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Age at Menarche: a Predictor of Diminished Ovarian Function?

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Age at Menarche: a Predictor of Diminished Ovarian Function? ORIGINAL ARTICLES: GYNECOLOGY AND MENOPAUSE Age at menarche: a predictor of diminished ovarian function? Andrea Weghofer, M.S., M.B.A., M.D., Ph.D.,a,b Ann Kim, M.S.,b David H. Barad, M.D., M.S.,b and Norbert Gleicher, M.D.b,c a Department of Obstetrics and Gynecology, Medical University Vienna, Vienna, Austria; b Center for Human Reproduction and Foundation for Reproductive Medicine, New York, New York; c Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University Medical School, New Haven, Connecticut Objective: To investigate whether age at menarche is associated with functional ovarian reserve (FOR) later in life. Design: Retrospective cohort study. Setting: Fertility center. Patient(s): Five hundred and two infertile women. Intervention(s): None. Main Outcome Measure(s): Levels of menarcheal age, antimullerian€ hormone (AMH), follicle-stimulating hormone (FSH), and functional ovarian reserve. Result(s): The mean age of the patients was 38.9 Æ 4.9 years, and their mean level of AMH was 1.4 Æ 2.0 ng/mL and of FSH was 10.7 Æ 6.1 mIU/mL. Their current age-specific diminished functional ovarian reserve (DFOR) was statistically significantly associated with early menarche, defined as age <13 years. Logistic regression analysis, adjusting for race, affirmed the higher likelihood of early age at menarche in infertile patients with DFOR. When women with DFOR were grouped into quartiles, early menarche (<25th percentile) was associated with statistically significantly higher DFOR risk than late menarche (>75th percentile). Conclusion(s): This study demonstrates a statistically significant impact of age at menarche on DFOR risk later in life among infertile women. The occurrence of menarche may relate to follicular pool size and/or speed of follicle recruitment, which in turn is predictive of occurrence of DFOR later in life. (Fertil SterilÒ 2013;100:1039–43. Ó2013 by American Society for Reproductive Medicine.) Use your smartphone Key Words: Antimullerian€ hormone (AMH), follicle-stimulating hormone (FSH), diminished to scan this QR code functional ovarian reserve, menarche, ovarian function and connect to the discussion forum for Discuss:You can discuss this article with its authors and with other ASRM members at http:// this article now.* fertstertforum.com/weghofera-menarche-diminishedovarian-function/ * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace. omen in the industrialized remaining reproductive life spans reduced pregnancy chances during W world increasingly defer increases in importance. Prospectively older age would thus be helpful. family building (1, 2).As determining a woman’s risk of Because the currently used ovarian fecundity declines with age (3), the developing diminished functional reserve markers are mainly tailored to ability to prospectively estimate ovarian reserve (DFOR) and thus assessing present functional ovarian reserve (FOR) (4), they may fail to pre- Received January 15, 2013; revised May 14, 2013; accepted May 28, 2013; published online June 27, ’ 2013. dict a woman s ovarian aging curve at A.W. has received research grant support, travel funds, and speaker honoraria from various pharma- later stages of life (5). Antimullerian€ ceutical and medical device companies unrelated to this study. A.K. has nothing to disclose. hormone levels also have recently D.H.B. has received research grant support, travel funds, and speaker honoraria from various pharmaceutical and medical device companies unrelated to this study; and is listed as an inventor been suggested to be predictive of on already awarded and still pending U.S. patents claiming beneficial effects on diminished menopause (6). ovarian reserve and embryo ploidy from DHEA supplementation, and diagnostic benefits from CGGn determinations on the FMR1 gene. N.G. has received research grant support, travel funds, Menopause, one stage in ovarian and speaker honoraria from various pharmaceutical and medical device companies unrelated to aging, convincingly reflects a woman’s this study; is listed as an inventor on already awarded and still pending U.S. patents claiming beneficial effects on diminished ovarian reserve and embryo ploidy from DHEA supplementa- follicle pool. At that point, only a small tion, and diagnostic benefits from CGGn determinations on the FMR1 gene; and owns shares number of follicles are left in ovaries, in Fertility Nutraceuticals, LLC, a company with no relationship to this study. Supported by extramural funds from the Foundation for Reproductive Medicine, and intramural generally considered below 1,000 funds through salary support from the Center for Human Reproduction. (7, 8). Menopause appears to be Reprint requests: Andrea Weghofer, M.S., M.B.A., M.D., Ph.D., Department of Obstetrics and Gynecol- genetically preprogrammed. Schuh- ogy, Medical University Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria (E-mail: [email protected]). Huerta et al. (9) demonstrated shared genetic loci for follicular pool size and Fertility and Sterility® Vol. 100, No. 4, October 2013 0015-0282/$36.00 Copyright ©2013 American Society for Reproductive Medicine, Published by Elsevier Inc. menopausal age. He et al. (10) reached http://dx.doi.org/10.1016/j.fertnstert.2013.05.042 similar conclusions when noting that VOL. 100 NO. 4 / OCTOBER 2013 1039 ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE gene clusters of steroid hormone synthesis and metabolism ‘‘genetic’’ informed consent. Only a minority of women pre- were involved in premature ovarian failure and physiologic sented with CGG repeat numbers above 55 repeats, too few age at menopause. Genetic control of menopause is also sug- to draw conclusions on the timing of menarche. Moreover, gested by high correlations of menopausal age between some of those carriers decided to go into egg donation and mothers and daughters (11). did not undergo a complete fertility evaluation. Therefore, Comparable associations also have been reported for age only women with so-called normal and gray-zone FMR1 at menarche. Twin studies suggest significant concordance of genotypes of less than 55 CGG repeats were eligible for the age at menarche between monozygotic and dizygotic twins analysis (19). (12). Generational studies, in turn, have suggested that Among the eligible patients, the FMR1 genotypes and ethnicity and the mother’s and grandmother’s ages at subgenotypes were further classified based on a previously re- menarche are highly predictive parameters for menarcheal ported normal range of 26 to 34 (median 30) CGG repeats: age (13). Normal (norm) was defined as both alleles within this normal Though timing of menarche cannot be attributed to a sin- range, heterozygous (het) was defined as one allele above gle trigger, reactivation of gonadotropin-releasing hormone (het-norm/high) or below (het-norm/low) the normal range, (GnRH) pulsatility has been assumed essential (14). The hy- and the homozygous (hom) genotype was reflected as both pothesis that GnRH pulsatility is influenced by ovarian activ- alleles outside normal range (24). Hormone and genetic tests ity, and the observation that follicular recruitment peaks were performed by commercial assays, as previously reported around menarche suggest a possible relationship between elsewhere (25). menarcheal age and a woman’s follicular pool (14, 15). To assess the impact of age at menarche on later ovarian Studies on the impact of the fragile X mental retardation function parameters, the age at menarche was categorized as gene (FMR1) on ovarian function further support a genetic early or late based on a median age at menarche of 13.0 years: contribution to ovarian aging (16, 17). That this gene impacts early <13 years, and late R13 years. The DFOR risk was then ovarian aging has recently also been confirmed in a mouse compared between women with early and late occurrence of model (18). In humans, CGG triple nucleotide repeats within menarche. Additionally, the study group was categorized premutation range (55–200 CGG repeats) on the FMR1 gene into menarcheal age quartiles to compare the DFOR risk considerably increase a woman’s risk of premature ovarian between the lowest and the highest quartiles. failure (POF, also known as primary ovarian insufficiency) The data we obtained only involved retrospective review and the risk of neuropsychiatric diseases primarily in males of medical records and a deidentified research database. Pa- (19). Within what are generally considered normal ranges, tients at our center signed an informed consent at initial CGG repeats appear to correlate with different ovarian aging consultation, which allows for such reviews if the patient’s patterns (20, 21). We investigated whether menarcheal age is medical record remains confidential and her identity is pro- later in life statistically significantly associated with DFOR tected. Specific genetic written consents were obtained for and possibly FMR1 genotypes. genetic analyses. These conditions were met in this case, allowing for expedited approval by the center’s institutional review board. MATERIALS AND METHODS This study investigated 502 consecutive infertility patients Statistical Analysis who underwent fertility evaluations at the Center for Human — Reproduction (CHR) in New York City between January 2005 Nonparametric tests namely, the Mann-Whitney U test and — and June 2012. All patients had a routine baseline evaluation; chi-square tests were performed to assess the potentially fi in addition to a
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