OVERVIEW OF MENOPAUSE

Key Points

1. Menopause is a normal physiologic event, defined as the final menstrual period (FMP) and reflecting loss of ovarian follicular function. 
2. Spontaneous or natural menopause is recognized retrospectively after 12 months of amenorrhea. It occurs at an average age of 52 years, but the age of natural menopause can vary widely from 40 to 58 years. Induced menopause refers to the cessation of menstruation that occurs after either bilateral oophorectomy or iatrogenic ablation of ovarian function (eg, by chemotherapy or pelvic radiation). 
3. The Stages of Reproductive Aging Workshop (STRAW) established a nomenclature and a staging system for the female reproductive aging continuum in 2001, which was revised in 2011 with the STRAW + 10 staging system. 
4. According to STRAW + 10, the term menopause transition refers to the span of time when menstrual cycle and endocrine changes occur, beginning with variation in the length of the menstrual cycle and ending with the FMP. 
5. Primary ovarian insufficiency describes a transient or permanent loss of ovarian function leading to amenorrhea in women aged younger than 40 years. This condition affects approximately 1% of women. Early menopause describes menopause occurring in women aged 40 to 45 years and is experienced by approximately 5% of women. Premature menopause can be used to refer to definitive cases of menopause before age 40, such as with the surgical removal of both ovaries.  
6. By the year 2025, the number of postmenopausal women is expected to rise to 1.1 billion worldwide.

 Recommendations for Clinical Care

1. Menopause can be viewed as a sentinel event that affords a unique opportunity for a dialogue between women and their healthcare providers to evaluate and improve health-related practices. (Level II)
2. Menopause counseling, including discussion of physiologic changes, assessment of menopause-related symptoms and treatment options, review of screening recommendations, and discussion of disease risk-reduction strategies and psychosocial issues, facilitates informed decision making among midlife and older women. (Level II)
3. By considering women’s concerns, values, and preferences, menopause practitioners have the potential to enhance women’s sense of well-being, not only at menopause but for the remainder of their lives. (Level III)  

OVARIAN AGING AND HORMONE PRODUCTION

Key Points

1. The menopause transition reflects the natural decline of ovarian follicular estrogen production. It is characterized by a number of menstrual cycle changes, with increasing episodes of amenorrhea. As ovarian production of estradiol diminishes further, complete absence of menstrual bleeding ensues.  
2. Menopause is defined retrospectively as the final menstrual period, occurring on average at age 52 years and diagnosed after 12 consecutive months of amenorrhea. 
3. Symptoms of the menopause transition, primarily vasomotor symptoms (VMS), cluster in the 2-year window immediately before and after the FMP, but may continue for many years in some women. 
4. Characteristic changes in the hypothalamic-pituitary-ovarian (HPO) axis during the menopause transition result from decreased ovarian feedback of inhibin and estradiol and are manifested primarily as elevations in follicle-stimulating hormone (FSH). Although central mechanisms may contribute to reproductive aging, they are less well characterized. 
5. Adrenal changes concurrent with the menopause transition include elevations in serum cortisol and transient elevations in dehydroepiandrosterone sulfate, androstenediol, and other adrenal androgens. 
6. Understanding sex steroid receptor function facilitates development of pharmacologic agents that selectively manipulate these receptors and effect a diverse array of clinical outcomes. 

Recommendations for Clinical Care

1. The onset and course of the menopause transition is best determined by menstrual-cycle monitoring with a paper or electronic menstrual calendar designed for this purpose. (Level I) 
2. Given the erratic nature of ovarian function during the menopause transition, hormonal measurements are difficult to interpret and in most instances should be avoided. (Level II) 
3. Although determinants of ovarian reserve, including levels of antimüllerian hormone (AMH), cycle day-3 FSH and estradiol, and ovarian antral follicle count, are available, their clinical use is best confined to counseling women seeking fertility rather than predicting time to menopause. (Level I) 
4. In healthy nonsmokers, low-dose oral contraceptives may be considered for the treatment of heavy or irregular bleeding during the menopause transition. These improve bleeding in part by reducing wide excursions in HPO hormone secretion. (Level I) 
5. As bothersome VMS may begin well before the cessation of menses, healthcare providers should ask their midlife patients about VMS and provide information regarding therapeutic options, even if they are still cycling. (Level II) 
6. Given that ovulatory cycles occur during the menopause transition, contraception is recommended until women have experienced 12 months of amenorrhea. (Level I) 
7. The risk of endometrial pathology is increased at the menopause transition because serum estrogen concentrations are intermittently elevated and ovarian progesterone production is diminished. Any heavy or irregular bleeding at midlife should be thoroughly evaluated. (Level I) 

PREMATURE MENOPAUSE AND PRIMARY OVARIAN INSUFFICIENCY

Key Points

1. Natural menopause occurs at approximately age 52 years. Premature menopause is a general term used to describe menopause that occurs before age 40 years. 
2. Primary ovarian insufficiency (POI) is the preferred term for premature ovarian failure, because this condition can be transient and can wax and wane. 
3. Primary ovarian insufficiency can arise from either decreased ovarian reserve or from ovarian follicular dysfunction. Although the etiology of POI is often idiopathic, it may be caused by genetic abnormalities, metabolic disturbances, pelvic surgery, radiation therapy, chemotherapy, or immune disorders. 
4. Treatment for menopausal symptoms associated with POI can include hormonal and nonhormonal approaches. 

Recommendations for Clinical Care

1. Evaluation of POI is warranted for any woman aged younger than 40 years who misses three or more consecutive menstrual cycles. (Level I) 
2. The baseline evaluation should include assays for human chorionic gonadotropin (hCG), FSH, estradiol, prolactin, and thyroid-stimulating hormone (TSH). The diagnosis of POI is confirmed by two elevated FSH levels drawn at least 1 month apart. (Level I) 
3. Further assessment of ovarian reserve with an AMH level and/or vaginal ultrasound determination of antral follicle count can be helpful in counseling and management. (Level II) 
4. For women with suspected POI, additional evaluation should include a karyotype and testing for a fragile X premutation, thyroid peroxidase antibodies, adrenal antibodies, fasting glucose, and serum calcium and phosphorus levels. Given that autoimmune endocrinopathies can evolve over time, ongoing surveillance in addition to baseline assessment is advised. (Level II) 
5. In women anticipating cancer treatment during the reproductive years, urgent referral to a fertility specialist should be considered for counseling regarding future childbearing and fertility-preservation options. Fertility counseling later in the course of cancer treatment is also important. (Level II) 
6. Hormone therapy or estrogen-containing hormonal contraception, if not contraindicated, is advised to treat menopause symptoms and preserve bone mineral density in women with premature menopause or POI. (Level I)