hormone replacement therapy hormone replacement therapy hormone replacement therapy (hrt), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. these symptoms can include hot flashes, vaginal atrophy, accelerated skin aging, vaginal dryness, decreased muscle mass, sexual dysfunction, and bone loss or osteoporosis. they are in large part related to the diminished levels of sex hormones that occur during menopause. this article is about hormone replacement therapy in menopause. for transgender applications, see transgender hormone therapy. for other forms, see hormone therapy. estrogens and progestogens are the main hormone drugs used in hrt. progesterone is the main female sex hormone that occurs naturally and is also manufactured into a drug that is used in menopausal hormone therapy. although both classes of hormones can have symptomatic benefit, progestogen is specifically added to estrogen regimens, unless the uterus has been removed, to avoid the increased risk of endometrial cancer. unopposed estrogen therapy promotes endometrial hyperplasia and increases the risk of cancer, while progestogen reduces this risk. androgens like testosterone are sometimes used as well. hrt is available through a variety of different routes. the long-term effects of hrt on most organ systems vary by age and time since the last physiological exposure to hormones, and there can be large differences in individual regimens, factors which have made analyzing effects difficult. the women's health initiative (whi) is an ongoing study of over 27,000 women that began in 1991, with the most recent analyses suggesting that, when initiated within 10 years of menopause, hrt reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementia; after 10 years the beneficial effects on mortality and coronary heart disease are no longer apparent, though there are decreased risks of hip and vertebral fractures and an increased risk of venous thromboembolism when taken orally. "bioidentical" hormone replacement is a development in the 21st century and uses manufactured compounds with "exactly the same chemical and molecular structure as hormones that are produced in the human body." these are mainly steroids derived from plants and can be a component of either registered pharmaceutical or custom-made compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and formal oversight. bioidentical hormone replacement has inadequate clinical research to determine its safety and efficacy as of 2017. the current indications for use from the united states food and drug administration (fda) include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or vaginal atrophy, and prevention of osteoporosis. medical uses approved uses of hrt in the united states include short-term treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and prevention of osteoporosis. the american college of obstetrics and gynecology (acog) approves of hrt for symptomatic relief of menopausal symptoms, and advocates its use beyond the age of 65 in appropriate scenarios. the north american menopause society (nams) 2016 annual meeting mentioned that hrt may have more benefits than risks in women before the age of 60. a consensus expert opinion published by the endocrine society stated that when taken during perimenopause or the initial years of menopause, hrt carries fewer risks than previously published, and reduces all cause mortality in most scenarios. the american association of clinical endocrinologists (aace) has also released position statements approving of hrt when appropriate. women receiving this treatment are usually post-, peri-, or surgically induced menopausal. menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity, defined as beginning twelve months after the final natural menstrual cycle. this twelve month time point divides menopause into early and late transition periods known as 'perimenopause' and 'postmenopause'. premature menopause can occur if the ovaries are surgically removed, as can be done to treat ovarian or uterine cancer. demographically, the vast majority of data available is in postmenopausal american women with concurrent pre-existing conditions and an average age of over 60 years. menopausal symptoms symptoms of menopause hrt is often given as a short-term relief from menopausal symptoms during perimenopause. potential menopausal symptoms include: hot flashes – vasomotor symptoms vulvovaginal atrophy – atrophic vaginitis and dryness dyspareunia – painful sexual intercourse due to vaginal atrophy and lack of lubrication bone loss – decreased bone mineral density, which can eventually lead to osteopenia, osteoporosis, and associated fractures decreased sexual desire defeminization – diminished feminine fat distribution and accelerated skin aging sleep disturbances and joint pain the most common of these are loss of sexual drive and vaginal dryness. heart disease the risks of coronary heart disease with hrt vary depending on age and time since menopause. the effect of hrt in menopause appears to be divergent, with lower risk of heart disease when started within five years, but no impact after ten. there may be an increase in heart disease if hrt is given twenty years post-menopause. this variability has led some reviews to suggest an absence of significant effect on morbidity. importantly, there is no difference in long-term mortality from hrt, regardless of age. a cochrane review suggested that women starting hrt less than 10 years after menopause had lower mortality and coronary heart disease, without any strong effect on the risk of stroke and pulmonary embolism. those starting therapy more than 10 years after menopause showed little effect on mortality and coronary heart disease, but an increased risk of stroke. both therapies had an association with venous clots and pulmonary embolism. hrt with estrogen and progesterone also improves cholesterol levels. with menopause, hdl decreases, while ldl, triglycerides and lipoprotein a increase, patterns that reverse with estrogen. beyond this, hrt improves heart contraction, coronary blood flow, sugar metabolism, and decreases platelet aggregation and plaque formation. hrt may promote reverse cholesterol transport through induction of cholesterol abc transporters. hrt also results in a large reduction in the pro-thrombotic lipoprotein a. studies on cardiovascular disease with testosterone therapy have been mixed, with some suggesting no effect or a mild negative effect, though others have shown an improvement in surrogate markers such as cholesterol, triglycerides and weight. testosterone has a positive effect on vascular endothelial function and tone with observational studies suggesting that women with lower testosterone may be at greater risk for heart disease. available studies are limited by small sample size and study design. low sex hormone binding globulin, which occurs with menopause, is associate with increased body mass index and risk for type 2 diabetes. blood clots clot in the greater saphenous vein; oral estrogen is associated with increased risk of venous blood clots due to increased liver formation of vitamin k-dependent clotting factors. effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism may vary with different estrogen and progestogen therapies, and with different doses or method of use. comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots, whereas when used orally, the risk of blood clots and pulmonary embolism is increased. skin and vaginal routes of hormone therapy are not subject to first pass metabolism, and so lack the anabolic effects that oral therapy has on liver synthesis of vitamin k-dependent clotting factors, possibly explaining why oral therapy may increase blood clot formation. while a 2018 review found that taking progesterone and estrogen together can decrease this risk, other reviews reported an increased risk of blood clots and pulmonary embolism when estrogen and progestogen were combined, particularly when treatment was started 10 years or more after menopause and when the women were older than 60 years. the risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary. risk of venous thromboembolism (vte) with hormone therapy and birth control (qresearch/cprd) typeroutemedicationsodds ratio (95% ci) menopausal hormone therapyoralestradiol alone ≤1 mg/day >1 mg/day1.27 (1.16–1.39)*1.22 (1.09–1.37)*1.35 (1.18–1.55)* conjugated estrogens alone ≤0.625 mg/day >0.625 mg/day1.49 (1.39–1.60)*1.40 (1.28–1.53)*1.71 (1.51–1.93)* estradiol/medroxyprogesterone acetate1.44 (1.09–1.89)* estradiol/dydrogesterone ≤1 mg/day e2 >1 mg/day e21.18 (0.98–1.42)1.12 (0.90–1.40)1.34 (0.94–1.90) estradiol/norethisterone ≤1 mg/day e2 >1 mg/day e21.68 (1.57–1.80)*1.38 (1.23–1.56)*1.84 (1.69–2.00)* estradiol/norgestrel or estradiol/drospirenone1.42 (1.00–2.03) conjugated estrogens/medroxyprogesterone acetate2.10 (1.92–2.31)* conjugated estrogens/norgestrel ≤0.625 mg/day cees >0.625 mg/day cees1.73 (1.57–1.91)*1.53 (1.36–1.72)*2.38 (1.99–2.85)* tibolone alone1.02 (0.90–1.15) raloxifene alone1.49 (1.24–1.79)* transdermalestradiol alone ≤50 μg/day >50 μg/day0.96 (0.88–1.04)0.94 (0.85–1.03)1.05 (0.88–1.24) estradiol/progestogen0.88 (0.73–1.01) vaginalestradiol alone0.84 (0.73–0.97) conjugated estrogens alone1.04 (0.76–1.43) combined birth controloralethinylestradiol/norethisterone2.56 (2.15–3.06)* ethinylestradiol/levonorgestrel2.38 (2.18–2.59)* ethinylestradiol/norgestimate2.53 (2.17–2.96)* ethinylestradiol/desogestrel4.28 (3.66–5.01)* ethinylestradiol/gestodene3.64 (3.00–4.43)* ethinylestradiol/drospirenone4.12 (3.43–4.96)* ethinylestradiol/cyproterone acetate4.27 (3.57–5.11)* notes: (1) nested case–control studies (2015, 2019) based on data from the qresearch and clinical practice research datalink (cprd) databases. (2) bioidentical progesterone was not included, but is known to be associated with no additional risk relative to estrogen alone. footnotes: * = statistically significant (p < 0.01). sources: see template. stroke multiple studies suggest that the possibility of hrt related stroke is absent if therapy is started within five years of menopause, and that the association is absent or even preventive when given by non-oral routes. ischemic stroke risk was increased during the time of intervention in the whi, with no significant effect after the cessation of therapy and no difference in mortality at long term follow up. when oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until five years from menopause, cohort studies in swedish women have suggested an association with hemorrhagic and ischemic stroke. another large cohort of danish women suggested that the specific route of administration was important, finding that although oral estrogen increased risk of stroke, absorption through the skin had no impact, and vaginal estrogen actually had a decreased risk. endometrial cancer endometrial cancer can be associated with hrt, particularly in those not taking a progestogen. in postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence. the duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease. endometrial cancer has been grouped into two forms in the context of hormone replacement. type 1 is the most common, can be associated with estrogen therapy, and is usually low grade. type 2 is not related to estrogen stimulation and usually higher grade and poorer in prognosis. the endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen. the extensive use of high-dose estrogens for birth control in the 1970s is thought to have resulted in a significant increase in the incidence of type 1 endometrial cancer. paradoxically, progestogens do promote the growth of uterine fibroids, and a pelvic ultrasound can be performed before beginning hrt to make sure there are no underlying uterine or endometrial lesions. androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent. there is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer. breast cancer studies regarding the association of breast cancer with hormone replacement are inconsistent and vary with type of replacement and time since menopause. while some evaluations suggest an increased risk, in others it is decreased. this inconsistency of effect has been suggested to imply a lack of meaningful impact of hrt on breast cancer risk. there is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone. the risk may be reduced with bioidentical progesterone, though the only prospective study that suggested this was underpowered due to the rarity of breast cancer in the control population. there have been no randomized controlled trials as of 2018. the relative risk of breast cancer also varies depending on the interval between menopause and hrt and route of synthetic progestin administration. the most recent follow up of the women's health initiative participants demonstrated a lower incidence of breast cancer in post-hysterectomy participants taking equine estrogen alone, though the relative risk was increased if estrogen was taken with medroxy-progesterone. estrogen is usually only given alone in the setting of a hysterectomy due to the increased risk of vaginal bleeding and uterine cancer with unopposed estrogen. hrt has been more strongly associated with risk of breast cancer in women with lower body mass indices (bmis). no breast cancer association has been found with bmis of over 25. it has been suggested by some that the absence of significant effect in some of these studies could