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Date of release: 19 November, 2008

Follicle stimulating hormone, estradiol, anti-Mullerian hormone and inhibin B in the menopausal transition


Three recent publications [1-3] have documented longitudinal changes in the circulating concentrations of follicle stimulating hormone (FSH), estradiol, anti-Mullerian hormone (AMH), also called Mullerian inhibiting substance (MIS), and inhibin B over approximately 10 years before the final menstrual period (FMP), with additional data for FSH and estradiol in the 10 following years. The hormone measurements were taken from samples collected on days 2-7 of the follicular phase from women enrolled in the longitudinal Michigan Bone Health and Metabolism Study (or from specimens collected within 15 days of the anniversary of enrolment for those who became amenorrheic); the earliest specimens dated from 1992.


For the study of FSH, AMH and inhibin B [1], 300 specimens were used from 50 women with six consecutive annual visits. The women were required to have an initial FSH < 14 mIU/ml, at least nine cycles per year, and subsequent documentation of 12 months amenorrhea. The mean age at initiation was 42 years, with a mean body mass index of 26.5; 18% of the women were smokers. The mean age at FMP was 50.5 years. Initial mean values were: AMH 0.626 ng/ml, inhibin B 69.8 pg/ml, FSH 7.6 mIU/ml, and estradiol 58.9 pg/ml. Log AMH declined linearly from -10 to -5 years from FMP, following which a single line around the assay detection level (0.05 ng/ml) gave the best fit of the data. Inhibin B levels declined to < 10 pg/ml (detection limit) 5 years before FMP, at which time the FSH concentrations had doubled to 15 mIU/ml. The authors concluded that the decline in concentration of AMH, in particular, to undetectable levels 5 years before FMP may represent a critical juncture in the menopausal transition. The baseline log AMH value was statistically associated with age at FMP. The authors suggested that, ‘AMH may act as an endocrine marker of follicle depletion, may reflect minimal ovarian reserve, and may signal the onset of the late stage of the menopause transition’.


Using data for 629 participants in the same study, the authors identified four major changes in rates of increase of FSH concentration [2], at -10 to -7 years, -7 to -2 years, a major rate increase from -2 to +1 years and a plateau 1 year later, with respect to FMP. For estradiol [3], levels were relatively stable from -10 to -2 years, with a decline of 67% between -2 and +2 years, and a further fall between 6 and 8 years post-FMP, noted particularly in non-obese women. The authors stated, ‘The report identifies four FSH stages and the FSH levels and ages that clinicians can use, along with menstrual cycle characteristics, to help interpret the likely status of women with respect to reproductive viability and menopause stage’.

Comment

The three cited papers provide a substantial database of changes in the follicular levels of FSH, estradiol, AMH and inhibin B in a large cohort of women from whom longitudinal samples were available over approximately 14 years. The data complement and confirm other studies (recently summarized [4]), providing data for a longer time, both before and after FMP. The studies are consistent with the now considerable evidence for the utility of AMH (and, to a lesser degree, inhibin B) as markers of ovarian reserve, reflecting the development of the growing follicles from resting primordial follicles, for AMH, and the growth of the small antral follicle cohort, for inhibin B. Both markers reflect the quantity of the ovarian follicle pool [5].
Although it is tempting to suggest that these data, for the readily available FSH and estradiol measures, can predict an individual woman’s menopausal status, this is unlikely to be of practical value. Although the data as presented suggest a progressive rise in FSH levels and a sharp fall in estradiol concentrations around FMP, the mean logarithmically transformed data hide considerable intra- and inter-individual variabilities. FSH levels do not rise smoothly. There is a variety of cycle types during the menopause transition [6] and, in some cycles, particularly those which are anovulatory, FSH will be markedly raised, while in others the levels remain comparable to those seen during the reproductive phase. The same is true for estradiol. Anovulatory cycles comprised 40-60% of all cycles in the 1-2 years before FMP [4]. Their occurrence is unpredictable and they may be preceded or followed by endocrinologically normal cycles. Levels of FSH during days 2-7 may therefore vary more than ten-fold within and between individuals.
AMH, though not widely available, is a useful predictor of menopausal status, although levels are undetectable for several years before FMP. The levels provide information indicative of low follicle numbers, but could not predict the occurrence of FMP within a specific timeframe. The usefulness of AMH is that it does not vary significantly throughout the menstrual cycle and levels do appear to fall progressively before FMP. Prospective longitudinal studies and the development of more sensitive assays will be required to document just how helpful measurements of AMH or inhibin B could be in predicting FMP. Both are already used as markers of ovarian reserve for women undergoing treatment for infertility.

Comentario

Henry Burger
Emeritus Director, Prince Henrys Institute of Medical Research, Clayton, Victoria, Australia

    References

  1. Sowers MR, Eyvazzadeh AD, McConnell D, et al. Anti-Mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab 2008;93:3478-83. Published September 2008.
    http://www.ncbi.nlm.nih.gov/pubmed/18593767

  2. Sowers MR, Zheng H, McConnell D, et al. Follicle stimulating hormone and its rate of change in defining menopause transition stages. J Clin Endocrinol Metab 2008;93:3958-64. Published October 2008.
    http://www.ncbi.nlm.nih.gov/pubmed/18647816

  3. Sowers MR, Zheng H, McConnell D, et al. Estradiol rates of change in relation to the final menstrual period in a population-based cohort of women. J Clin Endocrinol Metab 2008;93:3847-52. Published October 2008.
    http://www.ncbi.nlm.nih.gov/pubmed/18647803

  4. 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. Published July-August 2008.
    http://www.ncbi.nlm.nih.gov/pubmed/18574431

  5. teVelde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002;8:141-54. Published March-April 2002.
    http://www.ncbi.nlm.nih.gov/pubmed/12099629

  6. Robertson DM, Hale GE, Fraser IS, et al. A proposed classification system for menstrual cycles in the menopause transition based on changes in serum hormone profiles. Menopause 2008;15:1139-44. Published November-December 2008.
    http://www.ncbi.nlm.nih.gov/pubmed/18779761