Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports he is a consultant for and receives grant/research support from Bayer, Merck, ContraMed, and FHI360; receives grant/research support from Abbvie, HRA Pharma, Medicines 360, and CONRAD; and is a consultant for the Population Council.

SYNOPSIS: A larger epidemiologic study from Norway found no association between early menarche and age of menopause. Women with early menarche experience a longer fertility window, which may increase certain risks.

SOURCE: Bjelland EK, Hofvind S, Byberg L, Eskild A. The relation of age at menarche with age at natural menopause: a population study of 336 788 women in Norway. Hum Reprod 2018;33:1149-1157.

Age at menarche and menopause may influence a variety of health outcomes, including fertility and cancer. Bjelland and colleagues used the BreastScreen Norway cohort to determine if the age of menarche predicted the age of natural menopause and the reproductive period (duration of fertility). The Cancer Registry of Norway administers the BreastScreen Norway program, enrolling women 50 to 69 years of age into a screening program that includes biannual mammograms. More than 75% of eligible women participate in the program. During 2006-2014, enrolled women also received questionnaires about health history and current lifestyle as part of the screening program. The mean age at screening of this cohort was 57 years. A total of 392,238 women completed the questionnaire, and 336,788 provided information on age of menarche. Of these, 220,779 had undergone a natural menopause. The authors estimated the associations of age at menarche and reproductive period (in years) with menopause as crude hazard ratios with 95% confidence interval by applying Cox proportional hazard models and adjusted the data for year of birth. Then they adjusted for smoking, body mass index (BMI), and hormonal therapies.

The median ages at menarche and menopause in the study cohort were 13 and 51 years. Compared to those women with menarche at age ≤ 13 years, women who reported menarche at age ≥ 16 years reported onset of menopause one year later (e.g., 52 vs. 51 years). Overall, age at menarche was not associated linearly with age at menopause, and the absolute difference in mean age at menopause between any menarche age group did not exceed one year. Use of menopausal hormone therapy did not change the results. However, smoking reduced the median age at menopause by two years (50 vs. 52 years), and women with a BMI < 25 kg/m² were one year younger at menopause (51 years) than women with BMI ≥ 25 kg/m² (52 years).

Overall, the median duration of the reproductive period was 38 years (interquartile range, 35 to 41 years). The later menarche occurred, the shorter the median reproductive period — a decrease by one year for every one-year increase in age at menarche. This longer reproductive period of women with early menarche has bearing on contraceptive decisions, as well as health conditions influenced by hormonal exposure.

COMMENTARY

Our patients frequently request that we predict the future. In obstetrics, we can confidently predict that pregnancy will end around 38 weeks following conception. For menopause, 51 to 52 years of age provides another benchmark. The devil is always in the details for individuals, as these represent median values and not guarantees. All the recent advances in medical informatics have not yielded the crystal ball or retrospectoscope. For this reason, large population-based surveys continue to add value as we seek to improve the precision of our estimates.

This large cross-sectional survey from Norway provides additional information regarding the reproductive lifespan, at least for women of Northern European ancestry. The cohort included only a small number of women born outside Norway: 1.4% born in Asia and 0.2% in Africa. While this should make us question generalizability, other studies have shown similar results. Dorjgochoo and colleagues analyzed data from the Shanghai Women’s Health Study, a prospective cohort study designed to investigate associations of diet and lifestyle with chronic diseases.¹ Chinese women reported menopause at an earlier age (mean, 49.2 years).

Although the authors reported a significant trend of later menopause associated with late menarche, the absolute differences were not clinically important: a four-month difference for menarche at ≤ 11 years of age compared to ≥ 16 years of age. Similar to the Norwegian study, they did see a significant reduction in the reproductive span of over five years for women in the latest menarche group compared to the youngest. Results from 64,500 U.S. women aged 21 to 69 years who participated in the Black Women’s Health Study provide comparator data for an African-American population: mean (49.6) and median (50) age of menopause and no difference in onset with age of menarche.²

These results should not surprise us. Primordial germ cells end mitotic activity early in fetal life, reaching 6-7 million oogonia by 16-20 weeks. Beginning at 11-12 weeks, oogonia begin to undergo meiosis, become arrested at prophase I, and become primary oocytes. Over the next 20 weeks, the number of oocytes declines precipitously, such that about 500,000 to 2 million are present at birth. Loss of oocytes continues unchecked through childhood, with fewer than 300,000 to 500,000 remaining by the onset of puberty. At this point, gonadotropins contribute to the maturation of a pool of small antral follicles sensitive to follicle-stimulating hormone, and a complex feedback system results in selection and ovulation of a single dominate follicle. The rest of these developing follicles undergo apoptosis. Ovarian stimulation protocols can promote maturation of more than one of these follicles. Hormonal contraception can prevent maturation of any of them. But the vast majority continue down an apoptotic path at a highly predictable rate. Among populations of women, the math is the same. Menopause will occur between 49 and 52 years of age, and fertility declines years before this.

Women face complex decisions to balance fertility and career. Modern societies must do everything possible to make these decisions easier. Providing highly effective reversible options for contraception allows women to enjoy intimate relationships and delay childbearing. But our obligation as women’s health providers includes a responsibility to provide a check in about fertility aspirations. We don’t have a strategy to prevent ovarian aging. You use it, or you lose it.

REFERENCES

1. Dorjgochoo T, Kallianpur A, Gao YT, Cai H, et al. Dietary and lifestyle predictors of age at natural menopause and reproductive span in the Shanghai Women’s Health Study. Menopause 2008;15:924-933.
2. Palmer JR, Rosenberg L, Wise LA, et al. Onset of natural menopause in African American women. Am J Public Health 2003;93:299-306.