Obstetrics and Gynecology: Perimenopausal Health Mala Arora, Jyothi Unni
INDEX
×
Chapter Notes

Save Clear


Perimenopausal Health: Clinical Endocrinology and Symptomatology

1Marie-Odile Gerval MBBS, 2Panagiotis G Anagnostis MD PhD, 3, * Nick Panay BSc MRCOG MFSRH
1,3Department of Obstetrics and Gynecology Queen Charlotte's & Chelsea and Chelsea & Westminster Hospitals Imperial College London, London, UK
2Unit of Reproductive Endocrinology, Department of Obstetrics and Gynecology Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
 
INTRODUCTION
Perimenopause or menopausal transition is a period during which a woman experiences variable menstrual cycle changes and symptoms attributed to different degrees of decline in ovarian reserve.1 This transformation in a woman's reproductive life is due to the coalescence of different factors: acceleration of follicle loss, deterioration of structural and functional quality of oocytes, acceleration of the follicular growth process, making it less effective, and dysregulation of central neural processes involved in luteinizing hormone (LH) surge.1 Most women experience various menstrual length irregularities, initiating with a decrease in cycle length several years before and a subsequent length variation of 14–60 days during perimenopause. The late stage of perimenopause is defined as being when periods of greater than 60 days of amenorrhea occur, lasting 1–3 years until the final menstrual period (FMP), 12 months after which menopause is confirmed. Except for menstrual disturbances, a variable symptomatology may exist, depending on the fluctuations and subsequent decrease in estrogen levels.2,3 However, about 15–25% of women report very few changes in their menstrual cycles before FMP.4
To better describe the transition of a woman through different stages of reproductive age, the Stages of Reproductive Aging Workshop (STRAW) system has been developed, with its initial form in 20015 and its new updated version in 2011, now known as STRAW+10, in an attempt to re-evaluate criteria for defining the onset of late reproductive life and early menopausal transition, as well as to enable a more detailed classification of postmenopausal status.6 STRAW is regarded as the gold-standard staging system for describing transition to menopause and it is based not only on the menstrual pattern and symptomatology of the woman, but also on changes in specific endocrine biomarkers such as inhibin B and anti-Müllerian hormone (AMH).1,6
Perimenopause actually refers to stages −2, −1, and +1a of the STRAW classification system. Stage −2, also called “early menopausal transition”, is defined as a persistent difference of greater than or equal to 7 days in the length of consecutive cycles. It is also characterized by variably elevated early follicularphase follicle-stimulating hormone (FSH) with low inhibin B and AMH concentrations. Antral follicle count (AFC), another index used in the STRAW system, is also low. The duration of stage −2 is variable.6 Stage -1, also called “late menopausal transition”, is characterized by longer periods of amenorrhea 3(>60 days), with persistently elevated FSH (>25 IU/L) along with high estradiol levels. AFC, AMH, and inhibin B levels are low and its duration is estimated at 1–3 years. Finally, stage +1a refers to the first 12 months after the FMP.6 AMH and AFC are superior to FSH in terms of their value as markers of ovarian aging not only on the basis of their capacity for defining late reproductive stages and transition to perimenopause, but also with regard to the fact that they are not affected by menstrual cycle phase.6
Despite their contribution to a more detailed approach to a woman's transition to menopause, STRAW criteria also have some limitations. First, they are not applicable in women with primary ovarian insufficiency (POI), due to the high variability in reproductive aging in this state. POI is a term used for women under the age of 40 years with amenorrhea, sex steroid deficiency, and elevated gonadotropins. It affects about 1% of women younger than 40 years, 0.1% of those under 30 years, and 0.01% of those under 20 years. To diagnose POI, elevated FSH concentrations after 3–4 months of amenorrhea or menstrual irregularity are repeatedly needed (4 weeks apart).7 STRAW criteria are also not applicable to women with polycystic ovarian syndrome (PCOS), hypothalamic amenorrhea, chronic illnesses, such as human immunodeficiency virus infection, and those who have undergone chemotherapy (alkylating agents) or treatment with tamoxifen.6 It must be noted that in cases of hysterectomy or endometrial ablation, STRAW criteria are to be based only on the endocrine biomarkers of ovarian aging rather than on menstrual pattern, after a period of at least 3 months postsurgery.6 Furthermore, the lack of standardized assays for endocrine biomarkers, such as inhibin B and AMH, and their variability across nations constitute another limitation of the STRAW classification system.6
 
PHYSIOLOGY OF PERIMENOPAUSE
The prevailing concept is that the age-dependent loss of female fertility is due to a decline in both quality and quantity of ovarian follicles.1,3 The decline in ovarian reserve is mainly indicated by the decrease in AFC (follicles 2–10 mm in diameter),8,9 as well as in the total nongrowing follicle (NGF) and primordial follicle (PF) pool.9,10 AFC, NGF, and PF count seem to progressively decrease with advancing STRAW stage.9 At 5 months of gestational age, about 7 million NGFs exist, showing a progressive decrease thereafter, due to atresia either by necrosis or apoptosis at some stage of development, reaching ~300,000 at the beginning of puberty.3 At the age of 30 years, 12% of the initial NGF pool exists, further declining to 3% at the age of 40 years and to less than 1,000 at 50–51 years, the mean age of natural menopause.3 AFC is negatively associated with age (explaining 46% of its variance). This association with age seems to be greater than other markers such as total ovarian volume, total follicular volume, FSH, estradiol, and inhibin B.8 AFC is also negatively correlated with FSH, estradiol, 4and inhibin B.8 There is also a dramatic decrease in the number of follicles entering the growth phase with advancing age. The transition appears at age 38 years, after which the rate of follicle disappearance increases.11
In perimenopause, 20% of the cycles of less than or equal to 40 days duration are anovulatory, which increases to 80% when the cycle length is greater than or equal to 40 days.12 It has been shown that the follicular phase of the menstrual cycle becomes shorter as women get older, suggesting accelerated growth of antral follicles.13 The acceleration of follicle depletion is suggested to be a result of an early rise in FSH levels, due to an abnormal gonadotropin-releasing hormone (GnRH) pattern, which is a result of dysregulation of the GnRH pulse generator in the hypothalamus, caused by the progressive loss of control from other brain centers.3 It has been suggested that advanced dominant follicle growth starts in the luteal phase of the previous cycle, before menstruation.13,14 In parallel with the progressive loss of follicle numbers, oocyte quality also decreases with advancing reproductive aging and granulosa cell function declines.3 It has been shown that older women (>40 years), compared to younger ones, display a shorter follicular phase and cycle length (by 2–4 days), along with higher FSH levels in the late luteal and early follicular phase, contributing to decreased follicular and oocyte quality. This compromises fertility in aging women.14
 
HORMONAL CHANGES DURING PERIMENOPAUSE
 
Follicle-stimulating Hormone
The role of FSH is the selection of the dominant follicle and its maturation until ovulation, initiation of follicular growth, and stimulation of early follicular development.12 FSH also stimulates the granulosa cells to produce estradiol and inhibins A and B. During a normal menstrual cycle, the rise in estradiol levels in the early follicular phase is followed by an elevation of inhibin B, which inhibits FSH production. At the mid-follicular phase, FSH levels begin to decrease with a concomitant increase in LH levels. After selection of the dominant follicle, estradiol levels rise quickly, exerting a positive feedback on the gonadotropin cells and increasing their sensitivity to GnRH. This leads to a surge in LH concentrations, resulting in ovulation and development of the corpus luteum, which is thereafter the main resource of estradiol and progesterone (PG).15
The decrease in the NGF pool with age leads to a decline in inhibin B levels and to a subsequent loss of negative feedback on FSH which causes increasingly higher and lengthy elevations in FSH concentrations.1-3 In early perimenopause, due to the residual ovarian follicles, ovulatory cycles predominate, but the sustained elevation of FSH in late perimenopause increases cycle length variability, with a 5combination of normal-length ovulatory, superimposed ovulatory [luteal out-of-phase (LOOP)] and anovulatory cycles of variable length. In ovulatory cycles, FSH levels show little, if any, increase, but they show a marked rise in anovulatory cycles. Thus, the heterogeneity of follicular-phase FSH represents a mixture of ovulatory and anovulatory cycles.16,17 It must be noted that the threshold of FSH levels above which follicles are stimulated to further growth varies considerably in women and it is assumed to be related to polymorphisms in the FSH receptor (FSHR) gene.18 This monotropic rise in FSH levels is regarded as the endocrinological hallmark of menopausal transition and actually reflects the woman's ability to conceive.1-3 It is estimated that at the time of FMP, FSH levels have reached 50% of their final postmenopausal values and are also 10 to 15 times higher than those of the follicular phase in women of reproductive age.19 LH levels also increase with age but much later than FSH (with a difference of about 5 years).20
 
Estradiol and Progesterone
Estradiol concentrations may be elevated during the early follicular phase of the menstrual cycle, along with the increase in FSH levels, especially during the early perimenopause. This is mainly a reflection of accelerated follicular growth and shortening of the early follicular phase. Estradiol levels are not a reliable biomarker of menopausal transition, since they start to decline about 2 years before the FMP and stabilize 2 years afterward, along with FSH, defining the +1c STRAW stage.1,6,19 The major circulating estrogen after menopause is estrone, which is mainly produced through the peripheral conversion of the adrenal androstenedione via aromatase situated in adipose tissue.15 Only 5% of estrone is converted to estradiol via the enzyme 17β-hydroxysteroid dehydrogenase.21 Regarding PG, both mid-cycle and luteal-phase levels decline with advancing reproductive age, due to the absence of ovulation. Thus, the low PG concentrations detected are mostly of adrenal origin.1-3
 
Anti-Müllerian Hormone
Anti-Müllerian hormone is a member of the transforming growth factor (TGF)-β superfamily of peptides, playing a key role in human reproduction along with the other members of this family such as inhibins and activins. In the testes, AMH is produced by the Sertoli cells, inducing testicular differentiation and regression of the Müllerian ducts.22 In the ovary, AMH is secreted by the granulosa cells of late preantral and small antral follicles, and exerts an inhibitory effect on the primordial to primary follicle transition.23 AMH levels reflect the follicle cohort and allow a reliable assessment of ovarian reserve.22,23 AMH expression is regulated by estradiol, depending on the presence of estrogen 6receptors, in a sense that it is inhibited in human granulosa cells, which express more ERα than ERβ mRNA.24
It has been considered a promising diagnostic tool in cases of POI, PCOS, and assisted reproduction techniques.22 AMH concentrations are elevated during prepubertal years and gradually decline during reproductive aging, becoming undetectable at menopause.22 As mentioned above, AMH levels, along with those of inhibin B and AFC, are the first markers that decline at the early stage of menopausal transition (about 5 years before the FMP). Another advantage of AMH is that its levels remain almost stable during the menstrual cycle.22 AMH concentrations reflect the transition of resting PFs to growing follicles, declining to a time point 5 years prior to FMP, and appear to be more predictive than inhibin B with respect to time to FMP or age at FMP.25 Four studies have evaluated the capacity of AMH to predict time to menopause, yielding different results, but all showing its potential role as a strong predictor of time to menopause.25-28 One of these showed that with a baseline AMH level below 0.20 ng/mL, the median time to menopause is about 6 years in women 45–48 years of age and about 10 years in the 35–39 years age group. With levels above 1.50 ng/mL, the median time to menopause was 6.23 and 13.01 years in the oldest and youngest age group, respectively.26 This study also showed that AMH was a stronger predictor of time to menopause than FSH or inhibin B.26 Nevertheless, the utility of AMH is currently restricted due to lack of development of adequately sensitive and standardized assays. There is also inconsistency in accepted thresholds for normal AMH ranges, particularly in determining time to menopause.29
 
Inhibin B
Inhibins (A and B) are members of the TGF-β superfamily, produced by the granulosa cells of ovarian follicles. Their role is the inhibition of gonadotropins, mainly FSH. Inhibin A is secreted by the dominant follicle in the ovary. Its levels increase from the early follicular phase and remain high in the luteal phase, during which inhibin A is mainly secreted by the corpus luteum. However, its role in gonadotropin secretion is considered to be minor.17 Inhibin B is secreted by the granulosa cells of the antral follicles, from which the dominant follicle is generated. It is the major regulator of follicular-phase FSH levels. In the normal reproductive woman, its levels increase and become highest during the early follicular phase and, after a mid-cycle surge, they decline throughout the luteal phase.17,30
During menopausal transition (stage -3b of reproductive age or about 5 years before the FMP), inhibin B levels start to decrease along with AMH and AFC, as a result of the shrinkage of the follicle cohort, constituting one of the early 7indicators of ovarian aging.6,17,31 Significant inverse association between FSH and inhibin B levels has been demonstrated.32 Inhibin A levels also show a steady decline from at least 4 years before the FMP, becoming undetectable 1 year before the FMP, while inhibin B decreases over a shorter period.33 It is believed that the lower inhibin A concentrations in the luteal phase may also contribute to the rise in FSH.17 Inhibin levels are rarely used to assess ovarian reserve, response, or time to FMP because, with regard to FMP, the relationship of inhibin levels is not linear.
 
FACTORS AFFECTING MENOPAUSAL TRANSITION
Many factors seem to affect time of transition to menopause, such as smoking, diet, physical activity, socioeconomic status, and genetic predisposition, explaining in part the huge variation in the age of menopause. Smoking has been associated with a reduction in time to menopause,26,34,35 decrease in size of the ovarian follicle pool,36 delayed conception,37 and increase in FSH levels.38 It seems that toxic chemicals such as polycyclic aromatic hydrocarbons released by tobacco use, as well as by fossil fuel combustion, activate the aromatic hydrocarbon receptor leading to apoptosis of oocytes.39 Age of menopause may also be influenced by dietary patterns, since low-fat dairy products may delay the age of natural menopause.40 Other studies have shown that higher intake of polyunsaturated fat and higher levels of physical activity are associated with earlier onset of menopause, with hazard ratios for the highest versus lowest quartile of 1.15 [95% confidence interval (CI): 1.01–1.31] and 1.17 (95% CI: 1.02–1.34), respectively.41 With respect to physical activity, others have shown that low physical activity is associated with earlier menopause.35,42 Higher weight at baseline or weight gain between the ages of 20 and 40 years42 and higher alcohol consumption have also been associated with later age at FMP.34,35,42 Higher socioeconomic status and educational level and employment are associated with later menopause.34,43 Conflicting data exist with regard to the association of oral contraceptives with the age of menopause.44 Race and ethnicity do not seem to be significantly associated with the age of menopause.34
Given the heritability of age at menopause, a genetic concept has been developed in terms of determination of the size of the ovarian oocyte/follicle pool during fetal life and its rate of decline during development. This genetic variation mainly involves differences in gene expression (polymorphisms) between individuals.11 Genome-wide association studies (GWAS) have identified several menopause loci that function in diverse pathways including hormonal regulation, immune function, and DNA repair. In a recent GWAS, there was a significant association between intronic single-nucleotide polymorphisms (SNPs) on a disintegrin and metalloproteinase (ADAM) metallopeptidase with thrombospondin type I motif 89 (ADAMTS9) and SMAD family member 3(SMAD3) genes.45 Another study found a significant interaction between age at natural menopause and rs10407022 SNP in the AMH gene and rs11170547 SNP in the AMH receptor 2 (AMHR2) gene.46 SNP -482 A greater than G polymorphism (rs2002555) in the AMHR2 gene was also associated with age at menopause in another study.47 Furthermore, a place for FSHR gene polymorphisms which can influence ovarian activity, such as the Ser680 genotype, may also exist with regard to the genetic determination of the age of menopause. This genotype is associated with a relative resistance to FSH stimulation leading to slightly higher FSH concentrations, resulting in prolonged duration of the menstrual cycle.48
 
CLINICAL CONSEQUENCES OF PERIMENOPAUSE AND USE OF HRT
 
Quality of Life
Quality of life (QoL) can be defined as an individual's perception of his or her position in life in relation to the environment in which he or she lives and his or her expectations, standards, and concerns. Good QoL is a fundamental right and legitimate aspiration for everyone.
A majority of women will experience bothersome symptoms related to declining and/or fluctuating levels of estrogen during their menopausal transition. There is a growing body of evidence to confirm that these menopausal symptoms have a very negative effect on QoL for some women.49
Vasomotor symptoms, vaginal dryness, poor sleep, and depressed mood have all been found to worsen during the menopausal transition. Numerous controlled clinical trials support the beneficial effects of hormone replacement therapy (HRT) on improvement of QoL in menopausal women. The improvement in QoL has also been recognized in professional society recommendations.50-52
Hormone replacement therapy has also been shown to significantly decrease the number of fractures at hip and spine compared to placebo.53,54 Recent research has shown that even very low doses of HRT are effective in increasing bone density.55
 
Cardiovascular Prevention
Cumulative data support a “window of opportunity” for maximal reduction of coronary heart disease (CHD) and overall mortality and minimization of risks with HRT with initiation before 60 years of age and/or within 10 years of menopause and its continuation for 6 years or more.
9The age-stratified data analysis from the Women's Health Initiative (WHI), particularly for estrogen-alone HRT, showed a trend toward reduction of CHD risk and a significant reduction in mortality in the 50- to 59-year age group.
Recent data from the Danish Osteoporosis Prevention Study (DOPS),56 in which women with an average age of 50 years were randomized to HRT or no treatment, showed a 50% reduction in the primary outcome composite measure of myocardial infarction, mortality, and heart failure over a 16-year period (10 years randomized and 6 years observational) with no excess of stroke, venous thromboembolism, and breast cancer.
Publications from the Kronos Early Estrogen Prevention Study (KEEPS) and the Early versus Late Intervention Trial with Estrogen (ELITE) are expected to provide additional evidence for this window of opportunity. Many studies including WHI, DOPS, and a large meta-analysis56,57 of randomized controlled trials have all confirmed a window of opportunity for reducing mortality related to CHD.58
 
CONCLUSION
In conclusion, perimenopause or transition to menopause is characterized by a variable degree of decline in ovarian reserve and a pattern of monophasic elevation of gonadotropins and decline in gonadal steroids and peptides such as estradiol, inhibins, and AMH. The STRAW classification system has been developed to better clarify the different stages of a woman's reproductive aging. According to this system, perimenopause is described by the stages −2, −1, and +1a. The first event of perimenopause is the reduction in follicle cohort, which results in a decrease in inhibin B levels and consequent elevation of FSH concentrations and dysregulation of folliculogenesis, until a period of 12 months of amenorrhea exists defining the FMP. Alongside inhibin B, other reliable markers for identification of early changes in reproductive aging are AMH and AFC. Time to menopause is affected by variable parameters such as smoking, diet, physical activity, socioeconomic status, and genetic factors, such as FSH- and AMH-receptor gene polymorphisms.
While HRT is not appropriate for every woman, it may be beneficial for those with troublesome symptoms or other indications. In that setting, with initiation near menopause, the weight of evidence supports benefits over risks, with the potential to prevent or ameliorate downstream morbidity. In patients with POI, it proves beneficial in preserving bone mass and reducing age-related fracture morbidity.
Physicians should address the specific needs of individual patients entering menopause to balance the risks and benefits of HRT.
REFERENCES
  1. Santoro N, Randolph JF Jr. Reproductive hormones and the menopause transition. Obstet Gynecol Clin North Am. 2011; 38: 455–66.
  1. Dudley EC, Hopper JL, Taffe J, Guthrie JR, Burger HG, Dennerstein L. Using longitudinal data to define the perimenopause by menstrual cycle characteristics. Climacteric. 1998; 1: 18–25.
  1. te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002; 8: 141–54.
  1. Mansfield PK, Carey M, Anderson A, Barsom SH, Koch PB. Staging the menopausal transition: data from the TREMIN Research Program on Women's Health. Women's Health Issues. 2004; 14: 220–6.
  1. Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Climacteric. 2001; 4: 267–72.
  1. Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab. 2012; 97: 1159–68.
  1. Maclaran K, Horner E, Panay N. Premature ovarian failure: long-term sequelae. Menopause Int. 2010; 16: 38–41.
  1. Scheffer GJ, Broekmans FJ, Looman CW, Blankenstein M, Fauser BC, teJong FH, et al. The number of antral follicles in normal women with proven fertility is the best reflection of reproductive age. Hum Reprod. 2003; 18: 700–6.
  1. Hansen KR, Craig LB, Zavy MT, Klein NA, Soules MR. Ovarian primordial and nongrowing follicle counts according to the Stages of Reproductive Aging Workshop (STRAW) staging system. Menopause. 2012; 19: 164–71.
  1. Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab. 1987; 65: 1231–7.
  1. Faddy MJ, Gosden RG. A mathematical model of follicle dynamics in the human ovary. Hum Reprod. 1995; 10: 770–5.
  1. Metcalf MG, Donald RA, Livesey JH. Pituitary-ovarian function before, during and after the menopause: a longitudinal study. Clin Endocrinol (Oxf). 1982; 17: 489–94.
  1. Klein NA, Battaglia DE, Fujimoto VY, Davis GS, Bremner WJ, Soules MR. Reproductive aging: accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women. J Clin Endocrinol Metab. 1996; 81: 1038–45.
  1. van Zonneveld P, Scheffer GJ, Broekmans FJ, Blankenstein MA, de Jong FH, Looman CW, et al. Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women. Hum Reprod. 2003; 18: 495–501.
  1. Hale GE, Robertson DM, Burger HG. The perimenopausal woman: endocrinology and management. J Steroid Biochem Mol Biol. 2013; 142: 121–31.

  1. 11 O'Connor KA, Ferrell R, Brindle E, Trumble B, Shofer J, Holman DJ, et al. Progesterone and ovulation across stages of the transition to menopause. Menopause. 2009; 16: 1178–87.
  1. Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause. 2008; 15: 603–12.
  1. Perez Mayorga M, Gromoll J, Behre HM, Gassner C, Nieschlag E, Simoni M. Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab. 2000; 85: 3365–9.
  1. Burger HG, Dudley EC, Hopper JL, Groome N, Guthrie JR, Green A, et al. Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women. J Clin Endocrinol Metab. 1999; 84: 4025–30.
  1. Ahmed Ebbiary NA, Lenton EA, Cooke ID. Hypothalamic-pituitary ageing: progressive increase in FSH and LH concentrations throughout the reproductive life in regularly menstruating women. Clin Endocrinol (Oxf). 1994; 41: 199–206.
  1. Luu-The V, Dufort I, Pelletier G, Labrie F. Type 5 17beta-hydroxysteroid dehydrogenase: its role in the formation of androgens in women. Mol Cell Endocrinol. 2001; 171: 77–82.
  1. Ledger WL. Clinical utility of measurement of anti-Müllerian hormone in reproductive endocrinology. J Clin Endocrinol Metab. 2010; 95: 5144–54.
  1. Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, et al. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004; 10: 77–83.
  1. Grynberg M, Pierre A, Rey R, Leclerc A, Arouche N, Hesters L, et al. Differential regulation of ovarian anti-Müllerian hormone (AMH) by estradiol through α and β-estrogen receptors. J Clin Endocrinol Metab. 2012; 97:E 1649–57.
  1. Sowers MR, Eyvazzadeh AD, McConnell D, Yosef M, Jannausch ML, Zhang D, et al. Anti-Müllerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab. 2008; 93: 3478–83.
  1. Freeman EW, Sammel MD, Lin H, Gracia CR. Anti-Müllerian hormone as a predictor of time to menopause in late reproductive age women. J Clin Endocrinol Metab. 2012; 97: 1673–80.
  1. Tehrani FR, Solaymani-Dodaran M, Tohidi M, Gohari MR, Azizi F. Modeling age at menopause using serum concentration of anti-Müllerian hormone. J Clin Endocrinol Metab. 2013; 98: 729–35.
  1. Broer SL, Eijkemans MJ, Scheffer GJ, van Rooij IA, de Vet A, Themmen AP, et al. Anti-Müllerian hormone predicts menopause: a long-term follow-up study in normoovulatory women. J Clin Endocrinol Metab. 2011; 96: 2532–9.
  1. Rustamov O, Smith A, Roberts SA, Yates AP, Fitzgerald C, Krishnan M, et al. The measurement of anti-Müllerian hormone: a critical appraisal. J Clin Endocrinol Metab. 2014; 99: 723–32.
  1. Jaquet D, Gaboriau A, Czernichow P, Levy-Marchal C. Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J Clin Endocrinol Metab. 2000; 85: 1401–6.
  1. Danforth DR, Arbogast LK, Mroueh J, Kim MH, Kennard EA, Seifer DB, et al. Dimeric inhibin: a direct marker of ovarian aging. Fertil Steril. 1998; 70: 119–23.
  1. Robertson DM, Hale GE, Jolley D, Fraser IS, Hughes CL, Burger HG. Interrelationships between ovarian and pituitary hormones in ovulatory menstrual cycles across reproductive age. J Clin Endocrinol Metab. 2009; 94: 138–44.
  1. Overlie I, Mørkrid L, Andersson AM, Skakkebaek NE, Moen MH, Holte A. Inhibin A and B as markers of menopause: a five-year prospective longitudinal study of hormonal changes during the menopausal transition. Acta Obstet Gynecol Scand. 2005; 84: 281–5.
  1. Gold EB, Crawford SL, Avis NE, Crandall CJ, Matthews KA, Waetjen LE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol. 2013; 178: 70–83.
  1. Stepaniak U, Szafraniec K, Kubinova R, Malyutina S, Peasey A, Pikhart H, et al. Age at natural menopause in three central and eastern European urban populations: the HAPIEE study. Maturitas. 2013; 75: 87–93.
  1. Westhoff C, Murphy P, Heller D. Predictors of ovarian follicle number. Fertil Steril. 2000; 74: 624–8.
  1. Hull MG, North K, Taylor H, Farrow A, Ford WC. Delayed conception and active and passive smoking. The Avon Longitudinal Study of Pregnancy and Childhood Study Team. Fertil Steril. 2000; 74: 725–33.

  1. 12 Cooper GS, Baird DD, Hulka BS, Weinberg CR, Savitz DA, Hughes CL Jr. Follicle-stimulating hormone concentrations in relation to active and passive smoking. Obstet Gynecol. 1995; 85: 407–11.
  1. Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet. 2001; 28: 355–60.
  1. Carwile JL, Willett WC, Michels KB. Consumption of low-fat dairy products may delay natural menopause. J Nutr. 2013; 143: 1642–50.
  1. Nagata C, Wada K, Nakamura K, Tamai Y, Tsuji M, Shimizu H. Associations of physical activity and diet with the onset of menopause in Japanese women. Menopause. 2012; 19: 75–81.
  1. Morris DH, Jones ME, Schoemaker MJ, McFadden E, Ashworth A, Swerdlow AJ. Body mass index, exercise, and other lifestyle factors in relation to age at natural menopause: analyses from the breakthrough generations study. Am J Epidemiol. 2012; 175: 998–1005.
  1. Stanford JL, Hartge P, Brinton LA, Hoover RN, Brookmeyer R. Factors influencing the age at natural menopause. J Chronic Dis. 1987; 40: 995–1002.
  1. van Noord PA, Dubas JS, Dorland M, Boersma H, te Velde E. Age at natural menopause in a population-based screening cohort: the role of menarche, fecundity, and lifestyle factors. Fertil Steril. 1997; 68: 95–102.
  1. Pyun JA, Kim S, Cho NH, Koh I, Lee JY, Shin C, et al. Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population. Menopause. 2014; 21: 522–9.
  1. Braem MG, Voorhuis M, van der Schouw YT, Peeters PH, Schouten LJ, Eijkemans MJ, et al. Interactions between genetic variants in AMH and AMHR2 may modify age at natural menopause. PLoS One. 2013; 8:e59819.
  1. Kevenaar ME, Themmen AP, Rivadeneira F, Uitterlinden AG, Laven JS, van Schoor NM, et al. A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Hum Reprod. 2007; 22: 2382–8.
  1. La Marca A, Sighinolfi G, Argento C, Grisendi V, Casarini L, Volpe A, et al. Polymorphisms in gonadotropin and gonadotropin receptor genes as markers of ovarian reserve and response in in vitro fertilization. Fertil Steril. 2013; 99: 970–8.
  1. Zöllner YF, Acquadro C, Schaefer M. Literature review of instruments to assess health-related quality of life during and after menopause. Qual Life Res. 2005; 14: 309–27.
  1. Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010; 95(7 Suppl 1):S 1–66.
  1. Sturdee DW, Pines A, Archer DF, Baber RJ, Barlow D, Birkhäuser MH, et al. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric. 2011; 14: 302–20.
  1. North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause. 2010; 17: 242–55.
  1. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized controlled trial. JAMA. 2004; 290: 1729–38.
  1. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004; 291: 1701–12.
  1. Genant HK, Lucas J, Weiss S, Akin M, Emkey R, McNaney-Flint H, et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med. 1997; 157: 2609–15.
  1. 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: randomized trial. BMJ. 2012; 345:e6409.
  1. Hodis HN, Collins P, Mack WJ, Schierbeck LL. The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective. Climacteric. 2012; 15: 217–28.
  1. Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med. 2004; 19: 791–804.