The menopausal transition is the stage in reproductive life commonly defined as commencing with the onset of menstrual irregularity. Classic studies of the endocrinology of the transition postulated the existence of inhibin in women to explain the observed increase in follicle-stimulating hormone (FSH) levels without a significant decrease in estradiol (E2). Descriptions were provided of cycle characteristics during the transition, emphasizing the unpredictability of the endocrine changes rather than the occurrence of an orderly and progressive decline in ovarian function. Women older than the age of 45 exhibited menstrual irregularity when the average number of primordial follicles per ovary decreased to approximately 100. Inhibin B is a major regulator of FSH secretion and a product of small antral follicles. Its levels respond to the early follicular phase increase and decrease in FSH. The age-related decrease in ovarian primordial follicle numbers, which is reflected in a decrease in the numbers of small antral follicles, leads to a decrease in inhibin B, which in turn leads to an increase in FSH, hypothesized to act as a stimulus to the maintenance of circulating E2 in the follicular phase until late in the transition. Concurrently, the concentrations of testosterone do not change significantly. Early follicular phase FSH levels in women reporting menstrual irregularity fluctuate markedly, with a more uniform increase in levels when no menses have occurred for at least 3 months. Anovulatory cycles occur at increased frequency in the last 30 months before final menses or menopause. In ovulatory cycles, FSH shows little, if any, increase, but anovulatory cycles are usually characterized by low levels of inhibin B, markedly increased levels of FSH, and low levels of E2. Thus, the heterogeneity of follicular phase FSH represents a mixture of ovulatory and anovulatory cycles. Longitudinal data indicate that both ovulatory and anovulatory cycles occur after entry into both the early and late menopausal transition and that ovulatory cycles occur even after final menses. There is no endocrine marker of menopause, which may be primarily an endometrial event. Using the hormonal concentrations in ovulatory cycles observed in women in mid-reproductive age as controls and comparing such concentrations in late reproductive age women older than 45 either continuing to cycle regularly or having entered the early or late menopausal transition, a gradual increase in follicular phase FSH and E2 and a decrease in inhibin B were observed in ovulatory cycles. Anovulatory cycles showed markedly increased FSH with low E2 and inhibin B. No specific endocrine change was characteristic of either the early or late menopausal transition, confirming the observations of previous studies regarding the unpredictability of cycle characteristics and hormone changes with the approach of menopause. Antimüllerian hormone correlates with follicle numbers and shows a large age-related decrease to reach undetectable levels at menopause. Thus, the marked decrease in follicle numbers during late reproductive age appears to predispose to erratic and unpredictable cycle characteristics, with normal ovulatory cycles continuing to occur episodically. There is no specific endocrine marker of the early or late transition, making measurements of FSH or E2 unreliable in attempting to stage an individual with regard to approaching menopause.
Decreasing ovarian function in late reproductive age and during the menopausal transition is associated with decreased secretion of inhibin B and Anti-Mullerian Hormone, increased secretion of FSH and with the unpredictable occurrence of a mixture of normal ovulatory cycles, cycles with evidence of ovarian functional impairment, and anovulatory cycles.
Received February 18, 2007; revised and accepted March 17, 2008.
From the 1Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia; 2Department of Obstetrics and Gynaecology, University of Sydney, NSW, Australia; 3Office for Gender and Health, Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia.
Funding/support: The content of this article was presented by Dr. Burger during the NAMS/Wyeth Wulf H. Utian Endowed Lecture on October 5, 2007, in Dallas, TX. A generous endowment to NAMS from Wyeth Pharmaceuticals established this lectureship, with faculty selected by the NAMS Scientific Program Committee.
Financial disclosure: Dr. Burger is a dinner speaker, advisory board member, or consultant for Wyeth Pharmaceuticals, Organon (Australia Pty Ltd), and Novo Nordisk. Dr. Dennerstein is a consultant or advisory board member for Boehringer-Ingelheim, Bayer Schering Pharma Women's Healthcare, Wyeth Pharmaceuticals, Pfizer, and Besins. Drs. Hale and Robertson report no disclosures.
Address correspondence to: Henry G. Burger, MD, FRACP, Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia. E-mail: firstname.lastname@example.org