4.1 Ovarian follicle depletion

The peak number of 6-8 million ovarian oocytes/follicles is present in the female foetus at 20 weeks gestation. Reproductive aging is a continuous process involving follicle depletion (predominately due to atresia/ apoptosis rather than ovulation) commencing prior to birth, accelerating at approximately age 37 years and reaching  a “menopausal threshold” when  fewer than 1000 follicles remain (Figure 1). Individual variation in the number of oocytes and rate of depletion may explain the wide age range for natural menopause. Early (EM)/ premature menopause (PM) may result when there are fewer follicles initially (as may be present in Turner’s syndrome) or if a more rapid loss of follicles occurs (secondary to chemotherapy) as shown in Figure 1.

Figure 1: Age related decline in ovarian follicle numbers

(data derived from Faddy et al., 1992)

4.2 Endocrinology

Hormonal changes in the hypothalamo-pituitary-ovarian with reproductive aging are considered a consequence of follicle depletion (summarized in Table: Changes across the menopause transition from pre- to postmenopause) rather than being the result of a primary neuro-endocrine change. (Endocrine changes in the normal menstrual cycle.)

Elevated cycle day 3-8 follicle stimulating hormone (FSH) levels in the setting of regular menstrual cycles is a clinical indicator of reproductive aging and may occur 3-10 years prior to the menopausal transition. More recently, decreased inhibin B and anti-mullerian hormone (AMH)  levels have been identified as the earliest hormonal changes occurring in late reproductive age women. The menopausal transition is characterized by declining follicle numbers, variable hormonal levels and menstrual irregularity. There are no specific hormonal or biophysical predictors of menopause at present. Decreased AMH   (produced by ovarian follicles independently of FSH), decreased inhibin B (produced by ovarian follicles in negative feedback loop with FSH), elevated FSH levels and smaller ovarian volume /decreased ovarian follicle count on ultrasound are indicative of declining ovarian reserve.

Table: Changes across the menopause transition from pre- to postmenopause.

AMH- antimullerian hormone; FSH- follicle stimulating hormone; E- oestradiol;  Inh- inhibin B

Androgens and pre-androgens in women are produced by both the ovaries and adrenal glands with testosterone the significant bioactive form.  (see Table: Androgens and pre-androgens in women). In contrast to oestradiol, serum testosterone levels decline with age, decreasing by 40- 50 % between 20 and 45 years but not changing significantly across the menopause transition.

Table: Androgens and pre-androgens in women

Surgical menopause results in a rapid decrease in oestradiol levels within 24 hours. Total and free testosterone levels are 40- 50% lower than those of age matched women with natural menopause. Chemotherapy induced amenorrhoea is associated with elevated gonadotrophins, decreased  oestradiol and testosterone, decreased inhibin B and decreased AMH. 

References:

• Burger, Hale GE et al., A review of the hormonal changes during the menopausal transition: focus on findings from the Melbourne Women’s Midlife Health Project. Human Reproduction Update (2007) 13:559-565
• Burger HG, Hale GE et al., Cycle and hormonal changes during the perimenopause: the key role of ovarian function. Menopause (2008) 15:603-612.
• Davison SL, Bell R et al., Androgen levels in adult females: changes with age, menopause and oophorectomy. J Clin Endocrinol Metab (2005) 90: 3847-3853.
• Faddy MJ, Gosden RG et al., Accelerated disappearance of ovarian follicles in mid life: implications for forecasting menopause. Human Reproduction (1992) 7:1342-1346

5. Epidemiology

Content updated December 2010