Menopause: a natural event Henry Burger

Relationships between different time periods surrounding the menopause Final menstrual period (FMP) Menopause Postmenopause Perimenopause Menopausal transition Climacteric Mean age 51 years 1 year later International Position Paper: Women’s Health and Menopause, NIH (2002)

Ovarian follicle numbers with age Women in Block's study 100000 B Women from the present study with regular menses B 10000 B B 1000 J Postmenopausal women F F Primordial follicles/ovary B 100 F Perimenopausal women F F 10 F F 1 10 20 30 40 50 60 Age (years) Richardson et al. JCEM 1987

Hypothalamo-pituitary ovarian axis Hypothalamus Feedback hormones GnRH Steroids Pituitary Gonadotropins: - LH, FSH Inhibin Ovary

Relationships between FSH and inhibin B 4.5 < 40 years of age 4.0 > 40 years of age 3.5 3.0 Log (FSH) 2.5 2.0 1.5 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Log (inhibin B) Burger HG et al. Climacteric 2000

Geometric mean annual hormone levels relative to date of final menses 300 120 250 100 200 80 150 60 Estradiol (pmol/l) FSH (IU/l) 100 40 50 20 -4 -3 -2 -1 1 2 3 4 5 60 60 50 50 40 40 30 30 Inhibin B (ng/l) Inhibin A (ng/l) 20 20 * 10 (InhB) (InhA) 41% 36% 71% 43% 62% 57% 80% 65% 80% 78% 94% 10 -4 -3 -2 -1 1 2 3 4 5 Years around menopause * Percent of samples with undetectable inhibin Burger HG et al. JCEM 1999

Androgens in the menopausal transition In normal women, there is a 50% decrease in circulating concentrations of testosterone and dehydroepiandrosterone sulfate (DHEAS) from age 20 to age 451,2 There is little if any decline in testosterone during the transition2,3 DHEAS levels continue to fall with age, with no specific association with the transition The medical ‘myth’ that menopause is associated with an acute drop in androgens does not appear to be tenable any longer 1Zumoff 1995, 2Davison 2005; 3Burger 2000

Other endocrine features Loss of LH response to an estradiol challenge in the perimenopause1,2 Predominant circulating estrogen in reproductive life is estradiol, secreted by the ovary; postmenopausally it is estrone, produced by peripheral androgen aromatization3 Anti-Müllerian hormone (also called Müllerian inhibiting substance), a member of the TGF super family and a product of preantral and small antral follicles, is under investigation as a marker for the size of the ovarian follicle pool4 and a promising predictor for the occurrence of the transition5 1Van Look 1977; 2Weiss 2004; 3Maroulis 1976; 4Visser 2006; 5van Rooij 2004