Testing ovarian reserve to predict age at menopause

doi:10.1016/j.maturitas.2009.06.007

Maturitas

Volume 63, Issue 4, 20 August 2009, Pages 280-291

https://doi.org/10.1016/j.maturitas.2009.06.007 Get rights and content

Abstract

In modern society with women delaying pregnancy, predicting the age of the natural menopause with its preceding infertility will allow making informed choices about when to try starting to have children. Also if premature menopause could be predicted in young women, strategies could be instigated to reduce the long term health risks of early estrogen deficiency. This review examines the physiology of ovarian ageing, with the menopause being the final outcome. Long and short term predictive markers of the age of the menopause and the preceding natural infertility are evaluated.

Many subtle changes in the endocrine regulation of ovarian function with advancing age may seem interesting but currently are not clinically useful as a predictive test. Examples are changes in concentrations of estradiol, progesterone, luteinizing hormone (LH) and activin, as well as follicle dynamics. Other features hold more promise. Among these are chronological age, family history, anti-Müllerian hormone (AMH), poor response to in vitro fertilization (IVF), basal follicle-stimulating hormone (FSH) and the antral follicle count for long term prediction. For short term prediction, cycle shortening and occurrence of vasomotor symptoms may prove useful. To date, none of these markers has been found to have sufficient predictive accuracy in individual women. Results of new and ongoing longitudinal studies may provide better predictive models. In particular, use of genetic profiles may add to the accuracy of currently known markers.

Introduction

The menopause is the final menstrual period. The natural menopause can only be ascertained in retrospect after 12 consecutive months of spontaneous amenorrhoea. The age of the natural menopause has a normal distribution with a mean at approximately 51 years, varying between 40 and 60 years [1]. Since the introduction of a definition for premature ovarian failure for women below 40 years of age with a basal FSH of >40 IU/l [2], we regard normal menopause as occurring from age 40 onwards. Women between 40 and 45 experiencing natural menopause are regarded as reaching the menopause relatively early, but are considered as a representation of the lower end of the normal distribution. Whereas for some women the menopause may be a relief and the start of yet another phase of life, many experience this event and the associated physical symptoms and psychosocial impact as a burden.

The menopause has certain implications. It is the final sign that a woman's reproductive capacity has become exhausted. Also, early age at menopause has been associated with increased cardiovascular mortality [3], osteoporotic fracture [4] and colorectal cancer [5] as well as respiratory and urogenital disease [6].

In modern society being able to predict the age of menopause and occurrence of natural infertility may help women decide about when they should start attempting to have children. Furthermore, if premature or early menopause could be predicted with tests in young women, strategies could be instigated to reduce the long term health risks of estrogen deficiency.

Remarkably, while the average age at menarche has declined very significantly over the past 100 years, the average age of the menopause has remained quite constant. Important determinants of the age of the menopause are most likely to be epiphenomena of ovarian oocyte content and genetic factors.

This review provides an overview of the physiology of ovarian ageing. Predictive markers of the age of menopause and the preceding declining fertility are evaluated.

Section snippets

Female reproductive ageing, infertility and menopause

The reproductive ageing process is dominated by a gradual decrease in both oocyte quantity and quality [7]. From the initial 6–7 million primordial follicles present at the fourth month of fetal development [8], [9], [10], [11], [12], [13], [14], [15], only 400,000–600,000 primordial follicles remain at menarche [7], [10]. At menopause, the number of remaining follicles has dropped to below 1000 [15], [16], [17] (Fig. 1 [18], [19]). From the age of 31 years onwards, the declining follicle pool

Features of reproductive ageing and predictors of menopause

Factors that are able to predict age at menopause early in life should relate to the decreasing follicle pool over a period of several decades. Factors that change only in the later stages of ovarian ageing in principal cannot be used as early predictors. While identification of early predictors requires long term follow up, most studies use cross-sectional data.

Based on the available cross-sectional data, such a predictive test has not emerged, although some predictive ability has been

Discussion

Over the past two decades much effort has been put into attempts to more precisely forecast the age at menopause for individual women. For many reasons the notion that menopause normally occurs on the average age of 51 but that it may vary from 40 to 60 is unsatisfying. The ability to accurately predict the age of the last menstrual period is useful for two purposes: firstly because of the associated definitive infertility and secondly the associated subfertility starting many years earlier. As

Competing interest statement

JvD and CHdK have no competing interests. CBL has received fees and grant support from the following companies: Ferring, Merck Serono, and Schering Plough. FJB is a member of the external advisory board for Ferring Pharmaceuticals, Hoofddorp, the Netherlands. He receives no monetary payment.

Contributors

CBL: (1) substantial contributions to conception and design, and interpretation of data, (2) drafting the article, and revising the manuscript critically for important intellectual content, and (3) final approval of the version to be published. JvD: (1) substantial contributions to conception and design, and interpretation of data, (2) drafting the article, and revising the manuscript critically for important intellectual content, and (3) final approval of the version to be published. CHdK: (1)

Provenance

Commissioned and externally peer reviewed.

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Opportunistic salpingectomy (OS) is an attractive method for primary prevention of ovarian cancer. Although OS has not been associated with a higher complication rate, it may be associated with earlier onset of menopause.
To provide a systematic review and meta-analysis of the effect of OS on both age at menopause and ovarian reserve.
A search was conducted in the Cochrane Library, Embase and MEDLINE databases from inception until March 2022. We included randomized clinical trials and cohort studies investigating the effect of OS on onset of menopause and/or ovarian reserve through change in anti-Müllerian hormone (AMH), antral follicle count (AFC), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH). Data was extracted independently by two researchers. Random-effects meta-analyses were conducted to estimate the pooled effect of OS on ovarian reserve.
The initial search yielded 1047 studies. No studies were found investigating the effect of OS on age of menopause. Fifteen studies were included in the meta-analysis on ovarian reserve. Meta-analyses did not result in statistically significant differences in mean change in AMH (MD -0.07 ng/ml, 95%CI −0.18;0.05), AFC (MD 0.20 n, 95 % CI −4.91;5.30), E2 (MD 3.97 pg/ml, 95%CI −0.92;8.86), FSH (MD 0.33mIU/ml, 95%CI −0.15;0.81) and LH (MD 0.03mIU/ml; 95%CI −0.47;0.53).
Our study shows that OS does not result in a significant reduction of ovarian reserve in the short term. Further research is essential to confirm the absence of major effects of OS on menopausal onset since clear evidence on this subject is lacking.
Registration number PROSPERO CRD42021260966.
Age at natural menopause in women with a history of chronic diseases–A population-based cohort study
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Citation Excerpt :
Menopause, the absence of menstruation cycles for at least 12 months in non-pregnant women, is characterized by a gradual decrease in estrogen secretion due to the follicle pool depletion in the ovaries [1]. The average age at natural menopause (ANM) is around 50 years worldwide [2,3] and 51.2 years in Iranian women [4], although it varies widely between 40 and 60 years; these variations have significant reproductive implications and can also influence the women's health and quality of life [5–7]. The timing of menopause is clinically considered an important marker for subsequent morbidity and mortality among women [8,9].
This study was carried out to determine whether chronic diseases can influence age at natural menopause (ANM).
This population-based prospective study recruited all eligible women from participants in the Tehran Lipid and Glucose Study (TLGS). The Cox proportional-hazards model (unadjusted and adjusted) was used to assess associations of ANM with chronic diseases, including diabetes mellitus (DM), hypertension (HTN), dyslipidemia, metabolic syndrome (MetS), cardiovascular disease (CVD), chronic kidney disease (CKD), and thyroid disorders, which were not included simultaneously in the model because there were correlations between chronic diseases.
A total of 4662 women, aged 15–50 years, who had not reached menopause at initiation of the TLGS were included. Of these women, 1220 (26.2%) experienced menopause during the study follow-up. In the multivariable Cox regression model adjusted for potential confounders, women with DM [HR:1.75; 95%CI: (1.32, 2.32)], HTN [HR: 2.11; 95%CI: (1.64, 2.72)], MetS [HR: 2.01; 95%CI: (1.57, 2.58)], CVD [HR: 3.02; 95%CI: (1.93, 4.73)], CKD [HR: 2.64; 95%CI: (2.16, 3.22)], and thyroid disorders [HR: 1.41; 95%CI: (1.06, 1.88)] reached menopause earlier, while dyslipidemia was not associated with ANM.
This study demonstrates that women with a history of chronic diseases, such as metabolic disorders, cardiovascular events, and CKD, experience menopause earlier than their counterparts without such a history.
Interleukin-6 and interleukin-8 serum levels in prognosis of hormone-dependent breast cancer
2019, Cytokine
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The significant positive correlation between FSH and LH concentrations and a significant negative correlation between FSH and estradiol levels reported in this study were expected and might reflect ovarian physiology under hormonal therapy [18]. Thereby, lower estradiol coinciding with higher FSH levels indicates premenopausal ovarian suppression which was achieved by hormonal therapy administered to all patients [19]. Furthermore, in this study, FSH and age associated with a good disease outcome, in agreement with the previous finding of ER+ breast cancers being strongly affected by menopausal status and age [20].
Increasing amount of evidence points to the importance of immunity in breast cancer. The prognostic value of cytokines and their effect on tumorigenesis remains inconsistent.
To investigate the prognostic significance of IL6 and IL8 and their association with ER and HER2 in estrogen-dependent (ER+) breast cancer.
The study included 79 premenopausal women with early and locally advanced ER+ breast cancer. All patients received adjuvant hormonal therapy: tamoxifen alone (56/79) or combination with LHRH agonist goserelin (23/79). IL6 and IL8 serum protein levels were measured by ELISA. Cox proportional hazards regression analysis was implemented for prognostic evaluation of the data categorized based on metastasis outcome.
IL6 associated with good (P = 0.001, HR = 0.05) and IL8 with poor disease outcome (P = 0.03, HR = 2.5) in the whole group of patients. Multivariate analyses highlighted IL6 as the independent prognostic factor (P = 0.001, HR = 0.0007). When patients were classified according to ER or HER2 status, IL6 did not have prognostic significance in ER^low and ER^high subgroups, while IL8 retained prognostic significance only in the ER^high subgroup (P = 0.04, HR = 2.8). IL6 was significant in both HER2− (P = 0.001, HR = 0.05) and HER2+ subgroups (P = 0.002, HR = 0.04), while IL8 retained its prognostic significance only in the HER2+ subgroup (P = 0.001, HR = 77.8).
This study contributes to the clarification of the prognostic performance of IL6 and IL8 by providing their first prognostic evaluation in the homogenized ER+ breast cancer patient group. IL6 was indicated as a marker of favorable, whereas IL8 was a marker of unfavorable disease outcome.
Cardiovascular health and ovarian aging
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One in three American women will die from cardiovascular disease (CVD), making it the leading cause of death among women in the United States. Traditionally, CVD has been seen as a disease of postmenopausal women, yet increasingly, risk factors for CVD are being characterized earlier. Although menopause, and its associated hypoestrogenism, has been consistently linked to CVD risk, accelerated ovarian aging among premenopausal patients has become a focus of attempts to identify women with increased CVD risk earlier. We present a review of the evidence for the association between early menopause and diminished ovarian reserve with CVD and its risk factors.
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ReviewTesting ovarian reserve to predict age at menopause

Abstract

Introduction

Section snippets

Female reproductive ageing, infertility and menopause

Features of reproductive ageing and predictors of menopause

Discussion

Competing interest statement

Contributors

Provenance

Menstrual cyclicity and the pre-menopause

Maturitas

Incidence of premature ovarian failure

Obstet Gynecol

Age at menopause as a risk factor for cardiovascular mortality

Lancet

Early menopause: increased fracture risk at older age

Osteoporos Int

Age at menopause, body mass index, and the risk of colorectal cancer mortality in the Dutch Diagnostisch Onderzoek Mammacarcinoom (DOM) cohort

Epidemiology

Age at natural menopause and cause-specific mortality

Am J Epidemiol

The variability of female reproductive ageing

Hum Reprod Update

A quantitative and cytological study of germ cells in human ovaries

Proc R Soc Lond B Biol Sci

Quantitative morphological investigations of the follicular system in women; variations at different ages

Acta Anat (Basel)

A quantitative morphological investigation of the follicular system in newborn female infants

Acta Anat (Basel)

Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause

Hum Reprod

Morphometric studies of small follicles in ovaries of women at different ages

J Reprod Fertil

A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause

Hum Reprod

Is follicular atresia biphasic?

Fertil Steril

Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion

J Clin Endocrinol Metab

A model conforming the decline in follicle numbers to the age of menopause in women

Hum Reprod

Follicle dynamics during ovarian ageing

Mol Cell Endocrinol

Age-related changes in the ultrastructure of the resting follicle pool in human ovaries

Biol Reprod

Antral follicle counts are related to age at natural fertility loss and age at menopause

Menopause

Menstrual cycle length preceding menopause in relation to age at menopause

Maturitas

Population studies and genetic epidemiology in northeast Quebec

Can Stud Popul

Age at last childbirth and fertility at young age

A new statistical approach demonstrated menstrual patterns during the menopausal transition did not vary by age at menopause

J Clin Epidemiol

Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment

Hum Reprod

Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis

Hum Reprod

Is there a link between an extremely poor response to ovarian hyperstimulation and early ovarian failure?

Hum Reprod

Delaying childbearing: effect of age on fecundity and outcome of pregnancy

BMJ

Variation of the human menstrual cycle through reproductive life

Int J Fertil

Fertility, family planning, and women's health: new data from the 1995 National Survey of Family Growth

Vital Health Stat

Female subfertility

Lancet

Pregnancies and births resulting from in vitro fertilization: French national registry analysis of data 1986 to 1990

Fertil Steril

Factors that affect outcome of in-vitro fertilisation treatment

Lancet

Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment

Hum Reprod

The effect of in vitro fertilization on birth rates in western countries

Hum Reprod

Declining fecundity and ovarian ageing in natural fertility populations

Maturitas

Fecundity and natural fertility in humans

Review
Testing ovarian reserve to predict age at menopause