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menopause

Cessation of menstruation with age. Definitive when amenorrhea has lasted for 12 months. Etiology: 1) failure of ovarian follicular development in the presence of sufficient gonadotropin levels 2) gradual decline in ovarian function & estrogen production 3) age at natural menopause unaffected by tubal ligation [54] 4) pregnancy & breast-feeding may lower risk for early menopause [61] Epidemiology: 1) average age of menopause is 51-52 years [49] 2) range is 40-60 years 3) smokers may have accelerated menopause 4) 75-80% of women experience discomfort associated with menopause 5) 10-15% experience symptoms that interfere with activities of daily living 6) 25% complain of symptoms lasting more than 5 years Pathology: 1) declining estrogen levels result in onset of accelerated bone loss 2) skin thickness & collagen content are reduced, resulting in wrinkles 3) urogenital atrophy a) mucosa of vagina becomes extremely sensitive to estrogen b) vaginal atrophy c) increased susceptibility to bacterial vaginitis d) vulvar & labial atrophy e) atrophy of urethra & bladder trigone e) atrophy of pelvic support increasing risk of uterine prolapse, cystocele & rectocele f) change in vaginal endogenous flora from Lactobacillus to Streptococcus & Prevotella [33] 4) androgen deficiency may contribute to: [6] a) sarcopenia b) osteoporosis c) fatigue & psychological symptoms 5) progressive increase in risk of coronary artery disease a) estrogen acts directly on coronary arteries inducing vasodilation b) estrogen inhibits development of atheromatous plaques by favorable effects on lipoprotein profile c) higher serum testosterone in postmenopausal women increases risk of cardiovascular disease [48] - in contrast, higher serum estradiol in postmenopausal women associated with lower cardiovascular risk [48] 6) carotid intima-media thickness & adventitial diameter increase in the perimenopausal period [25] 7) cardiovascular disease may influence onset of menopause Genetics: - common gene variants affecting timing of menopause: - ETAA1, ZNF518A, PNPLA8, PALB2, SAMHD1 - SAMHD1 variants are associated with extended reproductive lifespan in women & increased all-cause cancer risk in both men & women [66] - UK Biobank identified gene-based associations : - CHEK2, DCLRE1A, HELB, TOP3A, BRCA2, CLPB - 5 genes harbouring variants with large effects - protein-truncating variants in ZNF518A are associated with earlier age at menopause (by 5.61 years) & later age at menarche (by 0.56 years) [66] - CHEK2 1.6 years later menopause - HELB 1.8 years later menopause - HROB 2.9 years earlier menopause - BRCA2 1.2 years earlier menopause - 4 genes associated with timing of menopause increase risk of cancer - BRCA2 (breast cancer, prostate cancer, pancreatic cancer, ovarian cancer, other) - CHEK2 (breast cancer, myeloid leukemia, prostate cancer) - PALB (breast cancer, pancreatic cancer, other) - SAMHD1 (prostate cancer, mesothelioma, breast cancer) - women homozygous for stop-gain variant rs117316434(A) in CCDC201 (p.(Arg162Ter) reached menopause 9 years earlier than other women - minor allele frequency ~1% - present in one in 10,000 northern European women [66] Clinical manifestations: 1) hypermenorrhea, oligomenorrhea & finally amenorrhea - MKSAP19 would disagree (see below)# 2) hot flashes* (16%) [7] a) mean duration 5.2 years [16] b) hot flashes often recurr after cessation of hormone replacement therapy (HRT) [11] 3) night sweats 4) vaginal dryness (26%) [7,17] a) dysparunia b) atrophic vaginitis* c) vaginal bleeding 5) genital irritation (10%) [7] 6) urinary stress incontinence [9] 7) symptoms of cystitis 8) insomnia, early awakening, irritability &/or anxiety (46-53%) 9) depression generally resolves within 1 year [28] 10) arthralgias ? [26] 11) weight gain NOT associated with menopause [4] 12) low estrogen levels of menopause associated with nighttime hot flashes, sleep disturbance, & depression [43] * the 2 manifestations that may be definitively attributed to menopause # irregular menses with period lasting 15 days is anovulatory bleeding or abnormal vaginal bleeding warranting endometrial biopsy without transvaginal ultrasound in perimenopausal women according to MKSAP19 [2] Laboratory: 1) in general, diagnosis is clinical & no specific laboratory testing is required [2] 2) for premature menopause (<40): serum FSH, serum TSH & serum prolactin [2] 3) serum gonadotropins a) serum follicle-stimulating hormone (serum FSH) is increased generally > 40 mIU/mL b) serum luteinizing hormone (serum LH) 1] during the perimenopausal period, LH levels remain in the high normal range 2] serum LH levels reach a peak 1-3 years after the menopause followed by a gradual decline c) serum FSH/serum LH ratio > 1 suggestive of menopause 4) Mullerian inhibiting substance in serum/plasma (PicoAMH Elisa) [52] 5) serum estradiol levels tend to be diminished 6) women on oral contraceptives a) check hormone levels on 7th day of pill-free interval b) serum estradiol < 25 pg/mL & FSH/LH ratio of > 1 indicates menopause 7) home menopause test NOT recommended [8] Special laboratory: - endometrial biopsy if breakthrough bleeding Complications: 1) osteoporosis - early menopause leads to more osteoporotic fractures & earlier death [21] - unintentional weight loss associated with highest risk of bone fracture in postmenopausal women [36] 2) atherosclerosis [62] - natural menopause before age 45 - 50% increased risk for coronary heart disease - 19% increased risk for cardiovascular mortality - 12% increased risk for overall mortality [42] - premature & early menopause are risk factors for cardiovascular disease whether natural or surgical (RR = 1.6 to 1.8) [57,59] - age of menopause not a cardiovascular risk factor [60] 3) sleep disturbance [31] 4) depression [13,19] generally resolves within 1 year [28] 5) sleep disturbance & depression increase cardiovascular risk [62] 6) hot flashes may persist in older menopausal women in a minority of cases 7) vasomotor symptoms of menopause are linked to dyslipidemia, insulin resistance, & hypertension [62] 8) memory loss ? [15] - verbal memory scores may be somewhat better with later menopause [49] 9) increased risk of new-onset asthma (RR=3.4) [38] 10) pregnancy is possible in the perimenopausal period even if menstrual cycles are irregular [2] Management: 1) topical agents a) vaginal moisturizers or lubricants b) vaginal estrogen for atrophic vaginitis c) transdermal estradiol(Climara) 50 micrograms/day - use in combination with progesterone if woman still has uterus 2) oral agents a) hormone replacement therapy short term < 3 years - estrogen is most effective therapy for vasomotor symptoms [2] - indications: - women < 60 years with 10 years of menopause [2] - intolerable vasomotor symptoms - low-dose estrogen may improve mood [23] - urinary incontinence, decreased libido are NOT indications [2] - may reduce cardiovascular risk when initiated during menopausal transition, but may be harmful when initiated > 10 years since menopause [62] - contraindications: - pregnancy, vaginal bleeding, liver disease, coronary artery disease, stroke venous thromboembolism, breast cancer, endometrial cancer - chest wall radiation - chemotherapy is not a contraindication [2] - unopposed estrogen: Premarin 0.625 mg QD if woman has had hysterectomy - cyclic therapy results in resumption of menses - Premarin 0.625 mg QD days continuously - Provera 5-10 mg QD days 1-14 - continuous therapy - Premarin 0.625 mg plus Provera 2.5 mg PO QD - Prempro is combination of Premarin plus Provera b) hot-flashes in estrogen-intolerant women - chest wall radiation but not chemotherapy increases risk for breast cancer [2] - Provera only - megace 20 mg PO BID - venlafaxine (Effexor): start 12.5 mg PO BID - serotonin re-uptake inhibitors (SSRI) - paroxetine (Paxil) 10-20 mg PO QD - only nonhormonal medication approved in U.S.for treatment of vasomotor symptoms of menopause - start 7.5 mg QHS, increase PRN to 25 mg QHS [56] - fluoxetine (Prozac) 20 mg PO QD - sertraline (Zoloft) 25-50 mg PO QD - escitalopram (Lexapro) 10-20 mg PO QD [18] - gabapentin (Neurontin): start 100 mg PO QHS (modest efficacy) [56] - pregabalin [2] c) clonidine 0.05-0.2 mg BID [2] - little or no benefit [56] d) evaluate annually for continued need of therapy [2] 3) diet & lifestyle a) lifestyle interventions may reduce cardiovascular risk [62] b) no evidence to support routine supplementation with calcium &/or vitamin D [22] c) soy protein enriched in isoflavones of limited benefit [9] d) oily fish & fresh legumes associated with a delay in menopause; refined pasta & rice associated with earlier menopause [46] 4) medicinal herbs a) black cohosh [2] is questionable recommendation - no effect on vasomotor activity [41] b) phytoestrogens - modest benefit for hot flashes & vaginal dryness [41] - no effect on night sweats - soy isoflavones - modest benefit for hot flashes & vaginal dryness [41] - no value in preventing hot flashes or loss of bone mineral density [20] c) pine bark extract appears of benefit for hot flashes [41] d) chinese herbal remedies (dong quai) of no benefit [41] e) MKSAP 19 concludes herbal therapies of unproven benefit [2] 5) exercise [27] - regular aerobic weight-bearing exercise - may reduce risk of hip fractures & total fracture risk [58] - may increase risk of knee fracture & arm or forearm fracture [58] 6) cognitive behavioral therapy for insomnia due to hot flashes [45] - mindfulness training, cognitive behavioral therapy, & behavior-based therapy helpful in relieving hot-flashes [47] 7) acupuncture may help treat some symptoms (hot flashes, sleep, emotions) [53] 8) patient education a) monthly self breast exam b) regular mammograms c) a mobile app from the North American Menopause Society [35] 9) dysfunctional uterine bleeding in perimenopausal women a) pelvic exam b) Pap smear c) endometrial biopsy Clinical trials: - KEEPS trial reports that estrogen-progesterone treatment started soon after menopause - relieves menopausal symptoms of hot flashes & night sweats - improves mood - improves bone mineral density - improves sexual function

Related

amenorrhea (oligomenorrhea) home menopause test hormone replacement therapy (HRT); estrogen replacement therapy; postmenopausal hormone replacement therapy hot flash; menopausal vasomotor symptom

Specific

menopausal disorder

General

age-related endocrinopathy

References

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