Issue: November 2015

Brand JD, et al.Diabetes Care. 2013;doi:10.2337/dc12-1020.
Christianson MS, et al.Menopause. 2013;doi:10.1097/GME.0b013e31828ced7f.
Ryan J, et al.BJOG. 2014;doi:10.1111/1471-0528.12828.
Sarrel PM, et al.Am J Public Health. 2013;doi:10.2105/AJPH.2013.301295.
Stuenkel CA, et al.J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-2236.
Svejme O, et al.BJOG. 2012;doi:10.1111/j.1471-0528.2012.03324.x.
Wellons M, et al.Menopause. 2012;doi:10.1097/gme.0b013e3182517bd0.

Disclosures: Manson, Minkin, Thacker and Wang report no relevant financial disclosures. Santen reports no relevant financial disclosures. Pinkerton reports no relevant financial disclosures.
November 24, 2015
14 min read

Experts dispel myths surrounding early menopause and risks of hormone therapy

Issue: November 2015

Brand JD, et al.Diabetes Care. 2013;doi:10.2337/dc12-1020.
Christianson MS, et al.Menopause. 2013;doi:10.1097/GME.0b013e31828ced7f.
Ryan J, et al.BJOG. 2014;doi:10.1111/1471-0528.12828.
Sarrel PM, et al.Am J Public Health. 2013;doi:10.2105/AJPH.2013.301295.
Stuenkel CA, et al.J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-2236.
Svejme O, et al.BJOG. 2012;doi:10.1111/j.1471-0528.2012.03324.x.
Wellons M, et al.Menopause. 2012;doi:10.1097/gme.0b013e3182517bd0.

Disclosures: Manson, Minkin, Thacker and Wang report no relevant financial disclosures. Santen reports no relevant financial disclosures. Pinkerton reports no relevant financial disclosures.
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Menopause typically brings with it a host of symptoms that can be unpleasant, at best, and at worst, can increase the risks for heart disease and early death. For women who go through early menopause those symptoms and health risks can be compounded, whether the transition is natural or due to surgery.

Early menopause affects a minority of women. About 1% of women younger than 40 years experience what is known as either premature menopause or primary ovarian insufficiency (defined as the loss of normal ovary function), whereas 5% of women younger than 45 years experience what is defined as early menopause. But for women in this group, the stakes are raised when it comes to health risks. Research indicates that early menopause, which results in the loss of estrogen and other hormones, increases the risks for cardiovascular disease, osteoporosis, type 2 diabetes, sleep disturbances, dementia and all-cause mortality.

“There’s a whole myriad of issues in earlier menopause or ovarian insufficiency,” Holly L. Thacker, MD, a women’s health specialist and director of the Cleveland Clinic Center for Specialized Women’s Health, told Endocrine Today. “The reason it’s more devastating to younger women, beside the whole fertility issue ... is because when you lose estrogen, you accelerate the aging process. So, if you start that process 10 or 20 years before the usual time, that’s obviously going to have adverse effects.”

Earlier menopause, more risks

In a 2012 study, Wellons and colleagues analyzed the association between a self-reported history of early menopause and future coronary heart disease and stroke, reviewing the history of 2,509 women (691 reporting natural or surgical early menopause before age 46 years) who participated in the Multi-Ethnic Study of Atherosclerosis, a longitudinal, cohort study of U.S. men and women followed between 2002 and 2008. In survival curves, the researchers found that women with early menopause had greater rates of CHD (P = .008) and lower rates of stroke-free survival (P = .0158). The risk remained after adjustment for age, race and traditional CVD risk factors, with an HR of 2.08 for CHD (95% CI, 1.17-3.7) and 2.19 for stroke (95% CI, 1.11-4.32).

The risk also increases for type 2 diabetes. In a prospective case-cohort study, Brand and colleagues analyzed data from 3,691 postmenopausal women with type 2 diabetes and 4,408 subcohort participants during a mean follow-up period of 11 years, examining the associations of menopausal age and reproductive life span with diabetes risk. Among women who had undergone menopause from ages 40 to 44 years, the HR for type 2 diabetes was 1.09 (95% CI, 0.9-1.31) relative to women going through menopause at ages 50 to 54 years. Women who underwent menopause before age 40 years had an HR of 1.32 (95% CI, 1.04-1.69) for type 2 diabetes, a 32% higher risk vs. women who went through menopause at ages 50 to 54 years. The risk persisted after multivariable adjustment, including BMI, waist circumference and smoking. The HR per standard deviation younger age at menopause was 1.08 (95% CI, 1.02-1.14).

According to JoAnn Manson, MD, DrPH, professor of medicine at Harvard Medical School and an endocrinologist at Brigham and Women’s Hospital, patients and clinicians should be aware that the findings of the Women’s Health Initiative regarding hormone therapy do not apply to women undergoing premature menopause.

Courtesy of Brigham and Women’s Hospital.

The early onset of menopause also affects cognitive function, according to recent research. In a population-based cohort study, Ryan and colleagues analyzed data from 4,868 French women aged at least 65 years to determine the association between age at menopause, type of menopause (surgical or natural) and the use of menopausal hormone therapy and cognitive function. Researchers analyzed the participants’ performance on a cognitive test battery at baseline and at 2, 4 and 7 years. Researchers calculated the change in test scores between each of the follow-ups and the baseline score to evaluate cognitive decline. Researchers found that women who entered menopause at ages 40 years or younger had worse verbal fluency (OR = 1.56; 95% CI, 1.12-1.87) and visual memory in later life (OR = 1.39; 95% CI, 1.09-1.77); the type of menopause was not significantly associated with cognitive function. In addition, premature menopause was associated with a 30% increased risk for decline in psychomotor speed and global cognitive function over 7 years, the researchers noted.

“Speculatively, our findings could be explained by a premature decline in estrogen exposure at a time when estrogen would have greatest neuroprotective effects,” Ryan and colleagues wrote. “We could then expect that supplementing estrogen in the form of exogenous estrogen-based HT at the time of premature menopause would help counteract the negative effects of cognitive function, but we failed to find strong supporting evidence for this.”

Several studies have linked a lower bone mineral density in women with early menopause and an increased risk for fracture later in life. In a 34-year population-based, prospective observational study evaluating the long-term effects of early menopause on the risk for osteoporosis, fracture and mortality, Svejme and colleagues analyzed data from 390 white European women aged 48 years at the start of the study. Women were divided into early menopause (occurring before age 47 years) and late menopause (occurring at age 47 years or later) groups. BMD was measured by single-photon absorptiometry in the distal forearm at baseline and again when women were aged 77 years; proximal femur and lumbar spine BMD were measured by DXA at age 77 years. Women who experienced early menopause had a 0.43 standard deviation lower BMD in the distal forearm at age 48 years and an RR at age 77 years of 1.83 (95% CI, 1.22-2.74) for osteoporosis, 1.68 (95% CI, 1.05-2.57) for fragility fracture and 1.59 (95% CI, 1.04-2.36) for mortality.

“The reason for the higher fracture risk among women with early menopause can only be speculated upon,” Svejme and colleagues wrote. “One of the most recognized risk factors for fractures is low BMD ... however, the lower BMD level does not seem to be entirely able to explain the increased fracture risk. We must therefore speculate as to whether factors beyond bone mass, such as inferior muscle strength or inferior neuromuscular function, ought to be found in women with early menopause.”

Estrogen is key

Most of the adverse health effects after early menopause can be traced to the loss of ovarian estrogen, said JoAnn Manson, MD, DrPH, an endocrinologist at Brigham and Women’s Hospital, and professor of medicine at Harvard Medical School.

“An early decline in ovarian estrogen is associated with an increased risk for heart disease, osteoporosis and all-cause mortality, and this is because estrogen does have a role,” Manson, one of the principal investigators for the landmark Women’s Health Initiative, told Endocrine Today. “The premature loss of estrogen can increase the risk for those conditions as demonstrated in a number of observational studies.”

Many women going through early menopause also experience a range of distressing symptoms, including vasomotor symptoms, more commonly known as hot flashes, difficulty sleeping, impaired concentration, mood swings and vaginal dryness. The severity of symptoms can vary depending on the type of menopause, Manson said.

“Symptoms will of course depend on whether it’s an early natural menopause or a surgical one, in which case symptoms can be abrupt; this can also occur following chemotherapy or radiation therapy,” Manson said. “For women who have early surgical menopause, there can be severe hot flashes, night sweats, difficulty sleeping, impaired concentration, an extreme state of what many of the women undergoing natural menopause go through. But the symptoms may be less dramatic if it’s a more gradual or natural premature menopause.”


Treatment and controversy

For many women going through premature or early menopause, there is relief to be found in HT, according to researchers. The Endocrine Society recently released a clinical practice guideline advocating HT as an effective treatment for most women 60 years or younger or less than 10 years past the onset of menopause who experience bothersome hot flashes and other symptoms and do not have contraindications.

Mary Jane Minkin

Many women, however, remain reluctant to use HT. The guideline, in part, was designed to address a decrease in the use of HT following the results of the 2002 WHI, which demonstrated that, in women aged 50 to 79 years (mean age, 63 years), estrogen plus progestin increased the risk for CV complications, deep vein thrombosis and breast cancer. The results led to widespread uncertainty among patients, and the use of estrogen and progestin and even estrogen alone has declined sharply since the WHI results were published.

Studies have suggested that the confusion surrounding HT may have led to adverse health events and death. Sarrel and colleagues analyzed the effects of estrogen avoidance on mortality rates after the WHI study on women aged 50 to 59 years who had undergone a hysterectomy. The researchers related excess mortality among women assigned to placebo in the WHI to the population of comparable women in the United States, incorporating the decline of estrogen use between 2002 and 2011.

“Over a 10-year span, starting in 2002, a minimum of 18,601 and as many as 91,610 postmenopausal women died prematurely because of the avoidance of estrogen therapy,” Sarrel and colleagues wrote. “[Estrogen therapy] in younger, postmenopausal women is associated with a decisive reduction in all-cause mortality, but estrogen use in this population is low and continuing to fall.”

The results have left some clinicians frustrated.

“What I’m hoping you’re going to be seeing, is a reanalysis [of the data],” Mary Jane Minkin, MD, FACOG, clinical professor in the department of obstetrics, gynecology and reproductive sciences at Yale University School of Medicine, told Endocrine Today. “Maybe we went a little overboard 13 years ago and scared the hell out of women for no good reason. If you don’t give these women in early menopause — whether surgical or natural — estrogen, you are putting them at a huge risk. That benefit so far outweighs these other hazards.”

“Young women’s bodies expect to have estrogen,” Erica T. Wang, MD, MAS, a reproductive endocrinologist and infertility specialist in the department of obstetrics and gynecology at Cedars-Sinai, told Endocrine Today. “There’s a lot of debate over hormone replacement, but that does not apply to early or premature menopause. Estrogen is important for cardiovascular health, osteoporosis prevention and overall well-being.

“When I see my patients in premature menopause, whether its surgical or natural, I tell them that we are giving them back the estrogen their body would normally be exposed to,” Wang said.

She said patients considering HT often express fears of increased breast cancer risk, citing the WHI study results on estrogen-progestin therapy. Estrogen therapy alone is not associated with a higher risk for breast cancer.

“Everyone is scared of breast cancer, and I completely understand that,” Wang said. “But we also have to educate women on the benefits of estrogen on other aspects of their health, such as bone protection.”

A timeframe for HT

Debate continues about how long women should be on HT. The North American Menopause Society (NAMS) recommends 5 years or less of estrogen-progestin treatment in women with a uterus, but the length of time can be individualized for each woman, and younger women in particular may need to be on treatment longer.

“I tell them I’d like to see them continue until at least their mid-40s, and then potentially tapering off,” Wang said. “The tapering process will be dependent on their symptoms and quality of life.”


Regardless of whether a woman going through early menopause is experiencing distressing symptoms, such as hot flashes, she should be treated with HT if it is the best option for her, Thacker said.

“[Women] have concerns because of misconceptions, the way the WHI was portrayed,” Thacker said. “The average age of those women [in the WHI] were in their 60s. Even with Prempro [an estrogen plus progestin indicated for women with a uterus, Wyeth Pharmaceuticals], the women who started under age 60 [years] still had a reduced death rate.”

“It’s so ingrained,” Thacker said of the fears surrounding HT. “I tell my patients, ‘Any time you hear something negative about the word “estrogen,” just plug in the word “women.” That’s actually what is meant.’ And it kind of turns on a light bulb. Any hormone, too much or too little, is not good. Without estrogen, women would not be feminized, women wouldn’t carry babies.”

The clinician conversation

In a 2013 study, researchers sent a Web-based survey to all American obstetrics and gynecology residency directors to assess current menopause teaching. Among the 510 responders, 67% reported that they had limited knowledge of the pathophysiology of menopause symptoms, 67% reported a limited knowledge of HT and 68% reported a limited knowledge of nonhormonal therapies. Similar responses were reported for knowledge of menopause and risks related to bone health, CVD and metabolic syndrome.

“Doctors should be talking to women, and they should be saying, ‘What symptoms are you having?’” Minkin said. “Even if a woman has no symptoms — 20% of women are blessed to have no hot flashes whatsoever — but, even with those women, you need to be talking about bones, you need to be talking hearts, you need to be talking brains.”

Minkin recommends low-dose HT even in the absence of bothersome symptoms to reduce these risks.

Manson agrees that clinicians must stress the benefits vs. the risks in the setting of early menopause.

“Most importantly, women with premature menopause should understand that the findings of the WHI, in terms of the balance of benefits and risk of HT, do not apply to their situation,” Manson said. “The WHI findings apply to a postmenopausal group of women with a mean age of 63 [years] at the time they were randomized to HT. So, for women who have early surgical menopause and do not have contraindications to estrogen therapy, the benefits are likely to outweigh the risks.

“In the premenopausal setting, estrogen is extremely important for maintenance of optimal health, and it’s important to nearly every organ system,” Manson said. “When we’re talking about natural menopause at a more typical age, there may be controversy about HT for purposes beyond symptom management, because estrogen plus progestin therapy is associated with a complex pattern of benefits and risks. But in the premature or early menopausal state, it’s more straightforward that the benefits of estrogen therapy would likely outweigh the risks in women without contraindications. The distinction is tremendously important, and hopefully, women will understand that, and their health care providers will help to clarify this distinction for them.”

Minkin said she suggests that women going through early menopause look for a menopause clinician who can go over the risks and benefits of treatment options.

“For certain people, the metabolic benefits of estrogen are so important,” Minkin said. “Even if they’re not feeling [symptomatic], they should be thinking about it.” – by Regina Schaffer



Should clinicians offer nonhormonal therapies to manage menopausal vasomotor symptoms?


The decision-making process should be shared between a woman and her health care provider.

The key question is how women with early menopause and hot flashes should be advised about symptom relief.

Richard Santen

The Endocrine Society recently published guidelines that recommended hormonal therapies for appropriate women but largely agreed with the NAMS position statement on nonhormonal methods for others. The Endocrine Society stated that women with mild or less bothersome vasomotor symptoms should consider a series of steps not involving medication, including turning down the thermostat, dressing in layers, avoiding alcohol and spicy foods and reducing obesity and stress. For those with moderate or severe vasomotor symptoms, hormonal therapies with estrogen alone (if no uterus) or estrogen plus a progestogen are most effective based on a large body of data and can be recommended unless the risks for cardiovascular disease, breast cancer or deep venous thrombosis are increased. An option available in the U.S. and Europe is the tissue selective estrogen complex (TSEC), which combines conjugated estrogen with bazedoxifene and eliminates the need for a progestogen.

For women with moderate or severe vasomotor symptoms [who are] unwilling to take hormone therapy or have contraindications, several options are effective. A key principle is that in randomized controlled trials, 30% of women with hot flashes respond to placebo. Notably, most experts consider the efficacy of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) agents to be the difference between placebo and drug. For example, a 30% reduction in the placebo group and a 70% reduction in treatment group equals only a minimal 40% drug-related reduction. However, a woman being treated does not care if the effect is due to placebo or due to the drug, but appreciates an improvement in symptoms.

In randomized controlled trials, the SSRIs and SNRIs reduce frequency and severity of symptoms overall by approximately 70%. Endocrine Society guidelines suggest that paroxetine, venlafaxine, desvenlafaxine citralopram, escitaloram, gabapentin and pregabalin are all equally effective. For those bothered mostly by nighttime vasomotor symptoms, gabapentin may be preferable as it also has welcome soporific properties. Recent studies suggest efficacy of cognitive behavior modification and hypnosis, but these therapies require trained practitioners and may not be practical to utilize. The Endocrine Society guideline classified genestein, S-equo, nonpurified isoflavones, red clover, high-dose or synthesized phytoestrogens, dietary soy and vitamin E as agents with inconsistent reports of benefit. Agents classified as having predominantly no benefit included black cohash, omega-3 fatty acids, acupuncture, exercise and a range of other complementary approaches, such as ginseng and wild yam. Modalities requiring further study included stellate ganglion block and guided relaxation.

To summarize, mild and less bothersome vasomotor symptoms are best treated with lifestyle modifications, and moderate to severe with hormonal therapy, depending on underlying risks and patient willingness. Nonhormonal therapies such as the SSRI/SNRI and gabapentinoids are not as effective as hormonal therapy, but provide significant relief.

Richard Santen, MD, is a professor of medicine in the division of endocrinology and metabolism at the University of Virginia Health Sciences System in Charlottesville, Virginia. Disclosure: Santen reports no relevant financial disclosures.


Hormone therapy remains the gold standard.

Up to 80% of women have hot flashes with 25% bothersome enough to seek therapy. Hot flashes on average last 7.2 years, varying by ethnic group and lasting longer among African American women in the SWAN trial. Hormone therapy remains the gold standard for relief of hot flashes and may have health benefits when started near menopause, particularly for women with early menopause. However, for those women who either cannot or choose not to take available hormonal therapies, nonhormonal options are needed. The NAMS panel reviewed the literature and provides evidence-based recommendations on these nonhormonal options, including herbal products in their 2015 position statement on nonhormonal management of menopause-associated vasomotor symptoms.

For nonprescription therapies, the NAMS panel recommended two behavioral approaches: a cognitive-behavioral therapy approach combining relaxation techniques, sleep hygiene and learning; and clinical hypnosis, which was better than a “structured attention” therapy approach and significantly better than no treatment in breast cancer survivors. Weight loss, stress reduction, a soy derivative (S-equol), and stellate ganglion block (nerve block) showed potential, but caution is recommended.

JoAnn V. Pinkerton

For prescription therapies improvements are seen, although in general they do not offer as much relief as HT. The NAMS panel recommended the FDA-approved nonhormonal therapy low-dose paroxetine salt. Although not approved by the FDA, the serotonin-norepinephrine reuptake inhibitors (SNRIs, such as venlafaxine), the gabapentinoids (gabapentin and pregabalin) and clonidine have been found effective over placebo but less effective than HT. For safety, the panel recommended use of the lowest dose with adjustment in dose as tolerated. Benefits and risks for individual patients need to be balanced, including lack of long-term safety and efficacy data.

For most lifestyle approaches, herbs and supplements the evidence was lacking or negative. Techniques unlikely to work include exercise, yoga, paced respiration and acupuncture. Similar lack of efficacy was seen with black cohosh, dong quai, evening primrose, flaxseed, maca, omega-3s, pollen extract, vitamins, relaxation, calibration of neural oscillations (a brain-training technique), homeopathy and chiropractic interventions.

JoAnn V. Pinkerton, MD, is medical director of the Midlife Health Center, professor of obstetrics and gynecology and vice chair of academic affairs at the University of Virginia, Charlottesville. Disclosure: Pinkerton reports no relevant financial disclosures.


Stuenkel CA, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-2236.

The North American Menopause Society. Menopause. 2015;doi:10.1097/GME.0000000000000546.