Menopause

WHO defines natural menopause as at least 12 consecutive months of amenorrhea not due to physiological/pathological causes. It’s a natural event reached upon exhaustion of primordial follicles The global age at menopause is on average 51 years (range 40-60 years) suggesting a distinct genetic control; with a strong correlation exists between mothers and daughters Menopausal health aspects include bone density, breast, the cardiovascular system, mood/cognitive function and sexual well being Common symptoms include: Hot flushes, night sweats, vaginal dryness and discomfort during sex, difficulty sleeping, low mood/anxiety, reduced libido Physical and emotional changes strongly affect women Closely associated with psychosocial events in midlife and ageing i.e. health issues, family and marital relations, sociocultural back ground and attitudes toward a sex life determine women’s experience of the menopause Effective health care support should be individually tailored to all aspects of the menopause when women feel particularly vulnerable

At birth the ovary contains about 500,000-1million primordial follicles Estimated that for 95% of women by 30yrs only 12% of max. pre-birth NGF population is present and by 40yrs only 3% remains. The ovarian reserve will determine the rate of decline of NGF & age of the menopause The initial ovarian pool of NGFs will determine how quickly they become The ovarian reserve will determine the onset of subfertility to sterility and to complete loss of menstrual cycles – the menopause

Genetics Autoimmunity Ethnicity Nutrition Androgens/PCOS In utero environment

The levels of AMH in the human circulation vary during the life cycle, with a sexually dimorphic pattern. Females produce virtually no AMH in utero After this, the graph is n shaped, with age and AMH, with the peak at around 20 years Declining levels of AMH with age AMH secretion from growing follicles What happens to levels of Inhibin B and FSH as approach peri-menopause? Link between AFC, AMH, Inhibin B and FSH Can AMH predict ovarian reserve? Relation between age-specific anti-Müllerian hormone (AMH) concentrations and the distribution of age at menopause. The left nomogram depicts the baseline AMH levels of 185 normo-ovulatory women and percentile declines. The right nomogram depicts the variation of age at menopause during approximately 11 years of follow up for different AMH percentiles

Measurements of AMH and AFC are used to diagnosed premature ovarian failure/insufficiency – but NICE recommendations NOT to use single blood test of AMH for diagnosis of POI Primary and secondary follicles produce AMH small antral and antral follicles produce Inhibin B FSH stimulates secondary, small antral follicles and antral follicles LH stimulates antral and ovulatory follicles Antral follicles produce oestrogen

Ovarian senescence begins around 35 years ends with menopause ~51 years. Decline in ovarian oestrogen largely related to number of primordial follicles, number of recruitable follicles in each ovarian cycle and proportion of follicles that reach adequate maturity Rise in FSH – loss of negative feed back Decline in inhibin B and AMH Decline in androgen synthesis in adrenal glands and ovaries Marked decline in fertility after age of 35 although this depends on ovarian reserve

Hot flashes and night sweats Vaginal dryness Sleep disturbance Mood symptoms Urinary symptoms Incidence increases from pre-menopause to peri menopause and decreases post menopause

Experienced by approximately 80% menopausal women, can last up to 5-13 years though number of episodes decrease with time Measuring frequency most objective way of assessing severity of menopausal symptoms Typically occurs on the face but can occur in other body areas such as arms and the torso Aetiology unknown but oestrogen interacts with the noradrenergic system in the brain which plays a major role in thermogenesis. Other neural systems have also been implicated such as the endorphin pathways ‘Wet’ flushing occurs through inappropriate vasodilation and activation of sweat glands through both central and peripheral mechanisms. Hormone withdrawal and emotions are both causes Dry’ flushing (no sweat!) can also be caused by several drugs, the carcinoid syndrome, phaeochromocytomas (rare tumour of adrenals) and mastocytosis (accumulation of mast cells in tissues including the skin) – differential diagnosis

Women can lose up to 20% of their bone density in the 5 to 7 years after the menopause (www.nhs.uk). The drop in bone density is caused by falling levels oestrogen, which impairs the normal cycle of bone remodelling i.e. increases amount of bone resorbed (osteoclastic activity) over the amount deposited (osteoblastic activity), leading to net loss of bone Although bone density decreases at the menopause, the risk of osteoporosis and fractures stays relatively low until women get much older, because bone density is only one of the things that affects bone strength. Treatment option include the use of bisphosphonate compounds, maintaining calcium and Vit.D levels, weight bearing exercises

GSM → relatively new term for the condition previously known as vulvovaginal atrophy, atrophic vaginitis, or urogenital atrophy Chronic, progressive, vulvovaginal, sexual, and lower urinary tract condition characterized by a broad spectrum of signs and symptoms Most of these symptoms attributed to the lack of oestrogen. These can have a great impact on the quality of life & treatment aimed at symptomatic relief

Defined as cessation of ovarian function before 40 years Affects 1:100 women before 40 years of age and 1:1000 women before 30 years of age Reasons include: Genetic Gonadal dysgenesis autoimmune idiopathic viral infections vaccinations congenital enzymatic deficiencies

Hypergonadotrophic-hypogonadism Low estradiol (<20 IU/l) Elevated FSH (>20 IU/l) Low AMH levels (< 0.5 ng/ml) Low inhibin B levels Assessed day 3 of the menstrual cycle

Symptoms are those similar to those observed at a normal menopause. Loss of oestrogen e.g. oligomenorrrhea, hot flushes, sweating, nervousness, skin changes, mucous membrane dryness  decreased bone mineral density (osteoporosis), metabolic changes, CVD, urogenital atrophy and early mortality Treatment: Treatment: HRT Combined oral contraceptive pill (but contain higher doses of steroids) Long term effects of menopause: Adverse effects on health and mortality HRT can lessen some of these risks but not all Provide HRT at least until natural age of menopause Psychological aspects of early menopause Individualising treatment both in terms of HRT and the psychological impact

Menopausal hormone replacement therapy (MRT) Tablets, skin patches, gels and implants to replace oestrogen Vaginal oestrogen creams/lubricants/moisturisers New non-oestrogen treatment for GSM CBT To help with low mood and anxiety Regular exercise and good diet To maintain bone strength and reduce weight and hence risk of various pathologies Natural/alternative therapies Bisphosphonates for bone density Neurokinin B (NKB) antagonists in Phase 2 clinical trials For treatment of hot flushes NKB hypothalamic neuropeptide involved in GnRH secretion and thought to stimulate activity of the vasomotor centre, resulting in hot flushes

Heart and Estrogen/Progestin Replacement Study (HERS) (CCEPT in postmenopausal women with CHD) HERS ended after 4.1 years due to risks Women’s Health Initiative (WHI) (healthy postmenopausal women) Prospective, randomised, double-blind, placebo-controlled studies of continuous-combined estrogen progestin therapy (CCEPT) or CEE only Evaluated only one hormone combination; no perimenopausal women WHI was stopped at 5.2 years –increased risk of breast cancer Million women study – started recruiting participants in 1996 to investigate effect of use of HRT amongst other things. Study includes 1 in 4 women in UK born between 1935 and 1950 Participants sent postal resurvey questionnaires every 3-5 years. http://www.millionwomenstudy.org/introduction/ Increased risk of breast cancer with HRT – but risk was very dependent on which type of HRT used and when it was started making it complex to dissect out the true impact