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The etiology of menopause: not just ovarian dysfunction but also a role for the central nervous system

Perlman, Barry; Kulak, David; Goldsmith, Laura, T.; Weiss, Gerson

Global Reproductive Health: June 2018 - Volume 3 - Issue 2 - p e8
doi: 10.1097/GRH.0000000000000008
Review Articles

Background: The hormonal changes which occur leading up to menopause have been described in multiple cross-sectional and longitudinal studies. Results from these studies document the occurrence of marked alterations in pituitary-hypothalamic function, along with the changes in the ovary, which play a role in the etiology of menopause. However, the role of pituitary-hypothalamic function in the menopausal transition (MT) has been generally overlooked.

Methods: Literature searches were performed using PubMed, Scopus, and Medline, for articles with content related to menopause and the MT. The searches were restricted to English language observational studies and reviews of human studies and clinical trials.

Results: During the MT, in addition to a reduction in the number of ovarian follicles, there is a marked reduction in the sensitivity of the central nervous system to both the positive and negative feedback effects of estrogen. These changes in sensitivity explain menstrual irregularities and systemic systems which are present in the time before the final menstrual period. Although the timing of menopause is difficult to predict, broad patterns in hormonal changes are seen, including a slow drop in inhibin B levels, followed by a monotropic rise in follicle-stimulating hormone during the late reproductive period. The MT is marked by irregular cycles with unpredictable luteinizing hormone levels and unpredictable ovulation. The levels of estrogen remain stable, or are even elevated through most of the MT, and levels of estrogen do not begin to decrease until late in the MT. The Stages of Reproductive Aging Workshop guidelines have improved the homogeneity of classifications in studies.

Conclusions: On the basis of longitudinal hormone studies, it is clear that desensitization of the hypothalamic-pituitary-ovarian feedback loop plays an important role, in addition to a decrease in follicle number and insensitivity of remaining follicles to the positive feedback of estrogen, to trigger ovulation. Further studies in humans are needed to elucidate the mechanisms responsible for these perimenopausal changes if proper therapeutic modalities for the symptoms associated with menopause can be developed.

Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, Newark, NJ

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 2 April 2018

Corresponding author. Address: Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, MSB E-506, 185 South Orange Avenue, Newark 07101-1709, NJ. E-mail address: perlman.barry@gmail.com (B. Perlman).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Received November 27, 2017

Accepted December 21, 2017

In the United States, there are nearly 70 million women over the age of 45 years, and 23 million between 45 and 55 years of age1. Eighty percent of women in the latter age group will experience symptoms related to menopause2. Symptoms such as heavy and/or irregular bleeding, breast tenderness, and hot flashes lead to increases in physician visits and the need for therapy, and reduce productivity3. Understanding of the underlying mechanisms responsible for menopause is necessary to enable proper treatment, explanation, and counseling of these patients. However, a complete explanation of the etiology of the menopause has yet to be provided. The data which demonstrate that a reduction in pituitary sensitivity to estradiol occurs during the menopausal transition (MT), in addition to the dysfunction in the ovary and its response to endogenous hormone signals, are reviewed in the current report. These newer data enhance our understanding of the etiology of the menopause, which is needed to assist physicians and patients in understanding and treating the symptoms that occur during this period.

Menopause, which is a normal life event, is defined as the absence of a menstrual period for 12 consecutive months associated with a hypergonadotropic state. The age of menopause onset is related to genetic, behavioral, and environmental factors. It has been shown that in different patient populations and ethnicities, the median age of menopause ranges from 49 to 52 years. In a World Health Organization study of 18,997 females from Asia, Australia, Africa, Europe, and North and South America, the median age of the final menstrual period (FMP) was 50 years4. However, both cross-sectional and prospective studies on diverse populations in the United States have consistently shown the median FMP to be between 51 and 52 years. The Study of Women’s Health Across the Nation (SWAN), of 14,620 ethnically diverse women between the ages of 40 and 55 years, found that the median age of the FMP was 51.4 years5. The SWAN study also showed a difference of age at menopause based on race, with Japanese women having a later natural menopause than Caucasian, African American, Hispanic, or Chinese women, who show no difference in age at menopause5. The Massachusetts Women’s Health Study, which studied 7828 Caucasian women age 45–55 years living in Massachusetts, also found that the median age of the FMP was 51.4 years6. Differences seen in age across a world population suggest that the occurrence of menopause is likely related to many different factors, including race, ethnicity, body habitus, lifestyle choices, and specific genetic polymorphisms. There are likely many genetic, environmental, and demographic factors that have yet to be elucidated.

Before the FMP, a transitional period referred to as perimenopause or the MT occurs. The length of the MT varies widely between individuals and in different studies, partly due to the heterogeneity in the definitions used for MT. Most studies, however, agree that about half of women will reach menopause within 4 years of the onset of menstrual irregularity. The vast majority of women will take between 2 and 6 years to reach menopause, with a small minority taking as long as 8 years7,8.

One challenge in studying the MT has been creating a classification system that is broad enough to accommodate the variation in symptoms, while maintaining useful definitions for patient care and study use. The World Health Organization defines the period of perimenopause somewhat vaguely as the period immediately before the menopause through the first year after menopause9. The Massachusetts Women’s Health Study recommends self-reported menstrual irregularities or 3–11 months of amenorrhea as the definition of perimenopause for epidemiologic use10.

In an effort to create more uniformity in epidemiologic studies and in clinical guidelines, the North American Menopause Society created the Stages of Reproductive Aging Workshop (STRAW) classification system in 200111. The goals of STRAW were to create a “relevant and useful staging system” that more accurately reflects the subtle changes and stages that lead to menopause, and to “revise the nomenclature” which had been confusing, utilizing poorly defined terms. STRAW defined 5 stages leading up to menopause and 2 following it designated: −5 to +2. Included is a late reproductive stage (−3) that precedes the MT (−2 and −1) but is marked by decreased reproductive potential or fecundity and a rise in follicle-stimulating hormone (FSH) levels on day 2–5 of the cycle. The MT is divided into an early (−2) and a late stage (−1) that directly precede the FMP (0) and menopause. Slight modifications by ReSTAGE and STRAW+10 simplified the classification criteria and expanded the system to allow its use in greater numbers of women12,13. STRAW+10 described early MT to be a persistent difference in cycle length of 7 or more days, while late MT was defined as amenorrhea of 60 or more days or an FSH level of 25 IU/L or higher13.

The MT is not progressive and linear, but rather varies from cycle to cycle, making it intrinsically difficult to categorize stages of the transition14. Many studies have recommended using biochemical markers, such as early follicular FSH levels of >20 mIU/mL and >40 mIU/mL to mark early and late MT, respectively15,16. The issue remains, however, that these levels of FSH can be seen in normal cycling women. The 2012 STRAW+10 guidelines, although based mostly on menstrual cycle changes, allow a random serum FSH level of at least 25 IU/L to define late MT. An FSH level of <25 IU/L, however, does not exclude patients from late MT, as there is considerable variation in serum FSH levels between cycles, specifically in perimenopausal women. Measurements of biochemical markers such as inhibin A and inhibin B and antimullerian hormone are expensive, and there is a lack of international standards for these markers. Thus, it is not thought that they are appropriate for epidemiologic use13. Reliance of menstrual changes suggested by the STRAW+10 guidelines excludes its use in women who at baseline have abnormal menstrual patterns, such as women with polycystic ovarian syndrome, uterine or ovarian anomalies, women who are chronically ill, or engaged in heavy aerobic exercise, and women who have previously undergone a hysterectomy. The STRAW+10 system is also limited, as many women may not transition through all the stages, and 10% of women will cease menstruating abruptly, with no period of prolonged irregularity17. The use of systemic symptoms, such as hot flushes, vaginal dryness, and/or breast swelling, to demarcate the MT has been assessed, but using these symptoms would provide low sensitivity and specificity, and thus this has not found general acceptance18. Ultimately, most studies use guidelines that allow for optimization to the goals of that study, and many longitudinal studies have simply used age as the primary criteria for inclusion to accommodate the significant variation in individual symptoms8,14,19.

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Symptoms

Clinical symptoms, which can have a major impact on the daily activities of women, are often the driving force to seek medical attention. Of all symptoms reported, 90% of women who have reached menopausal age experience abnormal bleeding, with episodes of bleeding lasting >10 days before the FMP20. A longitudinal study by Hale et al21, which compared menstrual bleeding in 39 perimenopausal women to that of 21 midreproductive age women, showed that menstrual bleeding after ovulation increases, from median levels of 30–55 mL in the early MT, and to 69 mL in the late MT.

In addition to irregular bleeding, many women will experience vasomotor symptoms22. Rates of women who have vasomotor symptoms vary by race, with the consistently highest rate reported by African Americans, followed by Hispanics and whites, and the lowest reported by Chinese and Japanese23,24. Studies have shown that the percentage of women who have vasomotor symptoms increases with age, with the greatest percentage of patients affected coinciding with the median age of menopause. A longitudinal study of women from Sweden by Rodstrom et al25, indicated that reported vasomotor symptoms are present in 11% of women at 38 years of age, in 60% in women at 54 years of age, and in 9% of women at 72 years of age. A meta-analysis by Politi et al26, including information from 35, 445 study participants, reported that vasomotor symptoms increased sharply 2 years before the FMP, peaked 1 year after the FMP, and did not return to premenopausal levels until 8 years after the FMP. The impact of symptoms on women is highly detrimental, with a significant reduction in quality of life27. An association with a hormonal pattern has been reported by Woods et al28, lower estrogen and higher FSH levels significantly associated with high-severity hot flashes.

Another common symptom often reported is breast tenderness. A longitudinal study by Dennerstein et al29, of 438 women between 45 and 55 years old who were observed for 7 years, consisting of a yearly questionnaire and day 4–8 FSH and estrogen levels measured annually, reported breast tenderness/soreness as the fourth most common symptom of women in the early MT. This study reported that, unlike any other symptoms, breast tenderness/soreness followed patterns of estrogen levels. A decline in symptoms occurred with progression from early to late perimenopause accompanied by decreased circulating estrogen levels. A further decline in breast tenderness/soreness was noted at 1, 2, and 3 years post-FMP29. As demonstrated in multiple studies, symptoms clearly exist and are very bothersome, but questions remain regarding the definitive time periods in which these symptoms occur.

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Endocrinology of the menstrual cycle in midreproductive age women

The understanding of the neuroendocrine regulation of the human menstrual cycle is based on studies in rhesus monkeys by Knobil30. The female rhesus monkey serves as an appropriate model for humans due to its 28 day menstrual cycle, 14 day luteal phase, and almost identical hormone secretion patterns as those of women. During a normal menstrual cycle, luteinizing hormone (LH) and FSH, secreted from the anterior pituitary, stimulate granulosa and theca cells in ovarian follicles. The granulosa cells produce estrogen, which exerts negative feedback to the brain and inhibits production of FSH31,32. Of the multiple follicles recruited, in most cases only a single dominant follicle will continue to grow and produce increasing amounts of estrogen. Initially, estrogen works as a negative feedback stimulus and decreases FSH production31,32. After a sufficient strength and duration of estrogen exposure, positive feedback (superimposed on negative feedback) of estrogen stimulates a surge of LH and FSH33. The LH surge subsequently triggers ovulation of the dominant follicle, which then transitions to its new role as a progesterone producing corpus luteum.

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Endocrinology of the MT

The MT is marked by wide fluctuations in the menstrual bleeding patterns and in hormone levels. FSH plays a major role controlling the normal menstrual cycle, with changes in levels during the MT and menopause. Klein et al demonstrated that normally cycling, 40–45 year old (n=21) women, had mean early (day 2–4) FSH levels of 9.3 IU/L, higher than the mean levels of 6.6 IU/L in 20–25 year old (n=20) normally cycling women34. Data from the SWAN study, reported by Randolph et al35, showed that FSH levels begin to rise 6 years before the FMP, with a maximum slope of rise 2 years before the FMP, and levels continue to rise for 2 years after the FMP before levels plateau. Rannevik et al16 reported that FSH levels begin to rise 60 months before FMP.

Individual FSH levels fluctuate, with lack of predictability being the norm. Metcalf et al36 found that women in the MT often had hormonal “patterns rarely seen at other times in reproductive life”. Women in the MT could have elevated gonadotropins with normal levels of estrogen, or high levels of estrogen with normal gonadotropin levels. Furthermore, this longitudinal study of Metcalf and colleagues, in which weekly urine samples were collected for 14–87 months from 31 perimenopausal women, 22 postmenopausal women, and 20 premenopausal women, demonstrated that perimenopausal women could have various patterns of gonadotropins consisting of 1-elevated levels of both FSH and LH, 2-high FSH with normal LH, or 3-low FSH with high LH. Elevated FSH was never seen in premenopausal women36. These studies help to clarify the variability in cycle types during the MT, and confirm that elevated FSH levels are not detected in younger premenopausal women. Further studies regarding changes in pulse regulation need to be conducted.

Basal levels of LH may be slightly higher during the late MT. However, this change has a minimal role. LH is normally released from the anterior pituitary in a pulsatile manner. During the MT these pulses may be wider, allowing for more release of hormone. Reame et al37 reported that mean LH concentrations and LH pulse amplitude during the late luteal phase in perimenopausal women were higher than in younger women. Matt et al38 found that perimenopausal women had greater LH interpulse interval time, greater LH pulse width, and greater LH half-life, than younger women, suggesting decreased LH pulse frequency, and prolonged LH pulse duration in perimenopausal women, with no change in LH amplitude. Santoro et al19 also reported total cycle LH levels are elevated in perimenopausal women.

Levels of luteal progesterone are lower during the MT. An early observational study by Santoro and colleagues, of 11 perimenopausal women and controls of postmenopausal and young women, showed that there is decreased excretion of luteal phase urinary pregnanediol glucuronide in the perimenopausal women than in younger normal subjects19. Urinary pregnanediol is an inactive metabolic product of progesterone that correlates with serum progesterone levels. Data from the Daily Hormone Study of the SWAN study, reported by Santoro et al39 demonstrated progesterone levels drop annually by an adjusted mean of 6.6%. This study included 848 women, age 43–53 years, who collected urine daily, for 1 cycle or up to 50 days, annually for 3 years. During this time period, the rate of ovulation decreased from 80.9% to 64.7%, and anovulatory prolonged cycles (>50 d) increased from 8.4% of cycles in year 1 to 24% by the third year39. Thus, as women transition toward menopause, a decrease in luteal progesterone can be expected.

Studies are in an agreement that estrogen levels do not decrease during the MT, but rather either remain the same or even increase. A prospective study by Rannevik et al16, of 160 women, followed from age 48, with blood samples taken every 6 months for 7–12 years, showed that estrogen levels were stable until 1–6 months before the FMP, then began to drop. Santoro et al19, reported greater estrone conjugate (E1c, an estradiol metabolite) excretion in 11 perimenopausal women aged 43–52 years old, than in a younger, control group of 11 midreproductive aged women, 19–38 years old. Another prospective study, performed by Burger et al, of 150 women, 45–55 years old, in which annual blood samples were collected for 6 years, showed high variability in serum estrogen levels, with a persistent drop not occurring until 1 year before the FMP40. The Daily Hormone Study of SWAN, reported by Santoro et al41, showed that mean total cycle integrated E1c levels and the daily E1c levels were the same for perimenopausal women, as that of younger women. A prospective study by Ferrell et al42, of 156 women, aged 25–58 years old, who were followed with daily urine for 6 months for a total of 5 years, reported that aggregrate E1c levels peaked between 35 and 40 years old. When viewed by individual, it could be seen that estrogen levels rose until 45 years of age, then began to decline42. That estrogen levels do not decline during the MT, but remain the same or increase may explain the symptoms which occur and frequently become more prevalent during this time period, including endometrial hyperplasia, enlarging leiomyomata, and dysfunctional bleeding.

During the MT, circulating inhibin B levels differ from levels seen in younger women. Early follicular serum inhibin B levels progressively decline through the entire MT. The changes appear to be related to age, with regularly ovulating older women having a significant reduction in early follicular serum inhibin B levels than that of younger women. An observational study by Welt et al43, in which inhibin B levels in early, mid and late follicular phase serum samples from regularly ovulating women younger than 35 years of age were compared with those of women aged 35–46 years, showed a significant decline in mean composite follicular phase inhibin B levels from 125 to 96 ng/L. Klein et al44 measured inhibin B in early follicular phase (day 3) serum samples from regularly ovulating women 20–25 years old and from women aged 40–45 years and showed a significant decline in mean inhibin B levels from 110 to 69.4 ng/L. Similar results were reported by Freeman et al45, who tracked early follicular phase (days 1–6) serum samples from regularly ovulating women aged 35–47 years over 5 years and reported that inhibin B levels dropped from mean levels of 78 to 40 ng/L during this time frame. With the understanding that there is a decrease in inhibin B levels during the transition, questions remain what endocrine role it plays. The role in humans remains unclear, with the data in humans being observational.

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Etiology of the MT

Van Look et al46, in a study of 9 women with apparent perimenopausal-related abnormal menstrual bleeding, found significant variations in gonadotropin levels and unpredictable ovulation. In this study, women with elevated plasma FSH levels had either anovulatory cycles, or ovulation with a shortened follicular phase. In the women with anovulation with either normal or high FSH levels, the levels of estrogen were often normal, and stimulation with adequate exogenous estrogen failed to induce an LH surge. The investigators concluded that there may be a “change in hypothalamic-pituitary sensitivity to the feedback effects of estrogen”46. Shideler et al47 also found that women in the MT with irregular menstrual intervals fluctuated between high gonadotropin/low estrogen cycles and high estrogen/normal gonadotropin cycles, with urinary estrogen metabolite levels rising as high as 2–3 times that of normal values from the same time in the cycle. Similarly, Santoro et al19, found that women in the MT had higher urinary estrogen and LH levels than their younger counterparts, in both the follicular and luteal phases.

The hypothesis that there is a reduction in pituitary positive and negative feedback to estrogen is supported by the data that during the MT estradiol levels remain the same, or are increased, and that there is a reduction in ovulatory cycles. Weiss and colleagues added significant support to the hypothesis that reduced estrogen sensitivity is a mechanism of menopause. Using data from The Daily Hormone Study subcohort of The SWAN Study, which analyzed daily samples of urinary gonadotropins and sex steroid metabolites from 848 ethnically diverse women with a mean age of 46 years, they found that 160 of these women did not show evidence of luteal activity48. To understand the cause of this luteal activity deficiency, Weiss et al8 classified the hormonal patterns of these women. They found that these anovulatory cycles fell into one of 3 hormonal pattern categories: estrogen increase and LH surge without ovulation (type 1), estrogen increase only without LH surge (type 2), or neither estrogen increase nor LH surge (type 3). The lack of ovulation in the presence of an adequate LH surge demonstrates that there is a defect at the level of the ovarian tissue. The absence of an LH surge in the presence of adequate increased estrogen shows that there is desensitization in the positive feedback effects of estrogen in the pituitary. A reduced ability to inhibit LH, when estrogen levels should have been adequate to provide negative feedback to the central nervous system, may be the “opening of the negative feedback loop between ovarian estrogen and pituitary LH, as is seen in postmenopausal women.” Results from this study lend significant support for the hypothesis that there is a relative hypothalamic-pituitary insensitivity to estrogen in aging women.

In a longitudinal follow-up of the same women, it was shown by Skurnick et al,14 that the transition to menopause is not strictly progressive. Women fluctuate between ovulatory and nonovulatory cycles, and within nonovulatory cycles, they fluctuate between each of the 3 hormonal pattern categories (type 1, 2, or 3) described by Weiss et al8 mentioned earlier. These findings add definitive and robust support to an earlier observation by Sherman et al49, that, in perimenopausal women, estradiol patterns do not necessarily correlate with LH patterns, and that evidence of an LH surge does not necessarily imply ovulation in perimenopausal women. These data show that women in the MT have significantly different patterns of serum LH and estradiol levels in different cycles.

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Follicular changes

Throughout a women’s life, starting in utero and ending after menopause, there is a progressive reduction in the number of ovarian follicles50. The process of follicular loss in utero includes rapid follicular atresia, resulting in about half of all follicles being actively destroyed by apoptosis. Follicles that remain are finite in number, with no development of new follicles. The process slows until puberty, at which time atresia proceeds, but at a slower pace. The progression of follicular loss can be seen in many different ways. Surgical studies have shown a reduced follicle count as women age. Richardson and colleagues counted the follicles from women age 45–55 years undergoing oophorectomy. The mean number of primordial follicles in the ovaries of women who were still menstruating regularly was 10-fold higher than that in perimenopausal women (1392 vs. 142)51. Radiographically, the number of antral follicles, the potential pool of follicles that can be recruited in a given cycle, can be visualized and counted. This number slowly declines throughout reproductive adulthood, most markedly in the late reproductive period and into the MT52. An observational study by Scheffer et al52, of 162 women aged 25–46 years, showed a clear negative correlation between age and antral follicle count. Thus, the etiology of the MT is 2-fold, with alterations in the pituitary-hypothalamus pathway, along with changes in the ovary both playing roles.

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Hypothalamic changes

While decreased sensitivity to estrogen and reduction of the number of ovarian follicles appear to drive the MT, GnRH production remains potent and robust well after menopause. During the MT, the number of GnRH neurons does not change, and secretion of GnRH appears to increase, consistent with the known increase in serum FSH and LH that persist after menopause53,54. GnRH gene expression in the medial basal hypothalamus is increased in postmenopausal women54.

GnRH secretion and the arcuate nucleus are likely under the control of Kisspeptin, Neurokinin B (NKB) and Substance P. In postmenopausal women, there is significant hypertrophy of neurons in the infundibular (arcuate) nucleus which express these proteins and the estrogen receptor55,56. The hypertrophy and maintenance of function in the arcuate nucleus add support to the theory that ovarian failure contributes to menopause. Studies on primates and/or humans have not yet clearly defined the specific mechanism of the LH surge or the location of the GnRH pulse generator, therefore it is difficult to completely understand the changes that occur before, during, and after menopause. The use of nonhormonal prescription medications including selective serotonin reuptake inhibiotors, serotonin-norepinephrine reuptake inhibitors, as well as anticonvulsant medications for management of vasomotor symptoms suggests increased information is required to further understand implications of neurotransmitters.

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Conclusions

The transition into menopause is frequently accompanied by significant distress for patients, due to symptoms including menstrual irregularities, hot flashes, and breast tenderness. This time period is marked by wide fluctuations in hormone levels. Levels of early follicular phase inhibin B and FSH begin to rise during the late reproductive years, before the MT, and menstrual cycles may become shorter and/or less frequent. Levels of estrogen are the same, or even higher than those of younger women for most of the MT, and do not begin to decline until the late stages which directly precede the FMP. Although the etiology of these changes has not yet been well determined, the data demonstrate that, not only there are deficiencies at the level of the ovary, but also quite meaningful desensitization to estrogen at the level of the pituitary. More research in humans is needed to elucidate these pathways and the role of the GnRH pulse generator and neurotransmitters in the MT and its symptoms.

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Author contribution

B.P.: manuscript preparation. D.K.: manuscript preparation, literature review, and analysis. L.T.G.: literature analysis, manuscript preparation, and revision. G.W.: conception, analysis, and revision of the article.

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Sources of funding

No specific funding was sought for the study, and departmental funds were used to support the authors throughout the study period and manuscript preparation.

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Conflict of interest statement

The authors declare that they have no financial conflict of interest with regard to the content of this report.

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Keywords:

Menopause; Menopausal transition; Estradiol; Symptoms; Hormone

Copyright © 2018 The Authors. Published by Wolters Kluwer on behalf of the International Federation of Fertility Societies. All rights reserved.