Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Dec 1.
Published in final edited form as: Fertil Steril. 2016 Oct 25;106(7):1580–1587. doi: 10.1016/j.fertnstert.2016.09.018

Hormone replacement therapy in young women with surgical primary ovarian insufficiency

Philip M Sarrel 1, Shannon D Sullivan 2, Lawrence M Nelson 3,*
PMCID: PMC5248494  NIHMSID: NIHMS825602  PMID: 27793381

Abstract

Bilateral oophorectomy performed in women before they are menopausal induces surgical primary ovarian insufficiency (Surgical POI), an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy most of these women develop severe symptoms of estrogen deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal estradiol replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal hormone therapies has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of estrogen therapy even in women in whom hormone replacement therapy is clearly indicated. Discussion of possible ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective hormone replacement therapy for women who will experience Surgical POI is clearly indicated.

Keywords: Premenopausal Oophorectomy, Ovarian Insufficiency, Surgical Menopause, Estrogen Therapy

Graphical Abstract

For young women undergoing bilateral oophorectomy, estrogen therapy effectively controls symptoms, lessens risk of disease, and reduces mortality. Disturbingly, many women go untreated due to inappropriate fears regarding estrogen use.

Introduction

Most bilateral oophorectomies occur at the time of hysterectomy and most hysterectomies occur between ages 35 and 45 with more than half of all hysterectomies in women age 45 or younger(1,2) As a result, Surgical primary ovarian insufficiency (POI) is the leading cause of ovarian hormone deficiency in premenopausal women. Although the number of hysterectomies has declined in recent years, there are still more than 200,000 women who undergo bilateral oophorectomy each year in the United States.(1,2) This is the sum of surgeries done 1) at the time of hysterectomy, 2) bilateral oophorectomy performed for treatment of ovarian pathology, and 3) “stand-alone” procedures to reduce risk in women genetically pre-disposed to breast and ovarian cancer. Bilateral salpingo-oophorectomy essentially eliminates ovarian cancer risk and reduces breast cancer risk in these women. (3)

The adverse effects of prophylactic oophorectomy are hormone deficiency related symptoms, increased risk of acquiring certain diseases, and increased morbidity and mortality.(4-6) These effects are similar to women who develop primary ovarian insufficiency (POI) by other mechanisms. However, in Surgical POI symptoms are more sudden in onset and consequences can be more severe.

Prior to 2002 more than 90% of women used estrogen therapy (ET) after bilateral salpingo-oophorectomy, likely a result of data showing estrogen therapy (ET) started close to the time of surgery (6,11) is effective in controlling symptoms, inhibiting disease processes, and reducing morbidity and mortality. Today, the figure is less than 10%. For young women who have undergone oophorectomy, not taking estrogen means years of loss of its protective effects. Nevertheless, fear of taking any kind of hormone therapy (HT) is pervasive despite the evidence for the safety and efficacy of estrogen therapy. (7)

Women undergoing natural menopause differ dramatically from women experiencing surgical menopause prior at a young age. In most cases women experiencing natural menopause have a gradual onset of ovarian hormone deficiency after prolonged intermittent and unpredictable ovarian function, inherent in the physiology of the process. Generally these women are treated with HT for symptoms, not as a replacement for missing ovarian hormones. This is the critical distinction for the clinician to keep in mind, and it is important to explain this to young women who will be undergoing bilateral oophorectomy.

Symptoms

Women who develop Surgical POI experience more severe and more frequent menopausal symptoms than women who experience natural menopause. (7b) (Figure 1) These symptoms occur almost immediately and can persist for decades. Untreated, symptoms such as hot flashes, sleep disturbance, fatigue, decreased sexual desire, anxiety and depressed mood often have a major impact on quality of life, capacity to function, and disease risk. (8-12) Also, delay in initiation of replacement estrogen has an adverse effect on bone health.(13)

Figure.

Figure

Symptoms compared as measured by the Greene Climacteric Scale between women experiencing natural menopause (Control) and women experiencing Surgical POI (primary ovarian insufficiency). A) Psychological, B) Somatic, C) Vasomotor, and D) Sexual Function. (8)

Menopausal symptoms should be regarded as important signals of pathophysiological changes. Although androgen deficiency can contribute to these changes, most appear to be due to estradiol deficiency. For example, hot flashes are a state of vasomotor instability during which arterial flow is affected by surging levels of epinephrine and norepinephrine.(12,14) Vasodilation occurs in the skin as core blood flow shunts to the periphery. Coronary artery constriction during hot flashes can occur with more than 30% of women experiencing chest pressure or pain during a severe episode.(12,15) Vaginal dryness signals decreased genital blood flow and cell loss eventuating in genital atrophy and the uro-genital syndrome of menopause.(16) Impaired cognition, impaired short-term memory, sleep disturbance and vasomotor instability reflect nervous system effects, including decreased brain blood flow and degenerative changes, pre-disposing to functional cognitive decline and dementia.(10,17,18)

The impact of untreated menopausal symptoms on quality of life is seen in studies of the effects on symptomatic women in the work-place.(19,20) For example, 252,000 working women with untreated hot flashes were compared to asymptomatic age-matched women. Over a 12 month period, the women with hot flashes showed increased work-loss, 1.1 million extra medical visits, and a health insurance bill almost $400,000,000 greater compared to the asymptomatic women. (19) A study of menopause symptoms and Dutch women concluded: “Over ¾ of women with severe menopausal symptoms report a low ability to undertake work.”(20)

Following bilateral oophorectomy, more than 80% of untreated women report one or more sex problems, including vaginal dryness with painful intercourse, inhibited sexual response, and loss of sexual desire.(21-23) The increased occurrence of sexual dysfunction following BSO is more distressing in premenopausal than in postmenopausal women.(23) Estrogen therapy has proved effective for restoring vaginal cytology and lubrication and in so-doing reducing the occurrence of dyspareunia.(15) It is also effective in restoring sex response. However, the problem of loss of sexual desire may require the addition of an androgen to achieve satisfactory results.(22,23)

Severe vasomotor symptoms are associated with more frequent and more severe levels of depression and anxiety. For example, Kronenberg reported depressed feelings during hot flashes were more common in women after surgical menopause than natural menopause and that suicidal thoughts during hot flashes occurred almost twice as often (10%) in these women.(12) With regard to hospitalization for attempted suicide, Rosenberg et al. compared women who had experienced natural menopausal to women aged 35 and younger who had undergone bilateral oophorectomy and had not used hormone replacement. They reported a relative risk of 2.4 for hospitalization for a suicide attempt in the women with Surgical POI..(24)

The pathophysiology that occurs with menopausal symptoms can contribute to subsequent disease risk. For example, The Study of Women's Health Across the Nation (SWAN) reported that hot flashes were associated with a higher incidence of insulin resistance and glucose levels.(10) More recently, the SWAN investigators reported that severe hot flashes were “robustly” associated with higher intima media-thickness (IMT), an important marker for subclinical cardiovascular disease.(25) In the Women's Health Initiative Study (WHI), more frequent and more severe symptoms were associated with an increased risk of hypertension, cardiovascular disease and stroke.(11)

With regard to cardiovascular risk, there has been a paradigm shift in thinking with regard to effects of estrogen deficiency on young women. Menopausal symptoms should be taken seriously and considered to be “canaries in the coal mine” signalling the need for medical attention and evaluation. (26)

Disease

In the past, “symptoms” of hormonal insufficiency have been at the center of managing menopause. Evaluation and treatment focused on control of symptoms for a limited time with the expectation that once a woman passed through the menopausal transition there would be no further need for hormonal intervention. However, starting in the 1950s, as the cardiovascular and bone consequences of ovarian hormone deficiency became more apparent, the role of ovarian hormone therapy for the prevention of disease emerged. Subsequently, many cohort studies and randomized clinical trials have been carried out to determine the connection between loss of ovarian function and disease development as well as the effects of hormone replacement in disease prevention. In this section, we describe the findings we feel are the most significant. We begin with the findings of the Mayo Clinic Cohort Study of Oophorectomy and Aging because it addresses our focus on women who have undergone bilateral oophorectomy, and its findings relate to most of the concerns that have been raised by other studies about the immediate and long-term effects of ovarian hormone deficiency.

The Mayo Clinic Cohort Study of Oophorectomy and Aging reports that following bilateral oophorectomy risk is increased for all-cause mortality (28%), coronary heart disease (33%), stroke (62%), cognitive impairment (60%), parkinsonism (80%), osteoporosis and bone fractures (50%), sexual dysfunction (40-110%), and, possibly, glaucoma. (5,6) The study shows even greater risks with earlier age at the time of Surgical POI. For example, all-cause mortality was increased by 67% in women who had undergone bilateral oophorectomy before age 45. Perhaps most important, the Mayo Clinic study indicates that starting ET at the time of oophorectomy and continuing until at least the age of natural menopause (age 51-52) significantly reduces most, but not all, of the increased risks seen in untreated women. These findings support the so-called “timing hypothesis” which, applied to cardiovascular, bone, and nervous system protection, argues for hormone replacement as close to the onset of hormone deficiency as possible.(27) Other studies besides the Mayo Clinic study, which show that starting estrogen therapy as close to the time of surgery optimizes cardiovascular protection, include the Danish Nurses Study, the WHI estrogen- only study, and the ELITE trial. Most of these studies indicate the best cardiovascular results were in women who used estrogen after oophorectomy for 10 years or more. (6,11,36,38)

For almost 70 years data has been accumulating that clarify the role of estradiol in disease prevention. Advances in molecular biology have enabled the identification of literally thousands of cellular actions of estradiol.(28) Most of these data refers to actions that affect bone, and the circulatory, urogenital, and nervous systems. Additionally, the clinical findings of estrogen reducing risk for developing breast cancer can be explained by a variety of molecular mechanisms including estrogen-induced apoptosis in breast cancer cells. (28,62)

Cardiovascular

In 1953, a Mayo Clinic autopsy study reported that 90% of the women with prior Surgical POI showed severe atherosclerosis cardiovascular disease. Among the women who had died prior to age 50, 50% had severe atherosclerotic disease. The youngest of the women, a 28 year-old developed surgical POI at age 23. The interval between oophorectomy and death averaged 11 years in the women who died before age 60. Over 80% of the women died before age 70.(29) Hormone replacement therapy is not mentioned in the report but it is safe to assume that very few would have been treated hormonally during the years following their surgery.

Since that initial report, multiple mechanisms have been described through which estrogen might inhibit atherosclerosis and maintains arterial function. These mechanisms include beneficial effects on cholesterol metabolism, direct actions in the arterial wall to inhibit atherosclerosis, and control of catecholamine release. (30,31)

We have already referred to the surges in catecholamine levels that occur with vasomotor symptoms and the correlation between these symptoms and risk for developing cardiovascular disease .(10,12,14,15) Estrogen modulation of catecholamine release helps to prevent coronary constriction while estrogen withdrawal may trigger arterial instability and spasm.(15) Surges of catecholamine levels in reaction to estradiol depletion occur at various times in a woman's life most notably at menopause and when women stop ET. These surges have been associated with vasomotor instability, coronary spasm, myocardial infarction, and mortality. (15, 32,33)

Evidence regarding the role of estrogen in slowing the atherosclerotic process is well documented in several trials.(34-36) Using measures of arterial calcium, three separate studies show that estrogen inhibits calcium deposition in coronary and carotid vessels as long as the intervention occurs within 3 to 6 years from the time of loss of ovarian function. In the National Institutes of Health Women's Health Initiative study, women who had not used estrogen after developing Surgical POI had more than a two-fold risk of excess calcium in their arteries when they were enrolled in the study.(35)

Multiple studies have reported a heightened cardiovascular disease risk among women who developed Surgical POI prior to age 50 compared to women with natural menopause.(37-39) For example, Ingellson et al. compared Swedish women post-hysterectomy, with and without bilateral oophorectomy, with each other and with women who had no surgery . The greatest risk for cardiovascular disease and stroke later in life was in the women who had undergone hysterectomy with bilateral oophorectomy. While all were under age 50, being younger at the time of Surgical POI further increased the risks. (37) Lokkegaard et al. reported increased risk for ischemic heart disease in women aged 40 to 45 who did not use hormone therapy (HT) for replacement after developing Surgical POI. Among those who did use HT, there was no increase in ischemic heart disease.(38) A meta-analysis showed ET has a greater effect in reducing CVD risk after surgical compared to non-surgical POI.(39)

Diabetes is a major risk factor for cardiovascular disease. A rise in fasting insulin, glucose levels, and obesity is seen with menopause,(40) and following the development of Surgical POI there is an increase in insulin resistance.(41) There are mixed findings regarding natural menopause and risk for diabetes. For Surgical POI, however, the association with development of diabetes and the metabolic syndrome appears to be more consistent. For example, the National Health and Nutrition Examination Survey/Epidemiologic Follow-up Study (NEFS) studied the association between diabetes and hysterectomy, with or without bilateral oophorectomy in a cohort of 2,597 women. (42) The average age for participants who had undergone hysterectomy with bilateral oophorectomy was 41.9 years. An elevated risk for diabetes was restricted to women with both hysterectomy and Surgical POI (HR 1.57, 95% CI 1.03-2.41). An earlier age of ovarian insufficiency, either natural or surgical, was associated with increased risk of diabetes, reaching a hazard ratio of 1.83 in women under age 40. The authors concluded women with Surgical POI “may represent a unique population with elevated risk for diabetes ...and its potential complications.”(42) A Norwegian national health study found that women who had developed Surgical POI as a result of risk reducing bilateral oophorectomy had a significantly increased risk of metabolic syndrome compared to age-matched controls (47% versus 36%; p=.001). (43)

In contrast, the Diabetes Prevention Program (DPP) reported a lower diabetes risk among women who had experienced Surgical POI as compared with control premenopausal women. However, 88% of the women in this study received hormone therapy. Significantly, diabetes did not develop in any of the hormone therapy users during the course of the study.(44)

Bone

There is an abundance of evidence linking bone loss to the estrogen deficiency induced by natural menopause which we will not review here. Women with Surgical POI are at greater risk for bone loss and fracture compared to naturally menopausal women, likely due to the acute and abrupt onset of estrogen and androgen deficiency. (45) At six years post-oophorectomy, almost twice the rate of bone loss has been seen in women with Surgical POI compared to women with natural menopause.(46) ET started within 3 years of the onset of Surgical POI restored BMD to pre-operative levels. Starting ET at 6 years after the onset of Surgical POI stopped bone loss but BMD was not restored to preoperative levels and stabilized at significantly lower levels.(46) Mucowski et al. reported decreased BMD in spine, hip and femoral neck after Surgical POI compared to postmenopausal women in whom the ovaries were not removed.(47)

Cognitive Decline

A series of major studies show an increased risk for cognitive decline and dementia in women with Surgical POI compared to women who experience natural menopause.(18,48-51) Rocca et al. showed that women who underwent unilateral or bilateral oophorectomy prior to natural menopause and were not treated with HRT had an increased risk of cognitive decline and dementia compared to a referent non-menopausal control population (HR 1.46, 95% CI 1.13-1.90).(48) Further, the risk of cognitive decline increased with younger age of oophorectomy, suggesting that increased duration of estrogen deficiency may be a causal factor. Women who underwent bilateral oophorectomy before age 49 and were given ET until at least age 50 had no increased risk of dementia.(49-51) Phung et al. found an increased risk of dementia after bilateral oophorectomy performed prior to natural menopause, with younger age at oophorectomy exacerbating cognitive decline.(49) Bove et al. also demonstrated that earlier age of surgical menopause was associated with more rapid cognitive decline and increased Alzheimer Disease neuropathology, in particular neuritic plaques. Their studies went on to show that hormone therapy, when initiated within 5 years of Surgical POI and continued for at least 10 years, was associated with decreased decline in cognition but not in Alzheimer Disease neuropathology. (18)

In the Cache County Study, 85% of the women used estrogen therapy following the onset of Surgical POI. Among these women, those who started ET within 5 years of surgery and continued for more than 10 years showed the greatest reduction in risk for developing Alzheimer Disease (HR 0.62; 95% CI 0.42-0.92).(50) In an in depth review Rocca et al. conclude that premenopausal women Surgical POI should initiate ET as close to the time of surgery as possible to maximize neuroprotective effects and reduce dementia risk.(51) Based on their review, Rocca et al recommend estrogen therapy for premenopausal women Surgical POI to slow cognitive decline and reduce the risk for dementia and also recommend that ET should be continued until at least the age of natural menopause.(51)

Mood Disorders

The Mayo Clinic Cohort of Oophorectomy and Aging Study reported that compared to age-matched women with intact ovaries women with onset of Surgical POI before the clinical onset of natural menopause have higher rates of depression (HR 1.54; 95% CI 1.04-2.26) and anxiety (HR 2.29; 95% CI 1.33-3.95). The increase in symptoms occurred in women who had not suffered from depression or anxiety before their surgery. In this study, estrogen use up to age 50 did not modify the risk for depression or anxiety.(52) A smaller Swedish study compared women after hysterectomy whose ovaries were removed or retained and did or did not take ET. Anxiety and depression were significantly greater in women with Surgical POI; ET significantly reduced the incidence and severity of the mood disorders among Swedish women with Surgical POI. (53)

Cohen et al. reported the risk for new onset depression is associated with more severe vasomotor symptoms.(54) Three months of treatment with transdermal estradiol (0.100 mg/day) alleviated symptoms of depression and even led to remission when initiated in very early menopause.(55)

No studies are available to specifically address the use of androgens for treatment of depression in women with Surgical POI. However, androgen replacement therapy in postmenopausal women has been shown to contribute to improved mood. (56)

Not all studies report psychological disorders related to Surgical POI. For example, the SWAN study compared women with and without bilateral oophorectomy aged 42 to 52 and found no increase in depression or anxiety levels. (57)

Mortality

Many randomized clinical trials and cohort studies indicate that Surgical POI is a significant risk factor for all-cause mortality and that ET after surgery reduces the risk of mortality mostly by reducing cardiovascular events. (6,58-60) Studies specifically indicating higher mortality risk in women with Surgical POI who did not use ET include the Mayo Clinic Cohort Study and the Nurse's Health Study.

The Mayo Clinic Cohort Study of Oophorectomy and Aging showed increased all-cause mortality of 67% in women who experienced Surgical POI prior to age 45.5,6 Among these women, those who did not take estrogen until the age of 45 or later accounted for most of the mortality (HR 1.84; 95% CI 1.27-2.68).(58) Women who experienced Surgical POI before age 45 and used estrogen until age 45 or longer showed a reduced mortality risk compared to the referent women (HR 0.65;95% CI 0.31-1.41).(58)

In the Nurse's Health Study (NHS), women who experienced Surgical POI before age 50 and who did not use ET had a higher risk for all-cause mortality compared with women who did use estrogen. Cardiovascular disease and stroke were responsible for most of the mortality. NHS women who had experienced Surgical POI before age 50 and never used ET showed an 85% increased risk for stroke and a 98% increased risk of coronary heart disease compared to women who did use ET. Among women with Surgical POI before age 45 those women who did not use estrogen experienced a significant increase in mortality rate compared with those who did(HR 1.44; 95% CI 0.67-0.99).(59)

A meta-analysis of hormone therapy and total mortality in younger postmenopausal women (mean age of 54.5 years) included data from 19 randomized clinical trials and 8 prospective observational studies totalling more than 3,000,000 patient years of surveillance. The mortality risk among estrogen users was reduced by 28% when all the data was combined. (60)

Cessation of HRT after exiting research studies has been related to increased mortality. This may be mediated in part by increased catechol release related to vasomotor symptoms, and this having an adverse effect on vascular function. The observation is important because most studies include deaths within 30 to 90 days of study completion in the assigned-treatment findings. For example, Mikkola et al. reported increased cardiovascular mortality in the year immediately following hormone therapy withdrawal with 25% of the deaths occurring in the first month. (33) The Finnish group related these findings to surges of epinephrine which occurred after hormone withdrawal.(33)

Unfortunately, since the release of the WHI results in 2002 many women with Surgical POI who could have benefited by using ET have not done so. This may well be related to media reporting and unwarranted fear of using any form of menopausal hormonal therapy, including an estrogen-only regimen for women who have had a hysterectomy and require no progestin treatment. Regrettably, it has been estimated between 2002 and 2011 failure to take ET has caused almost 50,000 women with Surgical POI to die prematurely (before age 70). (61)

Estrogen and Decreased Risk of Breast Cancer

Many factors have been identified that have led to avoidance of menopausal hormone therapy (MHT). (61) Of these, fear of increased risk for breast cancer is the one most often cited. Whenever discussion about MHT occurs, no matter how positive the findings fear of breast cancer frequently overshadows the good news. Essentially unnoticed are new concepts about hormone therapy and the protective effects of estrogen in the breast.(28,62) The WHI results, showing a statistically significant reduction in breast cancer risk in women who used ET after hysterectomy, have been confirmed in other randomized controlled trials including the Danish Osteoporosis Prevention Study (DOPS).(63,64) In both WHI and DOPS, women using ET after hysterectomy compared to placebo showed more than a 20% reduced risk of developing breast cancer and more than a 60% reduced risk of dying of breast cancer. In the WHI Study, almost 40% of the women had undergone bilateral oophorectomy prior to age 50, and all of the women in DOPS who had undergone bilateral oophorectomy had their surgery at age 49 or younger.

Of particular importance to women who have had risk reducing bilateral oophorectomy are studies of women carrying BRCA mutations and who have used ET. These studies show no subsequent increase in the risk of developing breast cancer with use of ET. (65-67) The NIH-sponsored Two Sister Study is a case-control study among a cohort of sisters with and without breast cancer diagnosed prior to age 50. Among the sisters who used ET, there was a 42% lower risk for developing young-onset breast cancer (95% CI: 0.34, 0.99). Use of estrogen plus progestin was likewise not associated with an increased risk of young-onset breast cancer in this population. (68)

The mechanisms through which estrogen acts to reduce breast cancer risk are discussed by Carroll et al(28) and Chlebowski and Anderson(62) These authors highlight the suppressive and apoptotic effects of estrogen in breast cancer cells.

Improving care for women with Surgical POI

Decreasing the frequency of bilateral oophorectomy at the time of hysterectomy in premenopausal women at low risk for ovarian cancer is one part of the solution to the problem of millions of women developing Surgical POI and losing the protective effects of estrogen at an age too young, and then failing to take ET.(5,60) Another part of the solution is to replace bilateral salpingo-oophorectomy with ovary-sparing bilateral salpingectomy.(69) The effectiveness of bilateral salpingectomy in reducing risk for ovarian cancer is close to that of bilateral salpingo-oophorectomy, while at the same time reducing the harmful effects of acute and chronic estrogen deficiency. The American College of Obstetrics and Gynecology has recommended ovarian conservation and bilateral salpingectomy in women age 45 or younger.(70) These proposals have made some impact and a reduction in bilateral oophorectomy in women under age 45 has occurred.(1,2) However, there is evidence that at least 20-30% of conserved ovaries fail within 6 months to 3 years after simple hysterectomy or bilateral salpingectomy; these women should be regularly monitored for signs and symptoms of hormone deficiency.(71-73)

A third part to the solution is to promote better understanding of the benefits of ET in women with Surgical POI. The timing hypothesis underscores the urgency of encouraging women to start ET soon after oophorectomy- with the utmost urgency in the youngest women. (5,6,36)

The dilemma is that, although data strongly supports using ET in young women with Surgical POI, societal factors overwhelm the findings and the steep decline in ET use in women with Surgical POI continues. (74) Complicating the issue, there is a lack of well-trained and experienced health care professionals able to deliver appropriate care for women with POI.(75) However, the tide may be turning. New findings are too compelling to ignore; the most recent studies continue to show cardiovascular, bone, neurological, urogenital and breast protection- especially in women who use ET immediately after the onset of Surgical POI.

For premenopausal women who have had a hysterectomy and bilateral oophorectomy, the benefits of ET far outweigh risks and treatment can be life-preserving, and in some cases life-saving. The recommendation that ET be continued until the age of natural menopause (51 to 52) is based on the findings of efficacy and safety of estrogen use to that age. However, there are significant findings which support continuing use of ET at least until the age of 60. (36,63,64) Women with Surgical POI who have hypoactive sexual desire may benefit from adding an androgen to their estrogen-only treatment, for hypoactive sexual.(76) Women who have undergone risk reduction bilateral oophorectomy with the uterus left in situ are in a different situation. Their treatment should be similar to that recommended for women who have experienced POI.

Summary and Conclusions

Surgical POI is the most frequent cause of premenopausal ovarian hormone deficiency. Loss of ovarian hormone production induces symptoms that should be taken seriously. The symptoms affect quality of life, capacity to function at home and in the workplace, and are associated with disease development and increased mortality. Estrogen therapy (ET) effectively controls most of these symptoms and inhibits pathological processes that can lead to osteoporosis, atherosclerosis, dementia, and other disorders. ET is most beneficial when started at the time of oophorectomy and continued at least until age 50. Extension of ET, for symptom control and disease prevention, at least until the age of 60, is supported by the findings of the WHI estrogen-only trial as well as other recent randomized clinical trials.

Perhaps the most significant reason women and clinicians fear and avoid ET is the mistaken belief that it increases their risk for developing breast cancer. In fact, ET does not increase breast cancer risk in premenopausal women including women who carry the BRCA 1 and 2 gene mutations.

It is unfortunate that fear of ET has led to widespread avoidance of its use. Facing this reality, some authors have advocated retention of ovaries at the time of hysterectomy in women age 45 and younger in order to maintain the protective effects of ovarian hormones. Others have advocated bilateral salpingectomy with hysterectomy, a procedure that would greatly reduce ovarian cancer risk while still retaining the ovaries.

Facts about the safety and efficacy of ET should be used to help women and their clinicians overcome their fears of hormone therapy. However, it is important to recognize that fear of hormone therapies has become deeply imbedded, publication of the positive findings for ET have had little impact, and the decline in use of ET continues.

Table.

Effect of delay in hormone replacement therapy on bone health in women undertaking bilateral risk reducing salpingo-oophorectomy (BRRSPO) ()

Length of estrogen deprivation Median age at BRRSPO (range) Median age at DEXA (range) DEXA normal Osteopenia (DEXA T score −1.0 to −2.4) Osteoporosis (DEXA T score <−2.4)
0 42.6 (31–48) 49 (41–61) 26 (84%) 4 (13%) 1 (3%)
1–23 months 42.9 (34–48) 50 (32–68) 6 (60%) 3 (30%) 1 (10%)
≥ 24 months 41.1 (24.9–48) 50 (38–78) 42 (54%) 26 (33%) 10 (13%)

Acknowledgments

This work was supported in part by the Intramural Research Program, National Institutes of Health, Bethesda, MD

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Contributor Information

Philip M. Sarrel, Obstetrics, Gynecology and Reproductive Sciences and Psychiatry, Yale University, New Haven, Connecticut.

Shannon D. Sullivan, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, Phone: 202-701-5174, Fax: 301-796-9712.

Lawrence M. Nelson, CAPT US Public Health Service, Intramural Research Program on Reproductive and Adult Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human, Development (NICHD), National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1109, Bethesda, MD 20892-1103.

References

  • 1.Asante A, Whiteman MK, Kulkarni A, Cox S, Marchbanks PA, Jamieson DJ. Elective oophorectomy in the United States: trends and in-hospital complications, 1998–2006. Obstet Gynecol. 2010;116:1088–1095. doi: 10.1097/AOG.0b013e3181f5ec9d. [PubMed: 20966693] [DOI] [PubMed] [Google Scholar]
  • 2.Wright JD, Herzog TJ, Tsui J, Ananth CV, Lewin SN, Lu YS, et al. Nationwide trends in the performance of hysterectomy in the United States. Obstet Gynecol. 2013;122:233–41. doi: 10.1097/AOG.0b013e318299a6cf. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Rebbeck TR, Kauff ND, Domcheck SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J. Natl Cancer Inst. 2009;191:80–87. doi: 10.1093/jnci/djn442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Gierach GL, Pfeiffer RM, Patel DA, Black A, Schairer C, Gill A. Long- term overall and disease-specific, mortality associated with benign gynecologic surgery performed at different ages. Menopause. 2014;21(6):592–601. doi: 10.1097/GME.0000000000000118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Shuster LT, Rhodes DJ, Gostout BS, Grosshardt BR, Rocca WA. Premature menopause or early menopause: long-term health consequences. Maturitas. 2010;65:161–166. doi: 10.1016/j.maturitas.2009.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric. 2015;18(4):483–91. doi: 10.3109/13697137.2015.1020484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Chubaty A, Shandro MT, Schuurmans N, Yuksel N. Practice patterns with hormone therapy after surgical menopause. Maturitas. 2011;69(1):69–73. doi: 10.1016/j.maturitas.2011.02.004. [DOI] [PubMed] [Google Scholar]
  • 8.Benshushan A, Rojansky N, Chaviv M, Arbel-Alon S, Benmeir A, Imbar T, et al. Climacteric symptoms in women undergoing risk-reducing bilateral salpingo-oophorectomy. Climacteric. 2009;12:404–409. doi: 10.1080/13697130902780846. [DOI] [PubMed] [Google Scholar]
  • 9.Nachtigall L. Hot flashes: is a hot flash just a hot flash? Menopause. 2014;2155(6):1–2. doi: 10.1097/GME.0000000000000250. [DOI] [PubMed] [Google Scholar]
  • 10.Thurston RC, El Khoudary SR, Sutton-Tyrrell K, Crandall CJ, Gold E, Sternfeld B, et al. Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women's Health Across the Nation. Menopause. 2011;18:1044–1051. doi: 10.1097/gme.0b013e31821f5d39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and the risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477. doi: 10.1001/jama.297.13.1465. [DOI] [PubMed] [Google Scholar]
  • 12.Kronenberg F. Hot flashes, epidemiology and physiology. Ann N Y Acad Sci. 1990;592:122–133. doi: 10.1111/j.1749-6632.1990.tb30316.x. [DOI] [PubMed] [Google Scholar]
  • 13.Challberg J, Ashcroft L, Lalloo F, Eckersley B, Clayton R, Hopwood P, et al. Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT. British Journal of Cancer. 2011;105:22–27. doi: 10.1038/bjc.2011.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Freedman RR. Physiology of hot flashes. Am J Hum Biol. 2001;13:453–464. doi: 10.1002/ajhb.1077. [DOI] [PubMed] [Google Scholar]
  • 15.Sarrel PM, Lindsay DC, Rosano GMC, Poole-Wilson PA. Angina and normal coronary arteries in women: gynecologic findings. Am J Obstet Gynecol. 1992;167:467–472. doi: 10.1016/s0002-9378(11)91431-8. [DOI] [PubMed] [Google Scholar]
  • 16.Sarrel PM. Sexuality and menopause. Obstet Gynecol. 1990;75(suppl):26S–30S. [PubMed] [Google Scholar]
  • 17.Thurston RC, Aizenstein HJ, Derby CA, Sejdic E, Maki PM. Menopausal hot flashes and white matter hyperintensities. Menopause. 2016;23(1):27–31. doi: 10.1097/GME.0000000000000481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA, De Jager PL. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology. 2014;82:222–9. doi: 10.1212/WNL.0000000000000033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Sarrel PM, Portman D, Lefebvre MA, Lafeuille MH, Grittner AM, Fortier J, et al. Incremental direct and indirect costs of untreated vasomotor symptoms. Menopause. 2015;22(3):260–66. doi: 10.1097/GME.0000000000000320. [DOI] [PubMed] [Google Scholar]
  • 20.Geukes M, VanAalst MP, Rebroek SJW, Laven JSE, Oosterhof H. The impact of menopause on work ability in women with severe menopausal symptoms. Maturitas. 2016;90:3–8. doi: 10.1016/j.maturitas.2016.05.001. [DOI] [PubMed] [Google Scholar]
  • 21.Graziottin A, Basson R. Sexual dysfunction in women with premature menopause. Menopause. 2004;11:766–77. doi: 10.1097/01.gme.0000139926.02689.a1. [DOI] [PubMed] [Google Scholar]
  • 22.Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343(10):682–8. doi: 10.1056/NEJM200009073431002. [DOI] [PubMed] [Google Scholar]
  • 23.Tucker PE, Bulsara MK, Salfinger SG, Tan JJ, Green H, Cohen PA. The effects of pre-operative menopausal status and hormone replacement therapy (HRT) on sexuality and quality of life after risk-reducing salpingo-oophorectomy. Maturitas. 2016 Mar;85:42–8. doi: 10.1016/j.maturitas.2015.12.004. [DOI] [PubMed] [Google Scholar]
  • 24.Rosenberg L, Hennekens CH, Rosner B, Belanger C, Rothman KJ, Speizer FE. Early menopause and the risk of myocardial infarction. Am J Obstet Gynecol. 1981;139:47–51. doi: 10.1016/0002-9378(81)90410-5. [DOI] [PubMed] [Google Scholar]
  • 25.Thurston RC, Barinas-Mitchell E, Jennings JR, Santoro N, von Kanel R, Chang Y, et al. Physiologically monitored hot flashes and subclinical cardiovascular disease among midlife women. Menopause. 2015;22:1371. [Google Scholar]
  • 26.Kerber IJ, Turner RJ. Eu-estrogenemia, KNDY Neurons, and Vasomotor Symptoms. JAMA Internal Medicine. 2015;175(9):1586. doi: 10.1001/jamainternmed.2015.3577. [DOI] [PubMed] [Google Scholar]
  • 27.Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Parts 1 and 2. J Am Geriatr Soc. 2013;61(6):1005–1018. doi: 10.1111/jgs.12140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Carroll JS, Meyer CA, Song J, LI W, Geistlinger TR, Eeckhoute J, et al. Genome-wide analysis of estrogen receptor binding sites. Nature Genetics. 2006;38(11):1289–1297. doi: 10.1038/ng1901. [DOI] [PubMed] [Google Scholar]
  • 29.Wuest JH, Dry TJ, Edwards JE. The degree of coronary atherosclerosis in bilaterally oophorectomized women. Circulation. 1953;7:801–808. doi: 10.1161/01.cir.7.6.801. [DOI] [PubMed] [Google Scholar]
  • 30.Forte TF, editor. American Heart Association Monograph Series. Futura Publishing Company; American Heart Association; Armonk, NY: 1997. Hormonal, Metabolic, and Cellular Influences on Cardiovascular Disease in Women. [Google Scholar]
  • 31.Gerhard M, Ganz P. How do we explain the clinical benefits of estrogen? From bedside to bench. Circulation. 1995;92(1):5–8. doi: 10.1161/01.cir.92.1.5. [DOI] [PubMed] [Google Scholar]
  • 32.Lantto H, Mikkola TS, Tuomikoski P, Viitasalo M, Vaananen H, Sovijarvi ARA, et al. Cardiac repolarization in recently postmenopausal women with or without hot flushes. Menopause. 2016;23(5):528–534. doi: 10.1097/GME.0000000000000564. [DOI] [PubMed] [Google Scholar]
  • 33.Mikkola TS, Tuomikoski P, Lytinen H, Korhonen P, Hoti F, Vattulainen P, et al. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J Clin Endocinol Metab. 2015;10:4588–94. doi: 10.1210/jc.2015-1864. [DOI] [PubMed] [Google Scholar]
  • 34.Allison MA, Manson JE, Langer RD, Carr JJ, Rossouw JE, Pettinger MB, et al. Oophorectomy, hormone therapy, subclinical coronary artery disease in women with hysterectomy: the Women's Health Initiative coronary artery calcium study. Menopause. 2008;15(4Pt 1):639–47. doi: 10.1097/gme.0b013e31816d5b1c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014;161:249–60. doi: 10.7326/M14-0353. [DOI] [PubMed] [Google Scholar]
  • 36.Hodis HN, Mack WJ, Henderson VW, Kono N, Stanczyk F, Selzer S, et al. Vascular effects of early vs late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221–31. doi: 10.1056/NEJMoa1505241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ingelsson E, Lundholm C, Johansson AL, Altman D. Hysterectomy and risk of cardiovascular disease: a population-based cohort study. Eur Heart J. 2011;32(6):745–50. doi: 10.1093/eurheartj/ehq477. [DOI] [PubMed] [Google Scholar]
  • 38.Lokkegaard E, Jovanovic Z, Heitmann BL, Kelding N, Ottesen B, Pedersen AT. The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy. Maturitas. 2006;53(2):226–33. doi: 10.1016/j.maturitas.2005.04.009. [DOI] [PubMed] [Google Scholar]
  • 39.Atsma F, Bartelink MEL, Grobbee DE, van der Schouw Y. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause. 2006;13(2):265–279. doi: 10.1097/01.gme.0000218683.97338.ea. [DOI] [PubMed] [Google Scholar]
  • 40.Carr MC. The emergence of the metabolic syndrome with the menopause. J Clin Endocrinol Metabol. 2003;88:2404–2411. doi: 10.1210/jc.2003-030242. [DOI] [PubMed] [Google Scholar]
  • 41.Pirimoglu ZM, Arslan C, Buyukbayrak EE, Kars B, Karsidag YK, Unal O, et al. Glucose tolerance of premenopausal women after menopause due to surgical removal of ovaries. Climacteric. 2011;14:453–457. doi: 10.3109/13697137.2010.539723. [DOI] [PubMed] [Google Scholar]
  • 42.Appiah D, Winters SJ, Homung CA. Bilateral oophorectomy and the risk of incident diabetes in postmenopausal women. Diabetes Care. 2014;37:725–33. doi: 10.2337/dc13-1986. [DOI] [PubMed] [Google Scholar]
  • 43.Dorum A, Tonstad S, Liavaag AH, Michelsen TM, Hildrum D, Dahl AA. Bilateral oophorectomy before 50 years of age is significantly associated with the metabolic syndrome and Framingham risk score: a controlled, population-based study (HUNT-2) Gynecol Oncol. 2008;109:377–383. doi: 10.1016/j.ygyno.2008.02.025. [DOI] [PubMed] [Google Scholar]
  • 44.Kim C, Edelstein SL, Crandall JP, Diabelea D, Kitabchi AE, Hamman RF, et al. Diabetes prevention program research group. Menopause and risk of diabetes in the Diabetes Prevention Program. Menopause. 2011;18:857–868. doi: 10.1097/gme.0b013e31820f62d0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Yoshida T, Takahashi K, Yamatani H, Takata K, Kurachi H. Impact of surgical menopause on lipid and bone metabolism. Climacteric. 2011;14:445–452. doi: 10.3109/13697137.2011.562994. [DOI] [PubMed] [Google Scholar]
  • 46.Lindsay R. The menopause: sex steroids and osteoporosis. Clin Obstet Gynecol. 1987;30(4):847–859. doi: 10.1097/00003081-198712000-00008. [DOI] [PubMed] [Google Scholar]
  • 47.Mucowski SJ, Mack WJ, Shoupe D, Kono N, Paulson R, Hodis HN. The effect of prior oophorectomy on changes in bone mineral density and carotid artery intima-media thickness in postmenopausal women. Fertil Steril. 2014;101(4):1117–1122. doi: 10.1016/j.fertnstert.2013.12.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grosshardt BR, deAndrade M, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–83. doi: 10.1212/01.wnl.0000276984.19542.e6. [DOI] [PubMed] [Google Scholar]
  • 49.Phung TK, Waltoft BL, Laursen TM, Settnes A, Kessing LV, Mortensen PB, Waldemar G. Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study. Dement Geriatr Cogn Disord. 2010;30(1):43–50. doi: 10.1159/000314681. [DOI] [PubMed] [Google Scholar]
  • 50.Shao H, Breitner JCS, Whitmer RA, Wang J, Hayden K, Wengreen H, et al. Hormone therapy and Alzheimer's Disease. Neurology. 2012;79(18):1846–52. doi: 10.1212/WNL.0b013e318271f823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Rocca WA, Grosshardt BR, Shuster LT. Oophorectomy, estrogen, and dementia: A 2104 Update. Mol Cell Endocrinol. 2014;389:7–12. doi: 10.1016/j.mce.2014.01.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Rocca WA, Grosshardt BR, Geda YE, Gostout BS, Bower JH, Maraganore DM, et al. Long-term risk of depressive and anxiety symptoms after early oophorectomy. Menopause. 2008;15(6):1050–1059. doi: 10.1097/gme.0b013e318174f155. [DOI] [PubMed] [Google Scholar]
  • 53.Nathorst-Boos J, von Schoultz B, Carlstrom K. Elective ovarian removal and estrogen replacement therapy-effects on sexual life, psychological well-being and androgen status. J Psychosom Obstet Gynaecol. 1993;14:283–293. doi: 10.3109/01674829309084451. [DOI] [PubMed] [Google Scholar]
  • 54.Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006;63(4):385–90. doi: 10.1001/archpsyc.63.4.385. [DOI] [PubMed] [Google Scholar]
  • 55.Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58(6):529–34. doi: 10.1001/archpsyc.58.6.529. [DOI] [PubMed] [Google Scholar]
  • 56.Zweifel JE, O'Brien WH. A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology. 1997;22(3):189–212. doi: 10.1016/s0306-4530(96)00034-0. [DOI] [PubMed] [Google Scholar]
  • 57.Gibson CJ, Joffe H, Bromberger JT, Thurston RC, Lewis TT, Khalil N, et al. Mood symptoms after natural menopause and hysterectomy with and without bilateral oophorectomy among women in midlife. Obstet Gynecol. 2012;119:935–41. doi: 10.1097/AOG.0b013e31824f9c14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Rivera CM, Grosshardt BR, Rhodes DJ, Brown RD, JR, Roger VL, Melton LJ, 3rd, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. 2009;16(1):15–23. doi: 10.1097/gme.0b013e31818888f7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Parker WH, Feskanich D, Broder MS, Chang E, Shoupe D, Farquhar CM, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses Health Study. Obstet Gynecol. 2013;121:709–16. doi: 10.1097/AOG.0b013e3182864350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Salpeter SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med. 2009;122:1016–1022. doi: 10.1016/j.amjmed.2009.05.021. [DOI] [PubMed] [Google Scholar]
  • 61.Sarrel PM, Njike VY, Vinante V, Katz DL. The Mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59. AJPH. 2013;103(9):1583–88. doi: 10.2105/AJPH.2013.301295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Chlebowski RT, Anderson GL. Changing Concepts: Menopausal Hormone Therapy and Breast Cancer. J Natl Cancer Inst. 2012;104:517–527. doi: 10.1093/jnci/djs014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305–1314. doi: 10.1001/jama.2011.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: a randomized trial. BMJ. 2012;345:e6409. doi: 10.1136/bmj.e6409. [DOI] [PubMed] [Google Scholar]
  • 65.Marchetti C, Iadarola R, Palaia I, di Donato V, Perniola G, Muzil L, et al. Hormone therapy in oophorectomized BRCA 1/2 mutation carriers. Menopause. 2014;21(7):763–768. doi: 10.1097/GME.0000000000000126. [DOI] [PubMed] [Google Scholar]
  • 66.Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROST Study Group. J Clin Oncol. 2005;23(31):7804–10. doi: 10.1200/JCO.2004.00.8151. [DOI] [PubMed] [Google Scholar]
  • 67.Armstrong K, Schwartz JS, Randall T, Rubin SC, Weber B. Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: a decision anaylysis. J Clin Oncol. 2004;22(6):1045–54. doi: 10.1200/JCO.2004.06.090. [DOI] [PubMed] [Google Scholar]
  • 68.O'Brien KM, Fei C, Sandler DP, Nichols HB, DeRoo LA, Weinberg CR. Hormone therapy and young-onset breast cancer. Am J Epidemiol. 2015;181(10):799–807. doi: 10.1093/aje/kwu347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Parker W, Broder M, Chang E, Feskanich D, Farquhar C, Liu Z, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstet Gynecol. 2009;113(5):1027–1037. doi: 10.1097/AOG.0b013e3181a11c64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.ACOG Committee on Practice Bulletins Elective and risk-reducing salpingo-oophorectomy. 2008 doi: 10.1097/01.AOG.0000291580.39618.cb. ACOG Practice Bulletin Number 89. [DOI] [PubMed] [Google Scholar]
  • 71.Moorman PG, Myers ER, Schildkraut JM, Iversen ES, Wand F, Warren N. Effect of hysterectomy with ovarian preservation on ovarian function. Obstet Gynec. 2011;118(6):1271–9. doi: 10.1097/AOG.0b013e318236fd12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Trabuco EC, Moorman PG, Algeciras-Schimnich A, Weaver AL, Cliby WA. Association of ovary-sparing hysterectomy with ovarian reserve. Obstet Gynecol. 2016;127:81, 9–827. doi: 10.1097/AOG.0000000000001398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Siddle N, Sarrel PM, Whitehead MI. The effect of hysterectomy on the age at ovarian failure: Identification of a subgroup of women with premature loss of ovarian function and literature review. Fertil Steril. 1987;47:94–100. doi: 10.1016/s0015-0282(16)49942-5. [DOI] [PubMed] [Google Scholar]
  • 74.Sprague BL, Trentham-Dietz A, Cronin KA. A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 199-2010. Obstet Gynecol. 2012;120(3):595–603. doi: 10.1097/AOG.0b013e318265df42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Manson JE, Kaunitz AM. Menopause Management- Getting clinical care back on track. N Engl J Med. 2016;374:803–806. doi: 10.1056/NEJMp1514242. [DOI] [PubMed] [Google Scholar]
  • 76.Wierman ME, Arlt W, Basson R, Davis SR, Miller KK, Murad MH, et al. Androgen therapy in women:a reappraisal: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(10):3489–510. doi: 10.1210/jc.2014-2260. [DOI] [PubMed] [Google Scholar]

RESOURCES