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Premature Menopause Current Topics in Menopause 415 aetiology, clinical features, diagnosis, and management of PM. It is assumed that readers are familiar with the management of natural age menopause. DEFINITIONS Premature menopause is defined as menopause occurring before the age of 40 years. This is an arbitrary cut off point designated by the World Health Organisation (WHO) [1]; ideally premature menopause (PM) should be defined as menopause occurring at an age two standard deviations below the population mean. This term includes both spontaneous and induced menopause (defined by the WHO as the cessation of menses following oophorectomy or chemotherapy/radiotherapy–induced ablation of ovarian function). Premature ovarian failure (POF) refers to the cessation of ovarian function associated with amenorrhoea and elevated gonadotrophins occurring in women less than 40 years of age. There is debate within the literature as to whether premature ovarian failure (POF) should refer only to spontaneous cessation of ovarian function and exclude induced ovarian failure [2]. Premature ovarian dysfunction [2] or primary ovarian insufficiency [3, 4] have been proposed as a substitute for POF due to the negative connotation associated with the word “failure” and the potential for recovery of ovarian function, but are not commonly applied. In practice, PM and POF are often used interchangeably. Pathophysiology of Premature Menopause 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 [5]. Individual variation in the number of oocytes and rate of depletion may explain the wide age range for natural 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 (for example, secondary to chemotherapy). Idiopathic spontaneous PM may involve both these mechanisms in addition to impaired/failure of follicular maturation [2, 6].
416 Current Topics in Menopause Vincent and Farrell Endocrinology It has been proposed that POF may be considered as accelerated or early reproductive aging although the exact pathogenetic mechanisms involved remain unclear [7]. Hormonal changes in the hypothalamo-pituitary-ovarian axis with reproductive aging are considered a consequence of follicle depletion. Elevated cycle day 3-8 follicle stimulating hormone (FSH) levels in the setting of regular menstrual cycles is a clinical indicator of normal reproductive aging and may occur 3-10 years prior to the menopausal transition [8]. 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 [8]. 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 [9]. There are no specific hormonal or biophysical predictors of menopause at present. PM is associated with elevated gonadotrophins, low or undetectable AMH, decreased inhibin B and low oestradiol [10]. Surgical menopause, secondary to bilateral oophorectomy, results in a rapid decrease within the first 24 hours in oestradiol levels [11, 12]. Total and free testosterone levels are 40- 50% lower than those of age matched women with natural menopause [13, 14]. Chemotherapy induced amenorrhoea is associated with elevated gonadotrophins, decreased oestradiol and testosterone, decreased inhibin B and undetectable AMH [15]. Epidemiology Spontaneous Premature Menopause The prevalence of spontaneous PM is generally accepted as 1% of women aged less than 40 years and 0.1% for those less than 30 years (based on population studies of predominately Caucasian women) [16, 17]. However, there does appear to be some variation related to ethnicity and the population studied which may reflect real differences and/or study bias. A lower prevalence of spontaneous POF was observed in Asian women (0.5-0.1%) compared with Caucasian, African American or Hispanic women (1-1.4%) living in the USA [17]. The prevalence of POF in women presenting with secondary amenorrhea has been reported as 4-
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