4.1 Ovarian follicle depletion

The peak number of 6-8 million ovarian oocytes/follicles are present in the fetus 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 (Faddy, Gosden et al. 1992)(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 or if a more rapid loss of follicles occurs (secondary to chemotherapy) as shown in Figure 1: Age related decline in ovarian follicle numbers.
 

Figure 1: Age related decline in ovarian follicle numbers (data derived from(Faddy, Gosden et al. 1992))

4.2 Endocrinology of natural menopause

Hormonal changes in the hypothalamo-pituitary-ovarian axis with reproductive aging are considered a consequence of ovarian follicle depletion (summarized in Table: Changes across the menopause transition from pre- to postmenopause) rather than being the result of a primary hypothalamic-pituitary neuro-endocrine change (see The Normal Menstrual Cycle and the Control of Ovulation). 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 (Burger, Hale et al. 2008). 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 a negative feedback loop with FSH), elevated FSH levels and smaller ovarian volume/decreased ovarian follicle count on ultrasound may be 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 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 (Davison, Bell et al. 2005).
 

Table: Androgens and pre-androgens in women

4.3 Endocrinology of menopause and amenorrhoea in women with breast cancer

Women diagnosed with breast cancer (BC) may experience menopause or menopausal symptoms either as a result of:

(i) natural menopause occurring concurrently with the BC diagnosis, or 

(ii) amenorrhea or menopause occurring as a result of BC treatment (chemotherapy or oophorectomy).

Endocrine changes associated with natural menopause are described in section 4.2. 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/menopause is related to both impaired follicular maturation and loss of ovarian follicles (see Figure 1) and may be temporary or permanent (menopause). In one prospective study, 41% of women treated with BC chemotherapy experienced an initial 6 months of amenorrhoea and 29% experienced 12 months of amenorrhoea following chemotherapy (Sukumvanich, Case et al. 2010). The endocrine changes associated with chemotherapy induced amenorrhea include elevated gonadotrophins, decreased oestradiol and testosterone, decreased inhibin B and decreased AMH (Walshe, Denduluri et al. 2006; Anderson and Cameron 2011). However, it is important to note that the use of tamoxifen or gonadotrohin releasing hormone agonists can render hormonal results difficult to interpret (see Diagnosis).
 

Selected References:

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.

Sukumvanich P, Case LD, Van Zee K, Singletary SE, Paskett ED, Petrek JA, Naftalis E, Naughton MJ. Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: a prospective study. Cancer (2010) 116:3102-3111.

Walshe JM, Denduluri N et al. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol. (2006) 24:5769-5779.

5. Causes of Menopause and Epidemiology

Content updated May 16, 2011