Andrew M. Kaunitz, MD

Although the use of intrauterine devices (IUDs) is increasing, these highly effective contraceptives remain underutilized in the United States, compared with other developed countries. Concerns about pain with insertion represent one barrier to use.

In a double-blind trial, Ngo and colleagues randomly assigned women presenting for first-time IUD placement from 2012 to 2014 to either:

• ketorolac, a potent nonsteroidal anti-inflammatory drug (NSAID) (1-mL gluteal intramuscular injection of 30 mg of ketorolac) or
• saline (1-mL saline intramuscular injection).

The injection was given 30 minutes prior to IUD placement.

Pain associated with injection of the study drug, speculum and tenaculum placement, uterine sounding, IUD placement, and postinsertion pain were measured using a visual analog scale from 0 cm (no pain) to 10 cm (worst pain possible).

Of 67 participants (mean age, approximately 27 years; white race, 33%; African-American race, 33%; median parity, 1), pain was similar between ketorolac and placebo arms for all parameters except postinsertion pain, which was 0 cm and 1.3 cm for ketorolac and placebo, respectively, 15 minutes after placement (P<.001).

Although approximately 75% of participants reported that pain from the injection was “not as bad” as the pain from IUD placement, about 1 in 5 indicated that injection pain was equivalent to pain from IUD placement. Regardless of study group allocation, more than 90% of participants reported being satisfied or very satisfied with IUD placement overall, and more than 75% said they would recommend IUD placement to a friend.

More than 90% of women were satisfied with IUD placement, regardless of study allocation

As Ngo and colleagues observe, the analgesic effect of ketorolac peaks 1 to 2 hours after injection. This observation may explain why pain reduction was noted only after IUD insertion. Although ketorolac is not expensive, logistic considerations may make its routine use prior to IUD placement unrealistic in many ambulatory settings. Further, the great majority of participants (>90%) reported being satisfied with their IUD placement experience overall, regardless of study allocation.

Earlier studies suggesting that preplacement oral NSAIDs are ineffective in reducing placement pain involved the administration of analgesia in the clinic less than 1 hour before IUD insertion. I agree with Ngo and colleagues that future trials of oral NSAIDs should focus on administration of the medication prior to arrival at the clinic.

What this evidence means for practice
Findings from this randomized controlled trial provide only limited support for injection of an NSAID prior to IUD placement.
--Andrew M. Kaunitz, MD

Although the use of intrauterine devices (IUDs) is increasing, these highly effective contraceptives remain underutilized in the United States, compared with other developed countries. Concerns about pain with insertion represent one barrier to use.

In a double-blind trial, Ngo and colleagues randomly assigned women presenting for first-time IUD placement from 2012 to 2014 to either:

• ketorolac, a potent nonsteroidal anti-inflammatory drug (NSAID) (1-mL gluteal intramuscular injection of 30 mg of ketorolac) or
• saline (1-mL saline intramuscular injection).

The injection was given 30 minutes prior to IUD placement.

Pain associated with injection of the study drug, speculum and tenaculum placement, uterine sounding, IUD placement, and postinsertion pain were measured using a visual analog scale from 0 cm (no pain) to 10 cm (worst pain possible).

Of 67 participants (mean age, approximately 27 years; white race, 33%; African-American race, 33%; median parity, 1), pain was similar between ketorolac and placebo arms for all parameters except postinsertion pain, which was 0 cm and 1.3 cm for ketorolac and placebo, respectively, 15 minutes after placement (P<.001).

Although approximately 75% of participants reported that pain from the injection was “not as bad” as the pain from IUD placement, about 1 in 5 indicated that injection pain was equivalent to pain from IUD placement. Regardless of study group allocation, more than 90% of participants reported being satisfied or very satisfied with IUD placement overall, and more than 75% said they would recommend IUD placement to a friend.

More than 90% of women were satisfied with IUD placement, regardless of study allocation

As Ngo and colleagues observe, the analgesic effect of ketorolac peaks 1 to 2 hours after injection. This observation may explain why pain reduction was noted only after IUD insertion. Although ketorolac is not expensive, logistic considerations may make its routine use prior to IUD placement unrealistic in many ambulatory settings. Further, the great majority of participants (>90%) reported being satisfied with their IUD placement experience overall, regardless of study allocation.

Earlier studies suggesting that preplacement oral NSAIDs are ineffective in reducing placement pain involved the administration of analgesia in the clinic less than 1 hour before IUD insertion. I agree with Ngo and colleagues that future trials of oral NSAIDs should focus on administration of the medication prior to arrival at the clinic.

What this evidence means for practice
Findings from this randomized controlled trial provide only limited support for injection of an NSAID prior to IUD placement.
--Andrew M. Kaunitz, MD

Although the use of intrauterine devices (IUDs) is increasing, these highly effective contraceptives remain underutilized in the United States, compared with other developed countries. Concerns about pain with insertion represent one barrier to use.

In a double-blind trial, Ngo and colleagues randomly assigned women presenting for first-time IUD placement from 2012 to 2014 to either:

• ketorolac, a potent nonsteroidal anti-inflammatory drug (NSAID) (1-mL gluteal intramuscular injection of 30 mg of ketorolac) or
• saline (1-mL saline intramuscular injection).

The injection was given 30 minutes prior to IUD placement.

Pain associated with injection of the study drug, speculum and tenaculum placement, uterine sounding, IUD placement, and postinsertion pain were measured using a visual analog scale from 0 cm (no pain) to 10 cm (worst pain possible).

Of 67 participants (mean age, approximately 27 years; white race, 33%; African-American race, 33%; median parity, 1), pain was similar between ketorolac and placebo arms for all parameters except postinsertion pain, which was 0 cm and 1.3 cm for ketorolac and placebo, respectively, 15 minutes after placement (P<.001).

Although approximately 75% of participants reported that pain from the injection was “not as bad” as the pain from IUD placement, about 1 in 5 indicated that injection pain was equivalent to pain from IUD placement. Regardless of study group allocation, more than 90% of participants reported being satisfied or very satisfied with IUD placement overall, and more than 75% said they would recommend IUD placement to a friend.

More than 90% of women were satisfied with IUD placement, regardless of study allocation

As Ngo and colleagues observe, the analgesic effect of ketorolac peaks 1 to 2 hours after injection. This observation may explain why pain reduction was noted only after IUD insertion. Although ketorolac is not expensive, logistic considerations may make its routine use prior to IUD placement unrealistic in many ambulatory settings. Further, the great majority of participants (>90%) reported being satisfied with their IUD placement experience overall, regardless of study allocation.

Earlier studies suggesting that preplacement oral NSAIDs are ineffective in reducing placement pain involved the administration of analgesia in the clinic less than 1 hour before IUD insertion. I agree with Ngo and colleagues that future trials of oral NSAIDs should focus on administration of the medication prior to arrival at the clinic.

What this evidence means for practice
Findings from this randomized controlled trial provide only limited support for injection of an NSAID prior to IUD placement.
--Andrew M. Kaunitz, MD

“Critical Window” HT Timing Is Revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to receive conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, research published in the Journal of the American Medical Association in October 2013 details findings from a 13-year follow-up of WHI HT clinical trial participants and better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95-1.45) and 0.94 in the ET arm (95% CI, 0.78-1.14). In both arms, women given HT had reduced risk for vasomotor symptoms, hip fractures, and diabetes, and increased risk for stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 at baseline, the risk for cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk for breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11-1.48). In contrast, in the ET arm, a significantly reduced risk for breast cancer materialized (HR, 0.79; 95% CI, 0.65-0.97) (see Table).

To put into perspective the elevated risk for breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming one glass of wine daily and lower than the HR noted with two glasses daily.¹

Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk for adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women ages 50 to 59 at baseline. In the EPT arm, the risk for MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risk for stroke, VTE, and gallbladder disease.

EPT increased the risk for breast cancer in all age-groups. However, the lower absolute risks for adverse events, and generally more favorable HRs for many outcomes, in younger women resulted in substantially lower rates of adverse events attributable to HT in the younger age-group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar).

REFERENCE
1. Chen WY, Rosner B, Hankinson SE, et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):1884-190.

Continue for ACOG Guidance on menopausal symptoms >>

ACOG Guidance on Menopausal Symptoms
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-216.

Despite findings from new studies, optimal ­management of menopausal symptoms remains controversial. In January 2014, ACOG issued ­guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.¹ Along with many of the clinicians reading this update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

“The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk­-benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, the American College of Obstetricians and Gynecologists recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized, based on each woman’s risk-benefit ratio and clinical presentation.”

Three new options for menopausal HT
The ACOG Practice Bulletin describes three formulations for the treatment of menopausal symptoms that have recently become available:
• In women with a uterus and with bothersome vasomotor symptoms, an alternative to EPT is oral tablets combining conjugated equine estrogen (0.45 mg) with the selective estrogen receptor modulator (SERM) bazedoxifene (20 mg).
• The oral SERM ospemifene (60 mg) is effective for relief of dyspareunia associated with vulvovaginal atrophy (also known as genitourinary syndrome of menopause).
• Paroxetine mesylate (7.5 mg) is the only FDA-approved nonhormonal formulation for management of vasomotor symptoms and is dosed lower than regimens used to treat psychiatric conditions.

Steer patients clear of compounded formulations
Every week, I encounter patients who have recently visited clinicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

“Because of a lack of FDA oversight, most compounded preparations have not undergone any rigorous clinical testing for either safety or efficacy, so the purity, potency, and quality of compounded preparations are a concern. In addition, both underdosage and overdosage are possible because of variable bioavailability and bioactivity. Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal HT…. Conventional HT is preferred, given the available data.”

REFERENCE
1. Geriatrics Care Online: Beers Pocket Card. www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf. Accessed July 21, 2015.

Continue for Testosterone improves parameters of sexual function >>

Testosterone Improves Parameters of Sexual Function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612-623.

No formulation of testosterone is approved by the FDA for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.¹

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0, 6.0, 12.5, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were five to six times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the two highest doses of testosterone.

REFERENCE
1. Kingsberg SA, Woodard T. Female sexual dysfunction: focus on low desire. Obstet Gynecol. 2015;125(2):477–486.

Continue to find out if HT is safe in statin users

Is HT Safe in Statin Users?
Berglind IA, Andersen M, Citarella A, Liet al. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376. Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publication of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women ages 40 to 74 who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of four years after beginning statins, until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks for mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk for CVD, compared with other estrogens¹).

REFERENCE
1. Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174(1):25–31.

“Critical Window” HT Timing Is Revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to receive conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, research published in the Journal of the American Medical Association in October 2013 details findings from a 13-year follow-up of WHI HT clinical trial participants and better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95-1.45) and 0.94 in the ET arm (95% CI, 0.78-1.14). In both arms, women given HT had reduced risk for vasomotor symptoms, hip fractures, and diabetes, and increased risk for stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 at baseline, the risk for cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk for breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11-1.48). In contrast, in the ET arm, a significantly reduced risk for breast cancer materialized (HR, 0.79; 95% CI, 0.65-0.97) (see Table).

To put into perspective the elevated risk for breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming one glass of wine daily and lower than the HR noted with two glasses daily.¹

Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk for adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women ages 50 to 59 at baseline. In the EPT arm, the risk for MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risk for stroke, VTE, and gallbladder disease.

EPT increased the risk for breast cancer in all age-groups. However, the lower absolute risks for adverse events, and generally more favorable HRs for many outcomes, in younger women resulted in substantially lower rates of adverse events attributable to HT in the younger age-group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar).

REFERENCE
1. Chen WY, Rosner B, Hankinson SE, et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):1884-190.

Continue for ACOG Guidance on menopausal symptoms >>

ACOG Guidance on Menopausal Symptoms
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-216.

Despite findings from new studies, optimal ­management of menopausal symptoms remains controversial. In January 2014, ACOG issued ­guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.¹ Along with many of the clinicians reading this update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

“The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk­-benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, the American College of Obstetricians and Gynecologists recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized, based on each woman’s risk-benefit ratio and clinical presentation.”

Three new options for menopausal HT
The ACOG Practice Bulletin describes three formulations for the treatment of menopausal symptoms that have recently become available:
• In women with a uterus and with bothersome vasomotor symptoms, an alternative to EPT is oral tablets combining conjugated equine estrogen (0.45 mg) with the selective estrogen receptor modulator (SERM) bazedoxifene (20 mg).
• The oral SERM ospemifene (60 mg) is effective for relief of dyspareunia associated with vulvovaginal atrophy (also known as genitourinary syndrome of menopause).
• Paroxetine mesylate (7.5 mg) is the only FDA-approved nonhormonal formulation for management of vasomotor symptoms and is dosed lower than regimens used to treat psychiatric conditions.

Steer patients clear of compounded formulations
Every week, I encounter patients who have recently visited clinicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

“Because of a lack of FDA oversight, most compounded preparations have not undergone any rigorous clinical testing for either safety or efficacy, so the purity, potency, and quality of compounded preparations are a concern. In addition, both underdosage and overdosage are possible because of variable bioavailability and bioactivity. Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal HT…. Conventional HT is preferred, given the available data.”

REFERENCE
1. Geriatrics Care Online: Beers Pocket Card. www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf. Accessed July 21, 2015.

Continue for Testosterone improves parameters of sexual function >>

Testosterone Improves Parameters of Sexual Function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612-623.

No formulation of testosterone is approved by the FDA for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.¹

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0, 6.0, 12.5, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were five to six times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the two highest doses of testosterone.

REFERENCE
1. Kingsberg SA, Woodard T. Female sexual dysfunction: focus on low desire. Obstet Gynecol. 2015;125(2):477–486.

Continue to find out if HT is safe in statin users

Is HT Safe in Statin Users?
Berglind IA, Andersen M, Citarella A, Liet al. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376. Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publication of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women ages 40 to 74 who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of four years after beginning statins, until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks for mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk for CVD, compared with other estrogens¹).

REFERENCE
1. Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174(1):25–31.

“Critical Window” HT Timing Is Revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to receive conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, research published in the Journal of the American Medical Association in October 2013 details findings from a 13-year follow-up of WHI HT clinical trial participants and better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95-1.45) and 0.94 in the ET arm (95% CI, 0.78-1.14). In both arms, women given HT had reduced risk for vasomotor symptoms, hip fractures, and diabetes, and increased risk for stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 at baseline, the risk for cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk for breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11-1.48). In contrast, in the ET arm, a significantly reduced risk for breast cancer materialized (HR, 0.79; 95% CI, 0.65-0.97) (see Table).

To put into perspective the elevated risk for breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming one glass of wine daily and lower than the HR noted with two glasses daily.¹

Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk for adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women ages 50 to 59 at baseline. In the EPT arm, the risk for MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risk for stroke, VTE, and gallbladder disease.

EPT increased the risk for breast cancer in all age-groups. However, the lower absolute risks for adverse events, and generally more favorable HRs for many outcomes, in younger women resulted in substantially lower rates of adverse events attributable to HT in the younger age-group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar).

REFERENCE
1. Chen WY, Rosner B, Hankinson SE, et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):1884-190.

Continue for ACOG Guidance on menopausal symptoms >>

ACOG Guidance on Menopausal Symptoms
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-216.

Despite findings from new studies, optimal ­management of menopausal symptoms remains controversial. In January 2014, ACOG issued ­guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.¹ Along with many of the clinicians reading this update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

“The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk­-benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, the American College of Obstetricians and Gynecologists recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized, based on each woman’s risk-benefit ratio and clinical presentation.”

Three new options for menopausal HT
The ACOG Practice Bulletin describes three formulations for the treatment of menopausal symptoms that have recently become available:
• In women with a uterus and with bothersome vasomotor symptoms, an alternative to EPT is oral tablets combining conjugated equine estrogen (0.45 mg) with the selective estrogen receptor modulator (SERM) bazedoxifene (20 mg).
• The oral SERM ospemifene (60 mg) is effective for relief of dyspareunia associated with vulvovaginal atrophy (also known as genitourinary syndrome of menopause).
• Paroxetine mesylate (7.5 mg) is the only FDA-approved nonhormonal formulation for management of vasomotor symptoms and is dosed lower than regimens used to treat psychiatric conditions.

Steer patients clear of compounded formulations
Every week, I encounter patients who have recently visited clinicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

“Because of a lack of FDA oversight, most compounded preparations have not undergone any rigorous clinical testing for either safety or efficacy, so the purity, potency, and quality of compounded preparations are a concern. In addition, both underdosage and overdosage are possible because of variable bioavailability and bioactivity. Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal HT…. Conventional HT is preferred, given the available data.”

REFERENCE
1. Geriatrics Care Online: Beers Pocket Card. www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf. Accessed July 21, 2015.

Continue for Testosterone improves parameters of sexual function >>

Testosterone Improves Parameters of Sexual Function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612-623.

No formulation of testosterone is approved by the FDA for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.¹

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0, 6.0, 12.5, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were five to six times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the two highest doses of testosterone.

REFERENCE
1. Kingsberg SA, Woodard T. Female sexual dysfunction: focus on low desire. Obstet Gynecol. 2015;125(2):477–486.

Continue to find out if HT is safe in statin users

Is HT Safe in Statin Users?
Berglind IA, Andersen M, Citarella A, Liet al. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376. Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publication of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women ages 40 to 74 who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of four years after beginning statins, until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks for mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk for CVD, compared with other estrogens¹).

REFERENCE
1. Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174(1):25–31.

Although bilateral salpingo-oophorectomy is known to prevent breast and ovarian cancer in BRCA mutation carriers,¹ published reports also have suggested that, among mutation carriers with breast cancer, oophorectomy improves survival. In this retrospective analysis, investigators focused on women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation, observing them for as long as 20 years after diagnosis. Survival rates were compared between women who did and did not undergo oophorectomy.

Details of the trial
Metcalfe and colleagues followed women with a BRCA1 or BRCA2 mutation and intact ovaries who were diagnosed with breast cancer at age 65 or younger between 1975 and 2008, tracking them for a mean of 12.5 years. Of 676 women, 345 underwent oophorectomy, usually with the intent of preventing ovarian cancer.

Overall, oophorectomy was associated with a 56% reduction in the risk of breast cancer-specific mortality (P = .005). Among breast cancer survivors with a BRCA1 mutation, oophorectomy was associated with a significant 62% reduction in breast cancer mortality. Among BRCA2 carriers, the observed 43% reduction in breast cancer mortality did not achieve statistical significance (P = .23).

Full impact of oophorectomy may be difficult to tease out
As Metcalfe and colleagues point out, recent improvements in breast imaging that have led to earlier diagnosis, as well as improvements in the treatment of breast cancer, might attenuate the mortality benefits observed with oophorectomy.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This important report underscores the importance of testing all women with early-stage breast cancer for BRCA mutations, and informs the management of known BRCA1 carriers with breast cancer.
—Andrew M. Kaunitz, MD

Although bilateral salpingo-oophorectomy is known to prevent breast and ovarian cancer in BRCA mutation carriers,¹ published reports also have suggested that, among mutation carriers with breast cancer, oophorectomy improves survival. In this retrospective analysis, investigators focused on women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation, observing them for as long as 20 years after diagnosis. Survival rates were compared between women who did and did not undergo oophorectomy.

Details of the trial
Metcalfe and colleagues followed women with a BRCA1 or BRCA2 mutation and intact ovaries who were diagnosed with breast cancer at age 65 or younger between 1975 and 2008, tracking them for a mean of 12.5 years. Of 676 women, 345 underwent oophorectomy, usually with the intent of preventing ovarian cancer.

Overall, oophorectomy was associated with a 56% reduction in the risk of breast cancer-specific mortality (P = .005). Among breast cancer survivors with a BRCA1 mutation, oophorectomy was associated with a significant 62% reduction in breast cancer mortality. Among BRCA2 carriers, the observed 43% reduction in breast cancer mortality did not achieve statistical significance (P = .23).

Full impact of oophorectomy may be difficult to tease out
As Metcalfe and colleagues point out, recent improvements in breast imaging that have led to earlier diagnosis, as well as improvements in the treatment of breast cancer, might attenuate the mortality benefits observed with oophorectomy.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This important report underscores the importance of testing all women with early-stage breast cancer for BRCA mutations, and informs the management of known BRCA1 carriers with breast cancer.
—Andrew M. Kaunitz, MD

Although bilateral salpingo-oophorectomy is known to prevent breast and ovarian cancer in BRCA mutation carriers,¹ published reports also have suggested that, among mutation carriers with breast cancer, oophorectomy improves survival. In this retrospective analysis, investigators focused on women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation, observing them for as long as 20 years after diagnosis. Survival rates were compared between women who did and did not undergo oophorectomy.

Details of the trial
Metcalfe and colleagues followed women with a BRCA1 or BRCA2 mutation and intact ovaries who were diagnosed with breast cancer at age 65 or younger between 1975 and 2008, tracking them for a mean of 12.5 years. Of 676 women, 345 underwent oophorectomy, usually with the intent of preventing ovarian cancer.

Overall, oophorectomy was associated with a 56% reduction in the risk of breast cancer-specific mortality (P = .005). Among breast cancer survivors with a BRCA1 mutation, oophorectomy was associated with a significant 62% reduction in breast cancer mortality. Among BRCA2 carriers, the observed 43% reduction in breast cancer mortality did not achieve statistical significance (P = .23).

Full impact of oophorectomy may be difficult to tease out
As Metcalfe and colleagues point out, recent improvements in breast imaging that have led to earlier diagnosis, as well as improvements in the treatment of breast cancer, might attenuate the mortality benefits observed with oophorectomy.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This important report underscores the importance of testing all women with early-stage breast cancer for BRCA mutations, and informs the management of known BRCA1 carriers with breast cancer.
—Andrew M. Kaunitz, MD

Of the approximately 1 million benign breast biopsies obtained annually from US women, some 10% yield a diagnosis of atypical hyperplasia, microscopically classified as ductal or lobular. Atypical hyperplasia represents a “proliferation of dysplastic, mono­tonous epithelial-cell populations that include clonal subpopulations. In models of breast carcinogenesis, atypical hyperplasia occupies a transitional zone between benign and malignant disease,” write Hartmann and colleagues, the authors of a recent special report in the New England Journal of Medicine.¹

Long-term follow-up studies have found atypical hyperplasia to confer a relative risk for breast cancer of 4.0. Although these findings are well established, the cumulative absolute risk for breast cancer conferred by a diagnosis of atypical hyperplasia only recently has been described. Hartmann and colleagues note that it approaches 30% over 25 years.¹

Recommendations for clinical practice
The authors of this special report do a service to women and their clinicians by pointing out the high long-term risk of malignancy faced by women with atypical hyperplasia of the breast. They also make a number of important recommendations for practice:

Most women will not develop breast malignancy
As Hartmann and colleagues point out, all is not dire once a woman is diagnosed with atypical hyperplasia of the breast. In most of these women, breast cancer will not develop—and if it does develop, it may occur at an age when mortality from other causes is more likely than from breast cancer. In this respect, women with atypical hyperplasia of the breast are different from carriers of BRCA mutations. Although women with atypical hyperplasia as well as mutation carriers are both at high lifetime risk for breast cancer, breast malignancies occur at an earlier age in mutation carriers. Accordingly, as the authors of this special report advise, in general, a diagnosis of atypical hyperplasia should not be considered an indication for risk-reducing bilateral mastectomy.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Of the approximately 1 million benign breast biopsies obtained annually from US women, some 10% yield a diagnosis of atypical hyperplasia, microscopically classified as ductal or lobular. Atypical hyperplasia represents a “proliferation of dysplastic, mono­tonous epithelial-cell populations that include clonal subpopulations. In models of breast carcinogenesis, atypical hyperplasia occupies a transitional zone between benign and malignant disease,” write Hartmann and colleagues, the authors of a recent special report in the New England Journal of Medicine.¹

Long-term follow-up studies have found atypical hyperplasia to confer a relative risk for breast cancer of 4.0. Although these findings are well established, the cumulative absolute risk for breast cancer conferred by a diagnosis of atypical hyperplasia only recently has been described. Hartmann and colleagues note that it approaches 30% over 25 years.¹

Recommendations for clinical practice
The authors of this special report do a service to women and their clinicians by pointing out the high long-term risk of malignancy faced by women with atypical hyperplasia of the breast. They also make a number of important recommendations for practice:

Most women will not develop breast malignancy
As Hartmann and colleagues point out, all is not dire once a woman is diagnosed with atypical hyperplasia of the breast. In most of these women, breast cancer will not develop—and if it does develop, it may occur at an age when mortality from other causes is more likely than from breast cancer. In this respect, women with atypical hyperplasia of the breast are different from carriers of BRCA mutations. Although women with atypical hyperplasia as well as mutation carriers are both at high lifetime risk for breast cancer, breast malignancies occur at an earlier age in mutation carriers. Accordingly, as the authors of this special report advise, in general, a diagnosis of atypical hyperplasia should not be considered an indication for risk-reducing bilateral mastectomy.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Of the approximately 1 million benign breast biopsies obtained annually from US women, some 10% yield a diagnosis of atypical hyperplasia, microscopically classified as ductal or lobular. Atypical hyperplasia represents a “proliferation of dysplastic, mono­tonous epithelial-cell populations that include clonal subpopulations. In models of breast carcinogenesis, atypical hyperplasia occupies a transitional zone between benign and malignant disease,” write Hartmann and colleagues, the authors of a recent special report in the New England Journal of Medicine.¹

Long-term follow-up studies have found atypical hyperplasia to confer a relative risk for breast cancer of 4.0. Although these findings are well established, the cumulative absolute risk for breast cancer conferred by a diagnosis of atypical hyperplasia only recently has been described. Hartmann and colleagues note that it approaches 30% over 25 years.¹

Recommendations for clinical practice
The authors of this special report do a service to women and their clinicians by pointing out the high long-term risk of malignancy faced by women with atypical hyperplasia of the breast. They also make a number of important recommendations for practice:

Most women will not develop breast malignancy
As Hartmann and colleagues point out, all is not dire once a woman is diagnosed with atypical hyperplasia of the breast. In most of these women, breast cancer will not develop—and if it does develop, it may occur at an age when mortality from other causes is more likely than from breast cancer. In this respect, women with atypical hyperplasia of the breast are different from carriers of BRCA mutations. Although women with atypical hyperplasia as well as mutation carriers are both at high lifetime risk for breast cancer, breast malignancies occur at an earlier age in mutation carriers. Accordingly, as the authors of this special report advise, in general, a diagnosis of atypical hyperplasia should not be considered an indication for risk-reducing bilateral mastectomy.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.