Treating menopausal women: Have we lost our way?

Early in the 20th century endocrinologists became convinced gonads secreted ‘sex’ hormones that were responsible for maintaining accessory sex organs and phenotypically differentiated secondary sexual characteristics. In 1923 Edgar Allen Edward Doisy published a paper on isolation of an ‘ovarian hormone’1 about same time Adolf Butenandt isolated oestrone from ovary. went to isolate progesterone 1934 testosterone 1935 which he was awarded Nobel prize 1939. The identification these so-called subsequent understanding hypothalamic-pituitary-gonadal feedback loop led development branch our profession known as reproductive endocrinology infertility or, more simply, medicine. advances seen this area medicine are numerous but, first among many, must be combined oral contraceptive pill (COCP). ‘sponsors’ Margaret Sanger, American libertarian Katherine McCormick, wealthy suffragette. ‘founders’ Gregory Pincus, zoologist John Rock, (Catholic) gynaecologist, but it pioneering work another scientist, Carl Djerassi who used Mexican yams substrate produce steroids including cortisone synthetic progestogen, norethindrone, set stage. correctly postulated appropriate progestogen would suppress ovulation. Synthetic progestogens (progestins) cheap well absorbed orally, allowing contraceptives. Later they played important role treating menstrual disorders menopause. Unfortunately, progestins bind receptors other than progesterone, permitting side effects. second great achievement was, course, vitro fertilisation (IVF). Whereas liberated women fear unplanned pregnancy, IVF offered hope millions whom pregnancy had seemed impossible. by Australian researchers is known, world’s third birth 1980. Of every 20 babies born today one due IVF. Menopause less lauded Compared excitement liberation associated with COCP joy successful IVF, menopause decidedly unglamorous. Even reluctant discuss their menopausal experiences. at expected age 45 55 years normal physiological process experienced all women. However, 10% will experience early between ages 40 nearly 4% loss ovarian function before 40, condition now premature insufficiency (POI).2 POI regarded pathological increased risk osteoporosis fracture, cardiovascular disease, possible cognitive impairment reduced life expectancy. use hormone therapy (MHT) treat accepted practice. MHT ‘normal’ somewhat controversial. Although many women, sequelae range unpleasant pathological. Typical well-known symptoms hot flushes, night sweats, poor sleep, muscle joint pain mood memory changes. These affect approximately 80% around 30% seek medical treatment. It mistake regard vasomotor trivial; can quality life, relationships, careers well-being. Apart immediate effects flush, recent research has found may also marker disease greater severity earlier onset being particular relevance.3 Cardiovascular increases after menopause, regardless onset, increase, although part ageing, protective oestrogen system. Loss leads bone density consequent fracture. For centuries endure without effective treatment affordable replacement (HRT) 1940s changed that. HRT proved highly Common regimens included conjugated oestrogens plus progestin when required endometrial protection. Subsequent observational studies clinical trials suggested benefits health improvement lipid parameters vascular health, both surrogate markers health. On negative small increase thromboembolic breast cancer, thought outweighed benefits. enjoying its heyday. As we know, publication initial data Women’s Health Initiative (WHI) randomised trials4 2002. To say alarming understatement. Harm said outweigh benefit, outcomes expressed relative rather absolute risks age, ethnicity or status, claims subsequently proven wrong. remarkable display hubris, released media journal. Women stopped using HRT, doctors prescribing schools specialist colleges teaching HRT. A generation left none wiser denied hormonal symptoms. Real harm have been caused data; 2013 paper5 estimated 18 000 91 younger postmenopausal US died prematurely because avoidance previous decade. Over time, WHI trial re-examined cohorts, alone combination medroxyprogesterone acetate (MPA) compared, long-term follow-up 20136 mortality 2017.7 Not surprisingly, confirmed that, healthy within ten last period, significant benefits, minimal morbidity no all-cause cause-specific compared placebo. cancer MPA not alone. New demonstrated lower doses transdermal attenuates oestrogens8 there different natural latter attenuating increasing disease.9 capacity sting tail. should thus surprise original (an non-body-identical MPA, progestogenic endocrine disruptor), yield comparable beneficial those endogenous body-identical yet differences synthetics frequently misunderstood ignored. Many remain dangerous. Comprehensive national international guidelines global consensus statement sought address concerns define place 21st century.10 Current recommend any overall plan maximise midlife women.11 indication, lowest dose first-choice considered ameliorate disease. suited form MHT, individualisation care essential. low-dose low compound, tibolone, even MHT. Tibolone unique molecule characterised selective tissue activity regulator (STEAR). Its hydroxylated metabolites receptors, exerting oestrogenic brain, vagina, while parent delta-4 isomer androgen receptors. endometrium prevent hyperplasia. Activity via lowering hormone-binding globulin weak androgenic users. effect androgenicity breast-specific inhibition sulphatase activity. reduces fracture risk, similar Observational studies8 events tibolone. Use tibolone personal history recurrence recommended Cochrane systematic review12 alleviated symptoms, modest best. suitable post- perimenopausal Long-term cancer.9 greatest remains cancer. most publication13 oestrogen-only incidence (hazards ratio (HR) 0.78, 95% CI 0.65–0.93) (HR 0.60, 0.37–0.97) 1.28, 1.13–1.45) again, mortality. This equates extra case per 1000 year, conferred obesity, inactivity alcohol. data8 suggest further choosing neutral, progestogen. spend 1/3 critical clinicians aware added chronic so measures taken minimise diseases years. this, minimum, involve ensuring, patients screening tests current, lifestyle aimed achieving diet, body weight, regular exercise, cessation smoking limited alcohol consumption discussed. Menopausal need appropriately canvassed. Despite review since released, misunderstandings true into outstanding taught us things, least initiated older ​oestrogens avoided favour alternatives. They did teach avoided. take heed lessons current evidence longer denying symptomatic