE was diagnosed in 115 women using transdermal estradiol and 164 women using oral estrogen. Compared with the rate in women initiating oral estrogen, women using transdermal estradiol had a significantly lower incidence of VTE than oral estrogen users (adjusted incidence rate ratio, 0.67).

Is HT safe for women who have a history of VTE?

The US Food and Drug Administration has designated a personal history of VTE as a contraindication to all estrogen and estrogen-progestin HT formulations in the package labeling for these products. Because accumulating evidence is reassuring in regard to the risk of VTE with transdermal HT, however, it seems reasonable to consider using HT in selected women who have a history of VTE.

In a retrospective cohort study, French investigators assessed the impact of oral and transdermal estrogen on the risk of recurrent VTE in 1,023 postmenopausal women who had an earlier diagnosis of VTE. During follow-up, most of the subjects did not use HT, although 103 used transdermal estrogen and 10 used oral estrogen.

Seventy-seven women experienced recurrent VTE during a mean of 79 months after discontinuing anticoagulation. Compared with non-use of estrogen therapy, use of transdermal estrogen was not significantly associated with recurrent VTE (hazard ratio [HR], 1.0); oral estrogen, however, was associated with a substantial and significantly increased risk of recurrent VTE (HR, 6.4).

Hysterectomy may accelerate the onset of menopause

Moorman PG, Myers ER, Schildkraut JM, Iversen ES, Wang F, Warren N. Effect of hysterectomy with ovarian preservation on ovarian function. Obstet Gynecol. 2011;118(6):1271–1279.

Novetsky AP, Boyd LR, Curtin JP. Trends in bilateral oophorectomy at the time of hysterectomy for benign disease. Obstet Gynecol. 2011;118(6):1280–1286.

Does hysterectomy hasten ovarian failure?

In a prospective cohort study from North Carolina, Moorman and colleagues followed 1) 406 women who did not have malignancy who underwent hysterectomy, with conservation of at least one ovary and 2) 465 women who had an intact uterus (overall age range, 30 to 47 years). Within 5 years of follow-up, ovarian failure had occurred in 60 women who had undergone a hysterectomy and in 46 women who had an intact uterus (adjusted HR, 1.9).

Ovarian failure occurred almost 2 years earlier in women who had undergone a hysterectomy than it did in those whose uterus was intact. The likelihood of ovarian failure was higher in the setting of unilateral oophorectomy than when both ovaries had been conserved.

Hysterectomy for benign disease: Are we performing fewer oophorectomies?

Investigators in New York State followed trends in concomitant bilateral oophorectomy among women undergoing hysterectomy for benign disease, from 2000 to 2006. Overall, the rate of concomitant oophorectomy declined by 8% during this period; among women younger than 55 years, the rate of oophorectomy declined by more than 10%. The rate of concomitant bilateral oophorectomy was higher among women who had a family history of breast or ovarian cancer and among those who had a personal history of breast cancer, ovarian cysts, or endometriosis.

Breaking news: NAMS updates guidance on hormone therapy

North American Menopause Society. The 2012 hormone therapy position statement of The North American Menopause Society. Menopause. 2012;19(3):257–271.

Position Statement emphasizes differences in the benefit-risk profile of estrogen–only HT and estrogen-progestin HT

Periodically, NAMS assembles a multidisciplinary panel of clinicians and researchers to evaluate new evidence about HT and reach consensus on guidance about using hormones, and then publishes a Position Statement on the subject. In March, NAMS published its updated (2012) position on HT.

Two recent, and important, analyses of data from the Women’s Health Initiative (WHI)^6,7 made an impact on the current revision to an earlier (2010) Position Statement; I had summarized those studies in the 2011 OBG Management Update on Menopause. One focused on breast cancer characteristics and mortality associated with use of combination estrogen-progestin HT; the other, outcomes after use of estrogen-only HT. Recap. Initial findings in the estrogen– progestin arm of the WHI, published in 2002,⁸ found that, after participants had used study medications (HT or placebo) for a mean of 5.2 years, their risk of invasive breast cancer was increased (HR, 1.26). This modestly elevated risk was only marginally significant (95% confidence limit, 1.00–1.59).

In 2010, investigators reported on breast cancer characteristics and mortality in WHI participants at a mean follow-up of 11 years. They found that combination HT users had breast cancer histology similar to that of subjects assigned to placebo, but that the tumors were more likely to be node-positive in combination HT users (23.7%, compared with 16.2% among placebo users). In addition, breast cancer mortality was slightly higher among users of HT (2.6 deaths, compared with 1.3 deaths, for every 10,000 woman-years of use) (HR, 1.96; 95% confidence interval [CI], 1.00–4.04); again, this elevated risk reached only marginal statistical significance.

Then, in 2011, WHI investigators reported their findings from the estrogen-alone arm of the study, in which post-menopausal, hysterectomized women were randomized to oral estrogen or placebo and took study medications for a mean of 6.8 years. (Recall that initial findings from the estrogen-only arm of WHI, published in 2004, found that the risk of invasive cancer was lower in women randomized to estrogen [HR, 0.77]—a reduction in risk that approached, but did not achieve, statistical significance [95% CI, 0.59–1.01].⁹) In the 2011 report, the lower risk of breast cancer in the estrogen group persisted; with almost 11 years mean follow-up, this prevention was found to be robust and statistically significant (HR, 0.77; 95% CI, 0.62–0.95).

The sobering increased risk of advanced-stage tumors and the marginally higher likelihood of fatal breast cancer associated with use of estrogen–progestin HT stands in stark contrast with the significant reduction in breast cancer associated with estrogen- only HT.

Accordingly, NAMS has modified its guidance. To step back for a moment, in the abstract of its 2010 Position Statement, NAMS had concluded that:

• Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable for women who initiate HT close to menopause but decreases in older women and with time since menopause in previously untreated women.

Contrast that with the conclusion in the abstract of the Society’s 2012 Position Statement:

• Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms and to prevent osteoporosis in women at high risk of fracture. The more favorable benefit-risk ratio for ET allows more flexibility in extending duration of use compared to EPT where the earlier appearance of increased breast cancer risk precludes a recommendation for use beyond 3 to 5 years.

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Often used in the evaluation of early pregnancy, the hCG discriminatory zone is based on the assumption that a serum ß-hCG level exceeding 1,000–2,000 mIU/mL in a woman who has a normal intrauterine pregnancy should be accompanied by a gestational sac that is visible via transvaginal US. When such a sac is not visible in the uterus, many practitioners conclude that the pregnancy is ectopic and tailor management accordingly.

In this study of women who were assessed between the years 2000 and 2010, investigators reviewed the records of those who underwent US and hCG measurement on the same (index) day, had detectable hCG, had no US evidence of intrauterine pregnancy on the index day, and were subsequently found to have a viable intrauterine pregnancy. Among 202 women who met these criteria, the hCG level fell into the following ranges:

• below 1,000 mIU/mL (80.2%)
• 1,000–1,499 mIU/mL (9.4%)
• 1,500–1,999 mIU/mL (5.9%)
• 2,000 mIU/mL or higher (4.5%).

The highest hCG value observed was 6,567 mIU/mL; the highest level of hCG observed in a woman who later delivered a term infant was 4,336 mIU/mL.

A case for abandoning the zone?

Many clinicians (and malpractice attorneys) are familiar with unfortunate cases of women who underwent uterine curettage or were given methotrexate, based on an hCG level found to be in the discriminatory zone without accompanying evidence of intrauterine pregnancy, only to lose what was, in fact, a potentially viable pregnancy.

By demonstrating the high variability in hCG levels among women who had early intrauterine pregnancy without definitive findings on US, the authors make a strong case for abandoning the concept of the discriminatory zone altogether.

We want to hear from you! Tell us what you think.

Often used in the evaluation of early pregnancy, the hCG discriminatory zone is based on the assumption that a serum ß-hCG level exceeding 1,000–2,000 mIU/mL in a woman who has a normal intrauterine pregnancy should be accompanied by a gestational sac that is visible via transvaginal US. When such a sac is not visible in the uterus, many practitioners conclude that the pregnancy is ectopic and tailor management accordingly.

In this study of women who were assessed between the years 2000 and 2010, investigators reviewed the records of those who underwent US and hCG measurement on the same (index) day, had detectable hCG, had no US evidence of intrauterine pregnancy on the index day, and were subsequently found to have a viable intrauterine pregnancy. Among 202 women who met these criteria, the hCG level fell into the following ranges:

• below 1,000 mIU/mL (80.2%)
• 1,000–1,499 mIU/mL (9.4%)
• 1,500–1,999 mIU/mL (5.9%)
• 2,000 mIU/mL or higher (4.5%).

The highest hCG value observed was 6,567 mIU/mL; the highest level of hCG observed in a woman who later delivered a term infant was 4,336 mIU/mL.

A case for abandoning the zone?

Many clinicians (and malpractice attorneys) are familiar with unfortunate cases of women who underwent uterine curettage or were given methotrexate, based on an hCG level found to be in the discriminatory zone without accompanying evidence of intrauterine pregnancy, only to lose what was, in fact, a potentially viable pregnancy.

By demonstrating the high variability in hCG levels among women who had early intrauterine pregnancy without definitive findings on US, the authors make a strong case for abandoning the concept of the discriminatory zone altogether.

We want to hear from you! Tell us what you think.

Often used in the evaluation of early pregnancy, the hCG discriminatory zone is based on the assumption that a serum ß-hCG level exceeding 1,000–2,000 mIU/mL in a woman who has a normal intrauterine pregnancy should be accompanied by a gestational sac that is visible via transvaginal US. When such a sac is not visible in the uterus, many practitioners conclude that the pregnancy is ectopic and tailor management accordingly.

In this study of women who were assessed between the years 2000 and 2010, investigators reviewed the records of those who underwent US and hCG measurement on the same (index) day, had detectable hCG, had no US evidence of intrauterine pregnancy on the index day, and were subsequently found to have a viable intrauterine pregnancy. Among 202 women who met these criteria, the hCG level fell into the following ranges:

• below 1,000 mIU/mL (80.2%)
• 1,000–1,499 mIU/mL (9.4%)
• 1,500–1,999 mIU/mL (5.9%)
• 2,000 mIU/mL or higher (4.5%).

The highest hCG value observed was 6,567 mIU/mL; the highest level of hCG observed in a woman who later delivered a term infant was 4,336 mIU/mL.

A case for abandoning the zone?

Many clinicians (and malpractice attorneys) are familiar with unfortunate cases of women who underwent uterine curettage or were given methotrexate, based on an hCG level found to be in the discriminatory zone without accompanying evidence of intrauterine pregnancy, only to lose what was, in fact, a potentially viable pregnancy.

By demonstrating the high variability in hCG levels among women who had early intrauterine pregnancy without definitive findings on US, the authors make a strong case for abandoning the concept of the discriminatory zone altogether.

We want to hear from you! Tell us what you think.

Scant research has focused on breast cancer in very young women. This retrospective case series by investigators at the Mayo Clinic assessed girls and women younger than 25 years who were given a diagnosis of primary breast cancer between 1935 and 2005 and who received care at that institution.

The investigators highlighted many of the challenges clinicians face when a young patient presents with a lump or other signs associated with breast cancer. For example, they note that, in its early stages, breast carcinoma in young women can be similar in appearance to fibroadenoma. When a patient postpones care or a clinician dismisses the lump because of a low index of suspicion, diagnosis can be delayed. That is problematic because invasive breast carcinoma in girls and young women is more aggressive and associated with a poorer prognosis overall.

Details of the trial

Eleven women 20 to 24 years old and one 18-year-old teen were found to have breast cancer. Of these, eight of the women detected the mass themselves, one observed bloody nipple discharge associated with constitutional symptoms, and another experienced severe constitutional symptoms associated with disseminated malignancy. In one case, the physician detected a breast mass in an asymptomatic woman. Details on the remaining woman were unavailable.

Palpable masses were noted in most of the women at the time of clinical evaluation, and the median greatest diameter was 4 cm. After the original history and exam, breast cancer was suspected in only 2 of the 11 women.

Among the 11 young women who had breast cancer, one had received mantle and abdominal radiotherapy for previously diagnosed Hodgkin’s disease. Two women had a family history suggesting hereditary breast cancer. None of the women were tested for a BRCA mutation. Regional or local recurrence was identified in three women, and contralateral breast cancer was found in two women (one of whom was subsequently also found to have ovarian cancer). At the time of the last follow-up (a median of 25.5 months), four women had died as a result of breast cancer, one had died from advanced ovarian cancer, two were alive with disease, and five were alive with no evidence of disease.

We want to hear from you! Tell us what you think.

Scant research has focused on breast cancer in very young women. This retrospective case series by investigators at the Mayo Clinic assessed girls and women younger than 25 years who were given a diagnosis of primary breast cancer between 1935 and 2005 and who received care at that institution.

The investigators highlighted many of the challenges clinicians face when a young patient presents with a lump or other signs associated with breast cancer. For example, they note that, in its early stages, breast carcinoma in young women can be similar in appearance to fibroadenoma. When a patient postpones care or a clinician dismisses the lump because of a low index of suspicion, diagnosis can be delayed. That is problematic because invasive breast carcinoma in girls and young women is more aggressive and associated with a poorer prognosis overall.

Details of the trial

Eleven women 20 to 24 years old and one 18-year-old teen were found to have breast cancer. Of these, eight of the women detected the mass themselves, one observed bloody nipple discharge associated with constitutional symptoms, and another experienced severe constitutional symptoms associated with disseminated malignancy. In one case, the physician detected a breast mass in an asymptomatic woman. Details on the remaining woman were unavailable.

Palpable masses were noted in most of the women at the time of clinical evaluation, and the median greatest diameter was 4 cm. After the original history and exam, breast cancer was suspected in only 2 of the 11 women.

Among the 11 young women who had breast cancer, one had received mantle and abdominal radiotherapy for previously diagnosed Hodgkin’s disease. Two women had a family history suggesting hereditary breast cancer. None of the women were tested for a BRCA mutation. Regional or local recurrence was identified in three women, and contralateral breast cancer was found in two women (one of whom was subsequently also found to have ovarian cancer). At the time of the last follow-up (a median of 25.5 months), four women had died as a result of breast cancer, one had died from advanced ovarian cancer, two were alive with disease, and five were alive with no evidence of disease.

We want to hear from you! Tell us what you think.

Scant research has focused on breast cancer in very young women. This retrospective case series by investigators at the Mayo Clinic assessed girls and women younger than 25 years who were given a diagnosis of primary breast cancer between 1935 and 2005 and who received care at that institution.

The investigators highlighted many of the challenges clinicians face when a young patient presents with a lump or other signs associated with breast cancer. For example, they note that, in its early stages, breast carcinoma in young women can be similar in appearance to fibroadenoma. When a patient postpones care or a clinician dismisses the lump because of a low index of suspicion, diagnosis can be delayed. That is problematic because invasive breast carcinoma in girls and young women is more aggressive and associated with a poorer prognosis overall.

Details of the trial

Eleven women 20 to 24 years old and one 18-year-old teen were found to have breast cancer. Of these, eight of the women detected the mass themselves, one observed bloody nipple discharge associated with constitutional symptoms, and another experienced severe constitutional symptoms associated with disseminated malignancy. In one case, the physician detected a breast mass in an asymptomatic woman. Details on the remaining woman were unavailable.

Palpable masses were noted in most of the women at the time of clinical evaluation, and the median greatest diameter was 4 cm. After the original history and exam, breast cancer was suspected in only 2 of the 11 women.

Among the 11 young women who had breast cancer, one had received mantle and abdominal radiotherapy for previously diagnosed Hodgkin’s disease. Two women had a family history suggesting hereditary breast cancer. None of the women were tested for a BRCA mutation. Regional or local recurrence was identified in three women, and contralateral breast cancer was found in two women (one of whom was subsequently also found to have ovarian cancer). At the time of the last follow-up (a median of 25.5 months), four women had died as a result of breast cancer, one had died from advanced ovarian cancer, two were alive with disease, and five were alive with no evidence of disease.

We want to hear from you! Tell us what you think.