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Wikipedia

Hormone replacement therapy

February 15, 2024

This article is about hormone replacement therapy in menopause. For transgender applications, see Transgender hormone therapy. For other forms, see Hormone 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.[1][2] Effects of menopause can include symptoms such as hot flashes, accelerated skin aging, vaginal dryness, decreased muscle mass, and complications such as osteoporosis (bone loss), sexual dysfunction, and vaginal atrophy. They are mostly caused by low levels of female sex hormones (e.g. estrogens) that occur during menopause.[1][2]

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.[1] 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.[3][4] Androgens like testosterone are sometimes used as well.[5] HRT is available through a variety of different routes.[1][2]

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.[6] 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.[7][8]

"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."[9] These are mainly steroids derived from plants[10] 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.[11] Bioidentical hormone replacement has inadequate clinical research to determine its safety and efficacy as of 2017.[12]

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.[13]

Medical uses edit

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.[13] The American College of Obstetrics and Gynecology (ACOG) approves of HRT for symptomatic relief of menopausal symptoms,[14] and advocates its use beyond the age of 65 in appropriate scenarios.[15] 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.[16]

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.[17] The American Association of Clinical Endocrinologists (AACE) has also released position statements approving of HRT when appropriate.[12]

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'.[4] 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.[18]

Menopausal symptoms edit

 
Symptoms of menopause

HRT is often given as a short-term relief from menopausal symptoms during perimenopause.[19] Potential menopausal symptoms include:[1][2]

The most common of these are loss of sexual drive and vaginal dryness.[4][22]

Sexual function edit

See also: Testosterone (medication) § Women
 
Atrophy of vaginal mucosa that occurs with menopause

HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40 and 69 years suggest that 75% of women remain sexually active after menopause.[4] With increasing life spans, women today are living one third or more of their lives in a postmenopausal state, a period during which healthy sexuality can be integral to their quality of life.[23]

Decreased libido and sexual dysfunction are common issues in postmenopausal women, an entity referred to hypoactive sexual desire disorder (HSDD); its signs and symptoms can both be improved by HRT.[5][24] Several hormonal changes take place during this period, including a decrease in estrogen and an increase in follicle-stimulating hormone. For most women, the majority of change occurs during the late perimenopausal and postmenopausal stages.[4] Decreases in sex hormone-binding globulin (SHBG) and inhibin (A and B) also occur. Testosterone is present in women at a lower level than men, peaking at age 30 and declining gradually with age; there is less variation during the menopausal transition relative to estrogen and progesterone.[4]

A global consensus position statement has advised that postmenopausal testosterone replacement to premenopausal levels can be effective for HSDD. Safety information for testosterone treatment is not available beyond two years of continuous therapy however and dosing above physiologic levels is not advised.[25] Testosterone patches have been found to restore sexual desire in post menopausal women.[26] There is insufficient data to evaluate the impact of testosterone replacement on heart disease, breast cancer, with most trials having included women taking concomitant estrogen and progesterone and with testosterone therapy itself being relatively short in duration. In the setting of this limited data, testosterone therapy has not been associated with adverse events.[25]

Not all women are responsive, especially those with preexisting sexual difficulties.[22] Estrogen replacement can restore vaginal cells, pH levels, and blood flow to the vagina, all of which tend to deteriorate at the onset of menopause. Pain or discomfort with sex appears to be the most responsive component to estrogen.[22] It also has been shown to have positive effects on the urinary tract.[22] Estrogen can also reduce vaginal atrophy and increase sexual arousal, frequency and orgasm.[22]

The effectiveness of hormone replacement can decline in some women after long-term use.[22] A number of studies have also found that the combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone.[22] Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties that is available in Europe, has the ability to improve mood, libido, and physical symptomatology. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been seen, though it also carries a similar risk profile to conventional HRT.[5]

Muscle and bone edit

There is a significant decrease in hip fracture risk during treatment that to a lesser degree persists after HRT is stopped.[27][28] It also helps collagen formation, which in turn improves intervertebral disc and bone strength.[29]

Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle.[30] Lower testosterone is associated with lower bone density and higher free testosterone is associated with lower hip fracture rates in older women.[31] Testosterone therapy, which can be used for decreased sexual function, can also increase bone mineral density and muscle mass.[25]

Side effects edit

Side effects in HRT occur with varying frequency and include:[32]

Common edit

Uncommon edit

Heart disease edit

 
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.[34][35][36] For women who are in early menopause and have no issues with their cardiovascular health, HRT comes with a low risk of adverse cardiovascular events.[37] There may be an increase in heart disease if HRT is given twenty years post-menopause.[38] This variability has led some reviews to suggest an absence of significant effect on morbidity.[39] Importantly, there is no difference in long-term mortality from HRT, regardless of age.[40]

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.[34] 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.[34]

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.[41] HRT also results in a large reduction in the pro-thrombotic lipoprotein a.[42] 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.[43][44] 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.[45]

Blood clots edit

 
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.[18] Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots,[18][46] whereas when used orally, the risk of blood clots and pulmonary embolism is increased.[47] 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.[48]

While a 2018 review found that taking progesterone and estrogen together can decrease this risk,[46] 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.[18][47]

The risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary.[49]

Stroke edit

Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause,[50] and that the association is absent or even preventive when given by non-oral routes.[8] Ischemic stroke risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy[27] and no difference in mortality at long term follow up.[6] 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.[50] 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.[8]

Endometrial cancer edit

 
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.[51] The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease.[52]

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.[53] The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen.[53] 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.[54]

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.[53]

Androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent.[55]

There is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.[56]

Breast cancer edit

In general, hormone replacement therapy to treat menopause is associated with only a small increased risk of breast cancer.[57][58][59] The level of risk also depends on the type of HRT, the duration of the treatment and the age of the person. Oestrogen-only HRT, taken by people who had a hysterectomy, comes with an extremely low level of breast cancer risk. The most commonly taken combined HRT (oestrogen and progestogen) is linked to a small risk of breast cancer. This risk is lower for women in their 50s and higher for older women. The risk increases with the duration of HRT. When HRT is taken for a year or less, there is no increased risk of breast cancer. HRT taken for more than 5 years comes with an increased risk but the risk reduces after the therapy is stopped.[58][59]

There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone.[6] The risk may be reduced with bioidentical progesterone,[60] 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.[61] The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of synthetic progestin administration.[62][63]

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.[64] 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.[65][66]

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.[67] It has been suggested by some that the absence of significant effect in some of these studies could be due to selective prescription to overweight women who have higher baseline estrone, or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate.[68]

Evaluating the response of breast tissue density to HRT using mammography appears to help assessing the degree of breast cancer risk associated with therapy; women with dense or mixed-dense breast tissue have a higher risk of developing breast cancer than those with low density tissue.[69]

Micronized progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration.[70]

For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen for local symptoms. Observational studies of systemic HRT after breast cancer are generally reassuring. If HRT is necessary after breast cancer, estrogen-only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy.[71] In women who are BRCA1 or BRCA2 mutation carriers, HRT does not appear to impact breast cancer risk.[72] The relative number of women using HRT who also obtain regular screening mammograms is higher than that in women who do not use HRT, a factor which has been suggested as contributing to different breast cancer detection rates in the two groups.[73]

With androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association.[74]

Ovarian cancer edit

HRT is associated with an increased risk of ovarian cancer, with women using HRT having about one additional case of ovarian cancer per 1,000 users.[75] This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT.[76] Regarding the specific subtype, there may be a higher risk of serous cancer, but no association with clear cell, endometrioid, or mucinous ovarian cancer.[76] Hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates.[77]

Other cancers edit

Colorectal cancer edit

In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer. However, the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones.[78] In colorectal cancer survivors, usage of HRT is thought to lead to lower recurrence risk and overall mortality.[79]

Cervical cancer edit

There appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with HRT and a weak increase in adenocarcinoma. No studies have reported an increased risk of recurrence when HRT is used with cervical cancer survivors.[80]

Neurodegenerative disorders edit

For prevention, the WHI suggested that HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50 and 55 years.[27] Other studies in perimenopause have shown HRT to be consistently associated with a lower risk of Alzheimer's.[81][82] With Parkinson's the majority of clinical and epidemiological studies show have demonstrated either no association[83][84] or inconclusive results.[81][85] A Danish study suggested an increased risk of Parkinson's with HRT in cyclical dosing schedules.[86]

With regards to treatment, randomized trials have shown that HRT improves executive and attention processes outside of the context of dementia in postmenopausal women, both in those that are asymptomatic and those with mild cognitive impairment.[87][88][89] Estrogen replacement appears to improve motor symptoms and activities of daily living in post menopausal women with Parkinson's, with significant improvement of UPDRS scores.[90] Clinical trials have also shown testosterone replacement to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women.[91] DHEA has not been found to improve cognitive performance after menopause.[31] Pre-clinical studies indicate that endogenous estrogen and testosterone are neuroprotective and can prevent brain amyloid deposition.[92][93]

Contraindications edit

The following are absolute and relative contraindications to HRT:[94]

Absolute contraindications edit

Relative contraindications edit

History and research edit

The extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin, one of the earlier forms of estrogen to be introduced.[95][96] From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an eight-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet.[95] It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium.[95] This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera).[95]

Trials edit

The Women's Health Initiative trials were conducted between 1991 and 2006 and were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy women.[95] Their results were both positive and negative, suggesting that during the time of hormone therapy itself, there are increases in invasive breast cancer, stroke and lung clots. Other risks include increased endometrial cancer, gallbladder disease, and urinary incontinence, while benefits include decreased hip fractures, decreased incidence of diabetes, and improvement of vasomotor symptoms. There is also an increased risk of dementia with HRT in women over 65, though at younger ages it appears to be neuroprotective. After the cessation of HRT, the WHI continued to observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist.[27] Other studies have also suggested an increased risk of ovarian cancer.[76]

The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its Data Monitoring Committee (DMC) due to perceived health risks, though this occurred a full year after the data suggesting increased risk became manifest. In 2004, the arm of the WHI in which post-hysterectomy patients were being treated with estrogen alone was also closed by the DMC. Clinical medical practice changed based upon two parallel Women's Health Initiative (WHI) studies of HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. One portion of the parallel studies followed over 16,000 women for an average of 5.2 years, half of whom took placebo, while the other half took a combination of CEEs and MPA (Prempro). This WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined CEEs and progestins exceeded their benefits. The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.[97]

Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier, between age 50 to 59, but higher when begun after age 60. In older patients, there was an apparent increased incidence of breast cancer, heart attacks, venous thrombosis, and stroke, although a reduced incidence of colorectal cancer and bone fracture. At the time, The WHI recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks.[97] Some of the WHI findings were again found in a larger national study done in the United Kingdom, known as the Million Women Study (MWS). As a result of these findings, the number of women taking HRT dropped precipitously.[98] In 2012, the United States Preventive Task Force (USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits.[99][100]

In 2002 when the first WHI follow up study was published, with HRT in post menopausal women, both older and younger age groups had a slightly higher incidence of breast cancer, and both heart attack and stroke were increased in older patients, although not in younger participants. Breast cancer was increased in women treated with estrogen and a progestin, but not with estrogen and progesterone or estrogen alone. Treatment with unopposed estrogen (i.e., an estrogen alone without a progestogen) is contraindicated if the uterus is still present, due to its proliferative effect on the endometrium. The WHI also found a reduced incidence of colorectal cancer when estrogen and a progestogen were used together, and most importantly, a reduced incidence of bone fractures. Ultimately, the study found disparate results for all cause mortality with HRT, finding it to be lower when HRT was begun during ages 50–59, but higher when begun after age 60. The authors of the study recommended that women with non-surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk.[97]

The data published by the WHI suggested supplemental estrogen increased risk of venous thromboembolism and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed.[101] These results were later supported in trials from the United Kingdom, but not in more recent studies from France and China. Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women.[102][103]

The WHI reported statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia."[104] The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with Prempro, the specific proprietary combination of CEEs and MPA studied.

After the increased clotting found in the first WHI results was reported in 2002, the number of Prempro prescriptions filled reduced by almost half. Following the WHI results, a large percentage of HRT users opted out of them, which was quickly followed by a sharp drop in breast cancer rates. The decrease in breast cancer rates has continued in subsequent years.[105] An unknown number of women started taking alternatives to Prempro, such as compounded bioidentical hormones, though researchers have asserted that compounded hormones are not significantly different from conventional hormone therapy.[106]

The other portion of the parallel studies featured women who were post hysterectomy and so received either placebo progestogen or CEEs alone. This group did not show the risks demonstrated in the combination hormone study, and the estrogen-only study was not halted in 2002. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in the estrogen-only study participants, risks of stroke and pulmonary embolism were increased slightly, predominantly in patients who began HRT over the age of 60.[107]

Several other large studies and meta-analyses have reported reduced mortality for HRT in women younger than age 60 or within 10 years of menopause, and a debatable or absent effect on mortality in women over 60.[108][109][110][111][17][112]

Though research thus far has been substantial, further investigation is needed to fully understand differences in effect for different types of HRT and lengths of time since menopause.[113][114][29] As of 2023, for example, no trial has studied women who begin taking HRT around age 50 and continue taking it for longer than 10 years.[115]

Available forms edit

See also: Sex-hormonal agent and List of sex-hormonal medications available in the United States

There are five major human steroid hormones: estrogens, progestogens, androgens, mineralocorticoids, and glucocorticoids. Estrogens and progestogens are the two most often used in menopause. They are available in a wide variety of FDA approved and non–FDA-approved formulations.[9]

In women with intact uteruses, estrogens are almost always given in combination with progestogens, as long-term unopposed estrogen therapy is associated with a markedly increased risk of endometrial hyperplasia and endometrial cancer.[1][2] Conversely, in women who have undergone a hysterectomy or do not have a uterus, a progestogen is not required, and estrogen can be used alone. There are many combined formulations which include both estrogen and progestogen.

Specific types of hormone replacement include:[1][2]

Tibolone – a synthetic medication available in Europe but not the United States– is more effective than placebo but less effective than combination hormone therapy in postmenopausal women. It may have a decreased risk of breast and colorectal cancer, though conversely it can be associated with vaginal bleeding, endometrial cancer, and increase the risk of stroke in women over age 60 years.[118][119]

Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes.[120] Sometimes an androgen, generally testosterone, can be added to treat diminished libido.[121][122]

Continuous versus cyclic edit

Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progestogens taken for about two weeks every month or every other month, a schedule referred to as 'cyclic' or 'sequentially combined'. Alternatively, 'continuous combined' HRT can be given with a constant daily hormonal dosage.[123] Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic.[124] Impact on breast density appears to be similar in both regimen timings.[125]

Route of administration edit

 
An intrauterine device can be used to receive HRT.

The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration:[1][2]

More recently developed forms of drug delivery are alleged to have increased local effect lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels.[1][2] Transdermal and vaginal estrogen, in particular, avoid first pass metabolism through the liver. This in turn prevents an increase in clotting factors and accumulation of anti-estrogenic metabolites, resulting in fewer adverse side effects, particularly with regard to cardiovascular disease and stroke.[126]

Injectable forms of estradiol exist and have been used occasionally in the past.[127][128] However, they are rarely used in menopausal hormone therapy in modern times and are no longer recommended.[127][129] Instead, other non-oral forms of estradiol such as transdermal estradiol are recommended and may be used.[127] Estradiol injectables are generally well-tolerated and convenient, requiring infrequent administration.[127][128] However, this form of estradiol does not release estradiol at a constant rate and there are very high circulating estradiol levels soon after injection followed by a rapid decline in levels.[127] Injections may also be painful.[127] Examples of estradiol injectables that may be used in menopausal hormone therapy include estradiol valerate and estradiol cypionate.[127][128] In terms of injectable progestogens, injectable progesterone is associated with pain and injection site reactions as well as a short duration of action requiring very frequent injections, and is similarly not recommended in menopausal hormone therapy.[130][128]

Bioidentical hormone therapy edit

Main article: Bioidentical hormone therapy

Bioidentical hormone therapy (BHT) is the usage of hormones that are chemically identical to those produced in the body. Although proponents of BHT claim advantages over non-bioidentical or conventional hormone therapy, the FDA does not recognize the term 'bioidentical hormone', stating there is no scientific evidence that these hormones are identical to their naturally occurring counterparts.[11][131] There are, however, FDA approved products containing hormones classified as 'bioidentical'.[12][9]

Bioidentical hormones can be used in either pharmaceutical or compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and regulatory oversight.[11] Most classifications of bioidentical hormones do not take into account manufacturing, source, or delivery method of the products, and so describe both non-FDA approved compounded products and FDA approved pharmaceuticals as 'bioidentical'.[9] The British Menopause Society has issued a consensus statement endorsing the distinction between "compounded" forms (cBHRT), described as unregulated, custom made by specialty pharmacies and subject to heavy marketing and "regulated" pharmaceutical grade forms (rBHRT), which undergo formal oversight by entities such as the FDA and form the basis of most clinical trials.[132] Some practitioners recommending compounded bioidentical HRT also use salivary or serum hormonal testing to monitor response to therapy, a practice not endorsed by current clinical guidelines in the United States and Europe.[133]

Bioidentical hormones in pharmaceuticals may have very limited clinical data, with no randomized controlled prospective trials to date comparing them to their animal derived counterparts. Some pre-clinical data has suggested a decreased risk of venous thromboembolism, cardiovascular disease, and breast cancer.[11] As of 2012, guidelines from the North American Menopause Society, the Endocrine Society, the International Menopause Society, and the European Menopause and Andropause Society endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk.[11][134]

Compounding edit

Compounding for HRT is generally discouraged by the FDA and medical industry in the United States due to a lack of regulation and standardized dosing.[11][131] The U.S. Congress did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the Federal Food, Drug, and Cosmetic Act (FDCA), but they have encountered obstacles in this role since that time. After 64 patient deaths and 750 harmed patients from a 2012 meningitis outbreak due to contaminated steroid injections, Congress passed the 2013 Drug Quality and Security Act, authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs, and reinforcing FDCA regulations for traditional compounding.[135] The DQSA and its reinforcement of provision §503A of the FDCA solidifies FDA authority to enforce FDCA regulation of against compounders of bioidentical hormone therapy.[135]

In the United Kingdom, on the other hand, compounding is a regulated activity. The Medicines and Healthcare products Regulatory Agency regulates compounding performed under a Manufacturing Specials license and the General Pharmaceutical Council regulates compounding performed within a pharmacy. All testosterone prescribed in the United Kingdom is bioidentical, with its use supported by the National Health Service. There is also marketing authorisation for male testosterone products. National Institute for Health and Care Excellence guideline 1.4.8 states: "consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective". The footnote adds: "at the time of publication (November 2015), testosterone did not have a United Kingdom marketing authorisation for this indication in women. Bioidentical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour."

Society and culture edit

Wyeth controversy edit

See also: Medical ghostwriter

Wyeth, now a subsidiary of Pfizer, was a pharmaceutical company that marketed the HRT products Premarin (CEEs) and Prempro (CEEs + MPA).[136][137] In 2009, litigation involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications.[136][137][138] The documents showed that Wyeth commissioned dozens of ghostwritten reviews and commentaries that were published in medical journals to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light.[136][137][138] Starting in the mid-1990s and continuing for over a decade, Wyeth pursued an aggressive "publication plan" strategy to promote its HRT products through the use of ghostwritten publications.[138] It worked mainly with DesignWrite, a medical writing firm.[138] Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals.[136]

These favorable publications emphasized the benefits and downplayed the risks of its HRT products, especially the "misconception" of the association of its products with breast cancer.[138] The publications defended unsupported cardiovascular "benefits" of its products, downplayed risks such as breast cancer, and promoted off-label and unproven uses like prevention of dementia, Parkinson's disease, vision problems, and wrinkles.[137] In addition, Wyeth emphasized negative messages against the SERM raloxifene for osteoporosis, instructed writers to stress the fact that "alternative therapies have increased in usage since the WHI even though there is little evidence that they are effective or safe...", called into question the quality and therapeutic equivalence of approved generic CEE products, and made efforts to spread the notion that the unique risks of CEEs and MPA were a class effect of all forms of menopausal HRT: "Overall, these data indicate that the benefit/risk analysis that was reported in the Women's Health Initiative can be generalized to all postmenopausal hormone replacement therapy products."[137]

Following the publication of the WHI data in 2002, the stock prices for the pharmaceutical industry plummeted, and huge numbers of women stopped using HRT.[139] The stocks of Wyeth, which supplied the Premarin and Prempro that were used in the WHI trials, decreased by more than 50%, and never fully recovered.[139] Some of their articles in response promoted themes such as the following: "the WHI was flawed; the WHI was a controversial trial; the population studied in the WHI was inappropriate or was not representative of the general population of menopausal women; results of clinical trials should not guide treatment for individuals; observational studies are as good as or better than randomized clinical trials; animal studies can guide clinical decision-making; the risks associated with hormone therapy have been exaggerated; the benefits of hormone therapy have been or will be proven, and the recent studies are an aberration."[95] Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors.[95] These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS.[95] In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion.[140][141] Pfizer, a company that produces Provera and Depo-Provera (MPA) and has also engaged in medical ghostwriting, continues to market Premarin and Prempro, which remain best-selling medications.[95][138]

According to Fugh-Berman (2010), "Today, despite definitive scientific data to the contrary, many gynecologists still believe that the benefits of [HRT] outweigh the risks in asymptomatic women. This non-evidence–based perception may be the result of decades of carefully orchestrated corporate influence on medical literature."[137] As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS.[142] The positive perceptions of many physicians of HRT in spite of large trials showing risks that potentially outweigh any benefits may be due to the efforts of pharmaceutical companies like Wyeth.[138][95]

Popularity edit

The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again.[126][143] Transdermal therapy, in part due to its lack of increase in venous thromboembolism, is now often the first choice for HRT in the United Kingdom. Conjugate equine estrogen, in distinction, has a potentially higher thrombosis risk and is now not commonly used in the UK, replaced by estradiol based compounds with lower thrombosis risk. Oral progestogen combinations such as medroxyprogesterone acetate have changed to dyhydrogesterone, due to a lack of association of the latter with venous clot.[144]

See also edit

References edit

  1. ^ a b c d e f g h i Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, Santen RJ (November 2015). "Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline" (PDF). J. Clin. Endocrinol. Metab. 100 (11): 3975–4011. doi:10.1210/jc.2015-2236. PMID 26444994.
  2. ^ a b c d e f g h Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH (July 2010). "Postmenopausal hormone therapy: an Endocrine Society scientific statement". J. Clin. Endocrinol. Metab. 95 (7 Suppl 1): s1–s66. doi:10.1210/jc.2009-2509. PMC 6287288. PMID 20566620.
  3. ^ Shuster, Lynne T.; Rhodes, Deborah J.; Gostout, Bobbie S.; Grossardt, Brandon R.; Rocca, Walter A. (2010). "Premature menopause or early menopause: Long-term health consequences". Maturitas. 65 (2): 161–166. doi:10.1016/j.maturitas.2009.08.003. ISSN 0378-5122. PMC 2815011. PMID 19733988.
  4. ^ a b c d e f Eden KJ, Wylie KR (1 July 2009). "Quality of sexual life and menopause". Women's Health. 6 (4): 385–396. doi:10.2217/WHE.09.24. PMID 19586430.
  5. ^ a b c Ziaei S., Moghasemi M., Faghihzadeh S. (2010). "Comparative effects of conventional hormone replacement therapy and tibolone on climacteric symptoms and sexual dysfunction in postmenopausal women". Climacteric. 13 (3): 147–156. doi:10.1016/j.maturitas.2006.04.014. PMID 16730929.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b c Manson, JE; Aragaki, AK; Rossouw, JE; Anderson, GL; Prentice, RL; LaCroix, AZ; Chlebowski, RT; Howard, BV; Thomson, CA; Margolis, KL; Lewis, CE; Stefanick, ML; Jackson, RD; Johnson, KC; Martin, LW; Shumaker, SA; Espeland, MA; Wactawski-Wende, J; WHI, Investigators. (12 September 2017). "Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials". JAMA. 318 (10): 927–938. doi:10.1001/jama.2017.11217. PMC 5728370. PMID 28898378.
  7. ^ Langer, RD; Hodis, HN; Lobo, RA; Allison, MA (February 2021). "Hormone replacement therapy – where are we now?". Climacteric. 24 (1): 3–10. doi:10.1080/13697137.2020.1851183. PMID 33403881. S2CID 230783545.
  8. ^ a b c Løkkegaard, E; Nielsen, LH; Keiding, N (August 2017). "Risk of Stroke With Various Types of Menopausal Hormone Therapies: A National Cohort Study". Stroke. 48 (8): 2266–2269. doi:10.1161/STROKEAHA.117.017132. PMID 28626058. S2CID 207579406.
  9. ^ a b c d Files, JA; Ko, MG; Pruthi, S (July 2011). "Bioidentical hormone therapy". Mayo Clinic Proceedings. 86 (7): 673–80, quiz 680. doi:10.4065/mcp.2010.0714. PMC 3127562. PMID 21531972.
  10. ^ "Bioidentical hormones". Cleveland Clinic. 12 December 2012.
  11. ^ a b c d e f Conaway E (March 2011). "Bioidentical hormones: an evidence-based review for primary care providers". J Am Osteopath Assoc. 111 (3): 153–64. PMID 21464264.
  12. ^ a b c Cobin, RH; Goodman, NF; AACE Reproductive Endocrinology Scientific, Committee. (1 July 2017). (PDF). Endocrine Practice. 23 (7): 869–880. doi:10.4158/EP171828.PS. PMID 28703650. Archived from the original (PDF) on 1 March 2019. Retrieved 1 March 2019.
  13. ^ a b . 2012. Archived from the original on 30 May 2013. Retrieved 14 May 2013.
  14. ^ Lewis, Ricki. "ACOG Revises Guidelines on Treating Menopause Symptoms". login.medscape.com. Medscape. Retrieved 4 March 2019.
  15. ^ "Hormone Therapy and Heart Disease – ACOG". www.acog.org. Committee on Gynecologic Practice. Retrieved 4 March 2019.
  16. ^ "Medscape". www.medscape.com.
  17. ^ a b Santen, RJ; Utian, WH (2010). "Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement". J Clin Endocrinol Metab. 95 S1–S66 (Supplement 1): s1–s66. doi:10.1210/jc.2009-2509. PMC 6287288. PMID 20566620.
  18. ^ a b c d Marjoribanks, Jane; Farquhar, Cindy; Roberts, Helen; Lethaby, Anne; Lee, Jasmine (17 January 2017). "Long-term hormone therapy for perimenopausal and postmenopausal women". The Cochrane Database of Systematic Reviews. 1 (1): CD004143. doi:10.1002/14651858.CD004143.pub5. ISSN 1469-493X. PMC 6465148. PMID 28093732.
  19. ^ "Menopause treatments". National Health Service, United Kingdom. 2019. Retrieved 23 February 2018.
  20. ^ Raine-Fenning NJ, Brincat MP, Muscat-Baron Y (2003). "Skin aging and menopause: implications for treatment". Am J Clin Dermatol. 4 (6): 371–8. doi:10.2165/00128071-200304060-00001. PMID 12762829. S2CID 20392538.
  21. ^ Zouboulis CC, Makrantonaki E (June 2012). "Hormonal therapy of intrinsic aging". Rejuvenation Res. 15 (3): 302–12. doi:10.1089/rej.2011.1249. PMID 22533363.
  22. ^ a b c d e f g Sarrel, P.M. (2000). Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause. Journal of Women's Health and Gender-Based Medicine, 9, 25–32
  23. ^ Miller M.M.; Franklin K.B.J. (1999). "Theoretical basis for the benefit of postmenopausal estrogen substitution". Experimental Gerontology. 34 (5): 587–604. doi:10.1016/S0531-5565(99)00032-7. PMID 10530785. S2CID 43031351.
  24. ^ Gonzalez M., Viagara G., Caba F., Molina E. (2004). "Sexual function, menopause and hormone replacement therapy (HRT)". The European Menopause Journal. 48 (4): 411–420. doi:10.1016/j.maturitas.2003.10.005. PMID 15283933.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ a b c Davis, SR; Baber, R; Panay, N; Bitzer, J; Perez, SC; Islam, RM; Kaunitz, AM; Kingsberg, SA; Lambrinoudaki, I; Liu, J; Parish, SJ; Pinkerton, J; Rymer, J; Simon, JA; Vignozzi, L; Wierman, ME (September 2019). "Global Consensus Position Statement on the Use of Testosterone Therapy for Women". The Journal of Sexual Medicine. 16 (9): 1331–1337. doi:10.1016/j.jsxm.2019.07.012. hdl:2158/1176450. PMID 31488288. S2CID 201845588.
  26. ^ Johansen, N; Lindén Hirschberg, A; Moen, MH (August 2020). "The role of testosterone in menopausal hormone treatment. What is the evidence?". Acta Obstetricia et Gynecologica Scandinavica. 99 (8): 966–969. doi:10.1111/aogs.13819. PMID 32027015. S2CID 211050248.
  27. ^ a b c d Manson, JE; Chlebowski, RT; Stefanick, ML; Aragaki, AK; Rossouw, JE; Prentice, RL; Anderson, G; Howard, BV; Thomson, CA; LaCroix, AZ; Wactawski-Wende, J; Jackson, RD; Limacher, M; Margolis, KL; Wassertheil-Smoller, S; Beresford, SA; Cauley, JA; Eaton, CB; Gass, M; Hsia, J; Johnson, KC; Kooperberg, C; Kuller, LH; Lewis, CE; Liu, S; Martin, LW; Ockene, JK; O'Sullivan, MJ; Powell, LH; Simon, MS; Van Horn, L; Vitolins, MZ; Wallace, RB (2 October 2013). "Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials". JAMA. 310 (13): 1353–68. doi:10.1001/jama.2013.278040. PMC 3963523. PMID 24084921.
  28. ^ Zhu, L; Jiang, X; Sun, Y; Shu, W (April 2016). "Effect of hormone therapy on the risk of bone fractures: a systematic review and meta-analysis of randomized controlled trials". Menopause. 23 (4): 461–70. doi:10.1097/GME.0000000000000519. PMID 26529613. S2CID 26110755.
  29. ^ a b Studd J (March 2010). "Ten reasons to be happy about hormone replacement therapy: a guide for patients". Menopause Int. 16 (1): 44–6. doi:10.1258/mi.2010.010001. PMID 20424287. S2CID 33414205.
  30. ^ Tiidus, PM (August 2011). "Benefits of estrogen replacement for skeletal muscle mass and function in post-menopausal females: evidence from human and animal studies". The Eurasian Journal of Medicine. 43 (2): 109–14. doi:10.5152/eajm.2011.24. PMC 4261347. PMID 25610174.
  31. ^ a b Shifren, JL; Davis, SR (August 2017). "Androgens in postmenopausal women: a review". Menopause. 24 (8): 970–979. doi:10.1097/GME.0000000000000903. PMID 28609390. S2CID 39876534.
  32. ^ Deleruyelle, LJ (2017). "Menopausal Symptom Relief and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy, Part 3". International Journal of Pharmaceutical Compounding. 21 (1): 6–16. PMID 28346192.
  33. ^ Suchowersky O, Muthipeedika J (December 2005). "A case of late-onset chorea". Nat Clin Pract Neurol. 1 (2): 113–6. doi:10.1038/ncpneuro0052. PMID 16932507. S2CID 11410333.
  34. ^ a b c Boardman, HM; Hartley, L; Eisinga, A; Main, C; Roqué i Figuls, M; Bonfill Cosp, X; Gabriel Sanchez, R; Knight, B (10 March 2015). "Hormone therapy for preventing cardiovascular disease in post-menopausal women". The Cochrane Database of Systematic Reviews. 2015 (3): CD002229. doi:10.1002/14651858.CD002229.pub4. hdl:20.500.12105/9999. ISSN 1469-493X. PMC 10183715. PMID 25754617. S2CID 22188456.
  35. ^ Hodis, HN; Mack, WJ; Henderson, VW; Shoupe, D; Budoff, MJ; Hwang-Levine, J; Li, Y; Feng, M; Dustin, L; Kono, N; Stanczyk, FZ; Selzer, RH; Azen, SP; ELITE Research, Group. (31 March 2016). "Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol". The New England Journal of Medicine. 374 (13): 1221–31. doi:10.1056/NEJMoa1505241. PMC 4921205. PMID 27028912.
  36. ^ Writing Group on Behalf of Workshop Consensus (October 2009). "Aging, menopause, cardiovascular disease and HRT. International Menopause Society Consensus Statement". Climacteric. 12 (5): 368–77. doi:10.1080/13697130903195606. PMID 19811229. S2CID 218865937.
  37. ^ "Committee Opinion No. 565: Hormone Therapy and Heart Disease". Obstetrics & Gynecology. 121 (6): 1407–1410. June 2013. doi:10.1097/01.AOG.0000431053.33593.2d. ISSN 0029-7844. PMID 23812486. S2CID 30775537.
  38. ^ Manson, JE; Chlebowski, RT; Stefanick, ML; Aragaki, AK; Rossouw, JE; Prentice, RL; Anderson, G; Howard, BV; Thomson, CA; LaCroix, AZ; Wactawski-Wende, J; Jackson, RD; Limacher, M; Margolis, KL; Wassertheil-Smoller, S; Beresford, SA; Cauley, JA; Eaton, CB; Gass, M; Hsia, J; Johnson, KC; Kooperberg, C; Kuller, LH; Lewis, CE; Liu, S; Martin, LW; Ockene, JK; O'Sullivan, MJ; Powell, LH; Simon, MS; Van Horn, L; Vitolins, MZ; Wallace, RB (2 October 2013). "Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials". JAMA. 310 (13): 1353–68. doi:10.1001/jama.2013.278040. PMC 3963523. PMID 24084921.
  39. ^ Saeaib, N; Peeyananjarassri, K; Liabsuetrakul, T; Buhachat, R; Myriokefalitaki, E (28 January 2020). "Hormone replacement therapy after surgery for epithelial ovarian cancer". The Cochrane Database of Systematic Reviews. 1 (1): CD012559. doi:10.1002/14651858.CD012559.pub2. PMC 7027384. PMID 31989588.
  40. ^ Manson, JE; Aragaki, AK; Rossouw, JE; Anderson, GL; Prentice, RL; LaCroix, AZ; Chlebowski, RT; Howard, BV; Thomson, CA; Margolis, KL; Lewis, CE; Stefanick, ML; Jackson, RD; Johnson, KC; Martin, LW; Shumaker, SA; Espeland, MA; Wactawski-Wende, J; WHI, Investigators. (12 September 2017). "Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials". JAMA. 318 (10): 927–938. doi:10.1001/jama.2017.11217. PMC 5728370. PMID 28898378.
  41. ^ Darabi, M.; Rabbani, M.; Ani, M.; Zarean, E.; Panjehpour, M.; Movahedian, A. (2011). "Increased leukocyte ABCA1 gene expression in post-menopausal women on hormone replacement therapy". Gynecological Endocrinology. 27 (9): 701–705. doi:10.3109/09513590.2010.507826. PMID 20807164. S2CID 203464.
  42. ^ Gregersen, I; Høibraaten, E; Holven, KB; Løvdahl, L; Ueland, T; Mowinckel, MC; Dahl, TB; Aukrust, P; Halvorsen, B; Sandset, PM (December 2019). "Effect of hormone replacement therapy on atherogenic lipid profile in postmenopausal women". Thrombosis Research. 184: 1–7. doi:10.1016/j.thromres.2019.10.005. hdl:10852/75276. PMID 31677448.
  43. ^ Spoletini, I; Vitale, C; Pelliccia, F; Fossati, C; Rosano, GM (December 2014). "Androgens and cardiovascular disease in postmenopausal women: a systematic review". Climacteric. 17 (6): 625–34. doi:10.3109/13697137.2014.887669. PMID 24559253. S2CID 33413274.
  44. ^ Davis, SR; Baber, R; Panay, N; Bitzer, J; Perez, SC; Islam, RM; Kaunitz, AM; Kingsberg, SA; Lambrinoudaki, I; Liu, J; Parish, SJ; Pinkerton, J; Rymer, J; Simon, JA; Vignozzi, L; Wierman, ME (September 2019). "Global Consensus Position Statement on the Use of Testosterone Therapy for Women". The Journal of Sexual Medicine. 16 (9): 1331–1337. doi:10.1016/j.jsxm.2019.07.012. hdl:2158/1176450. PMID 31488288. S2CID 201845588.
  45. ^ Shifren, JL; Davis, SR (August 2017). "Androgens in postmenopausal women: a review". Menopause. 24 (8): 970–979. doi:10.1097/GME.0000000000000903. PMID 28609390. S2CID 39876534.
  46. ^ a b Scarabin, P.-Y. (August 2018). "Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis". Climacteric. 21 (4): 341–345. doi:10.1080/13697137.2018.1446931. ISSN 1473-0804. PMID 29570359. S2CID 4229701.
  47. ^ a b Boardman, HM; Hartley, L; Eisinga, A; Main, C; Roqué i Figuls, M; Bonfill Cosp, X; Gabriel Sanchez, R; Knight, B (10 March 2015). "Hormone therapy for preventing cardiovascular disease in post-menopausal women". The Cochrane Database of Systematic Reviews. 2015 (3): CD002229. doi:10.1002/14651858.CD002229.pub4. hdl:20.500.12105/9999. ISSN 1469-493X. PMC 10183715. PMID 25754617. S2CID 22188456.
  48. ^ Olié, V. R.; Canonico, M.; Scarabin, P. Y. (2010). "Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women". Current Opinion in Hematology. 17 (5): 457–463. doi:10.1097/MOH.0b013e32833c07bc. PMID 20601871. S2CID 205827003.
  49. ^ Rott, H (2014). "Prevention and treatment of venous thromboembolism during HRT: current perspectives". International Journal of General Medicine. 7: 433–40. doi:10.2147/IJGM.S46310. PMC 4155999. PMID 25210472.
  50. ^ a b Carrasquilla GD, Frumento P, Berglund A, Borgfeldt C, Bottai M, Chiavenna C, Eliasson M, Engström G, Hallmans G, Jansson JH, Magnusson PK, Nilsson PM, Pedersen NL, Wolk A, Leander K (November 2017). "Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies". PLOS Med. 14 (11): e1002445. doi:10.1371/journal.pmed.1002445. PMC 5693286. PMID 29149179.
  51. ^ Chlebowski, RT; Anderson, GL; Sarto, GE; Haque, R; Runowicz, CD; Aragaki, AK; Thomson, CA; Howard, BV; Wactawski-Wende, J; Chen, C; Rohan, TE; Simon, MS; Reed, SD; Manson, JE (March 2016). "Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women's Health Initiative Randomized Trial". Journal of the National Cancer Institute. 108 (3): djv350. doi:10.1093/jnci/djv350. PMC 5072373. PMID 26668177.
  52. ^ Archer, DF (2001). "The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women". Menopause. 8 (4): 245–51. doi:10.1097/00042192-200107000-00005. PMID 11449081. S2CID 38526018.
  53. ^ a b c Kim, JJ; Kurita, T; Bulun, SE (February 2013). "Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer". Endocrine Reviews. 34 (1): 130–62. doi:10.1210/er.2012-1043. PMC 3565104. PMID 23303565.
  54. ^ Young, Robert; Arlan F., Jr Fuller; Fuller, Arlan F.; Michael V. Seiden (2004). Uterine cancer. Hamilton, Ont: B.C. Decker. ISBN 978-1-55009-163-2.
  55. ^ Zang, H; Sahlin, L; Masironi, B; Eriksson, E; Lindén Hirschberg, A (June 2007). "Effects of testosterone treatment on endometrial proliferation in postmenopausal women". The Journal of Clinical Endocrinology and Metabolism. 92 (6): 2169–75. doi:10.1210/jc.2006-2171. PMID 17341565.
  56. ^ "Endometrial cancer risk was lower in women who used continuous combined HRT than in non-users". Evidence-based Obstetrics & Gynecology. 8 (1–2): 68–69. March 2006. doi:10.1016/j.ebobgyn.2006.01.011. ISSN 1361-259X.
  57. ^ Collaborative Group on Hormonal Factors in Breast Cancer (September 2019). "Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence". Lancet. 394 (10204): 1159–1168. doi:10.1016/S0140-6736(19)31709-X. PMC 6891893. PMID 31474332.
  58. ^ a b "Risk of breast cancer with HRT depends on therapy type and duration". NIHR Evidence. National Institute for Health and Care Research. 20 December 2021. doi:10.3310/alert_48575.
  59. ^ a b Vinogradova Y, Coupland C, Hippisley-Cox J (October 2020). "Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases". BMJ. 371: m3873. doi:10.1136/bmj.m3873. PMC 7592147. PMID 33115755.
  60. ^ Fournier, A. S.; Berrino, F.; Clavel-Chapelon, F. O. (2007). "Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study". Breast Cancer Research and Treatment. 107 (1): 103–111. doi:10.1007/s10549-007-9523-x. PMC 2211383. PMID 17333341.
  61. ^ Zeng, Z; Jiang, X; Li, X; Wells, A; Luo, Y; Neapolitan, R (2018). "Conjugated equine estrogen and medroxyprogesterone acetate are associated with decreased risk of breast cancer relative to bioidentical hormone therapy and controls". PLOS ONE. 13 (5): e0197064. Bibcode:2018PLoSO..1397064Z. doi:10.1371/journal.pone.0197064. PMC 5955567. PMID 29768475.
  62. ^ Beral, V; Reeves, G; Bull, D; Green, J; Million Women Study, Collaborators. (16 February 2011). "Breast cancer risk in relation to the interval between menopause and starting hormone therapy". Journal of the National Cancer Institute. 103 (4): 296–305. doi:10.1093/jnci/djq527. PMC 3039726. PMID 21278356. {{cite journal}}: |first5= has generic name (help)
  63. ^ Letendre, I.; Lopes, P. (2012). "Ménopause et risques carcinologiques". Journal de Gynécologie Obstétrique et Biologie de la Reproduction. 41 (7): F33–F37. doi:10.1016/j.jgyn.2012.09.006. PMID 23062839.
  64. ^ Chlebowski, RT; Anderson, GL; Aragaki, AK; Manson, JE; Stefanick, ML; Pan, K; Barrington, W; Kuller, LH; Simon, MS; Lane, D; Johnson, KC; Rohan, TE; Gass, MLS; Cauley, JA; Paskett, ED; Sattari, M; Prentice, RL (28 July 2020). "Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials". JAMA. 324 (4): 369–380. doi:10.1001/jama.2020.9482. PMC 7388026. PMID 32721007.
  65. ^ Anderson, G. L.; Limacher, M.; Assaf, A. R.; Bassford, T.; Beresford, S. A.; Black, H.; Bonds, D.; Brunner, R.; Brzyski, R.; Caan, B.; Chlebowski, R.; Curb, D.; Gass, M.; Hays, J.; Heiss, G.; Hendrix, S.; Howard, B. V.; Hsia, J.; Hubbell, A.; Jackson, R.; Johnson, K. C.; Judd, H.; Kotchen, J. M.; Kuller, L.; Lacroix, A. Z.; Lane, D.; Langer, R. D.; Lasser, N.; Lewis, C. E.; Manson, J. (2004). "Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy: The Women's Health Initiative Randomized Controlled Trial". JAMA: The Journal of the American Medical Association. 291 (14): 1701–1712. doi:10.1001/jama.291.14.1701. PMID 15082697.
  66. ^ Stefanick ML; Anderson GL; Margolis KL; et al. (2006). "Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy". JAMA. 295 (14): 1647–57. doi:10.1001/jama.295.14.1647. PMID 16609086.
  67. ^ "Association between hormone replacement therapy use and breast cancer risk varies by race/ethnicity, body mass index, and breast density". JNCI Journal of the National Cancer Institute. 105 (18). 2013. doi:10.1093/jnci/djt264. ISSN 0027-8874.
    • In turn citing: Hou, N.; Hong, S.; Wang, W.; Olopade, O. I.; Dignam, J. J.; Huo, D. (2013). "Hormone Replacement Therapy and Breast Cancer: Heterogeneous Risks by Race, Weight, and Breast Density". JNCI Journal of the National Cancer Institute. 105 (18): 1365–1372. doi:10.1093/jnci/djt207. ISSN 0027-8874. PMC 3776262. PMID 24003037.
  68. ^ Kuhl, H.; Schneider, H. P. G. (2013). "Progesterone – promoter or inhibitor of breast cancer". Climacteric. 16 (Suppl 1): 54–68. doi:10.3109/13697137.2013.768806. PMID 23336704. S2CID 20808536.
  69. ^ Azam, S; Lange, T; Huynh, S; Aro, AR; von Euler-Chelpin, M; Vejborg, I; Tjønneland, A; Lynge, E; Andersen, ZJ (June 2018). "Hormone replacement therapy, mammographic density, and breast cancer risk: a cohort study". Cancer Causes & Control. 29 (6): 495–505. doi:10.1007/s10552-018-1033-0. PMC 5938298. PMID 29671181.
  70. ^ Stute, P; Wildt, L; Neulen, J (April 2018). "The impact of micronized progesterone on breast cancer risk: a systematic review". Climacteric. 21 (2): 111–122. doi:10.1080/13697137.2017.1421925. PMID 29384406. S2CID 3642971.
  71. ^ Management of the menopause after breast cancer Archived 7 April 2016 at archive.today, from The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. College Statement C-Gyn 15. 1st Endorsed: February 2003. Current: November 2011. Review: November 2014
  72. ^ Gordhandas, S; Norquist, BM; Pennington, KP; Yung, RL; Laya, MB; Swisher, EM (April 2019). "Hormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits". Gynecologic Oncology. 153 (1): 192–200. doi:10.1016/j.ygyno.2018.12.014. PMID 30661763. S2CID 58593390.
  73. ^ Heinig, M; Schwarz, S; Haug, U (16 February 2021). "Self-selection for mammography screening according to use of hormone replacement therapy: A systematic literature review". Cancer Epidemiology. 71 (Pt A): 101812. doi:10.1016/j.canep.2020.101812. PMID 33608235. S2CID 231970420.
  74. ^ Kotsopoulos, J; Narod, SA (January 2012). "Androgens and breast cancer". Steroids. 77 (1–2): 1–9. doi:10.1016/j.steroids.2011.10.002. PMID 22015396. S2CID 32022318.
  75. ^ Collaborative Group on Epidemiological Studies of Ovarian Cancer (12 February 2015). "Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies". The Lancet. 385 (9980): 1835–1842. doi:10.1016/S0140-6736(14)61687-1. PMC 4427760. PMID 25684585.
  76. ^ a b c Shi, LF; Wu, Y; Li, CY (April 2016). "Hormone therapy and risk of ovarian cancer in postmenopausal women: a systematic review and meta-analysis". Menopause. 23 (4): 417–24. doi:10.1097/GME.0000000000000550. PMID 26506499. S2CID 32195397.
  77. ^ Guidozzi, F (December 2013). "Estrogen therapy in gynecological cancer survivors". Climacteric. 16 (6): 611–7. doi:10.3109/13697137.2013.806471. PMID 23952524. S2CID 38122562.
  78. ^ "Menopausal Hormone Therapy and Cancer Risk". www.cancer.org. Retrieved 4 March 2019.
  79. ^ Jang, YC; Huang, HL; Leung, CY (9 December 2019). "Association of hormone replacement therapy with mortality in colorectal cancer survivor: a systematic review and meta-analysis". BMC Cancer. 19 (1): 1199. doi:10.1186/s12885-019-6428-0. PMC 6902524. PMID 31818262.
  80. ^ Vargiu, V; Amar, ID; Rosati, A; Dinoi, G; Turco, LC; Capozzi, VA; Scambia, G; Villa, P (25 November 2020). "Hormone replacement therapy and cervical cancer: a systematic review of the literature". Climacteric. 24 (2): 120–127. doi:10.1080/13697137.2020.1826426. PMID 33236658. S2CID 227166430.
  81. ^ a b Dye, RV; Miller, KJ; Singer, EJ; Levine, AJ (2012). "Hormone replacement therapy and risk for neurodegenerative diseases". International Journal of Alzheimer's Disease. 2012: 258454. doi:10.1155/2012/258454. PMC 3324889. PMID 22548198.
  82. ^ Campdelacreu, J (November 2014). "Parkinson disease and Alzheimer disease: environmental risk factors". Neurologia (Barcelona, Spain). 29 (9): 541–9. doi:10.1016/j.nrl.2012.04.001. PMID 22703631.
  83. ^ Nicoletti, A; Nicoletti, G; Arabia, G; Annesi, G; De Mari, M; Lamberti, P; Grasso, L; Marconi, R; Epifanio, A; Morgante, L; Cozzolino, A; Barone, P; Quattrone, A; Zappia, M (December 2011). "Reproductive factors and Parkinson's disease: a multicenter case-control study". Movement Disorders. 26 (14): 2563–6. doi:10.1002/mds.23951. PMID 21956541. S2CID 40143658.
  84. ^ Noyce, AJ; Bestwick, JP; Silveira-Moriyama, L; Hawkes, CH; Giovannoni, G; Lees, AJ; Schrag, A (December 2012). "Meta-analysis of early nonmotor features and risk factors for Parkinson disease". Annals of Neurology. 72 (6): 893–901. doi:10.1002/ana.23687. PMC 3556649. PMID 23071076.
  85. ^ Wang, P; Li, J; Qiu, S; Wen, H; Du, J (2015). "Hormone replacement therapy and Parkinson's disease risk in women: a meta-analysis of 14 observational studies". Neuropsychiatric Disease and Treatment. 11: 59–66. doi:10.2147/NDT.S69918. PMC 4317144. PMID 25657580.
  86. ^ Rugbjerg, K; Christensen, J; Tjønneland, A; Olsen, JH (April 2013). "Exposure to estrogen and women's risk for Parkinson's disease: a prospective cohort study in Denmark". Parkinsonism & Related Disorders. 19 (4): 457–60. doi:10.1016/j.parkreldis.2013.01.008. PMID 23402992.
  87. ^ Yoon, BK; Chin, J; Kim, JW; Shin, MH; Ahn, S; Lee, DY; Seo, SW; Na, DL (August 2018). "Menopausal hormone therapy and mild cognitive impairment: a randomized, placebo-controlled trial". Menopause. 25 (8): 870–876. doi:10.1097/GME.0000000000001140. PMID 29846283. S2CID 44174553.
  88. ^ Rasgon, NL; Geist, CL; Kenna, HA; Wroolie, TE; Williams, KE; Silverman, DH (2014). "Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia". PLOS ONE. 9 (3): e89095. Bibcode:2014PLoSO...989095R. doi:10.1371/journal.pone.0089095. PMC 3951184. PMID 24622517.
  89. ^ Schmidt R, Fazekas F, Reinhart B, Kapeller P, Fazekas G, Offenbacher H, Eber B, Schumacher M, Freidl W (November 1996). "Estrogen replacement therapy in older women: a neuropsychological and brain MRI study". Journal of the American Geriatrics Society. 44 (11): 1307–13. doi:10.1111/j.1532-5415.1996.tb01400.x. PMID 8909345. S2CID 22921797.
  90. ^ Parkinson Study Group POETRY, Investigators. (December 2011). "A randomized pilot trial of estrogen replacement therapy in post-menopausal women with Parkinson's disease". Parkinsonism & Related Disorders. 17 (10): 757–60. doi:10.1016/j.parkreldis.2011.07.007. PMID 21824799.
  91. ^ Diamanti-Kandarakis, E; Dattilo, M; Macut, D; Duntas, L; Gonos, ES; Goulis, DG; Gantenbein, CK; Kapetanou, M; Koukkou, E; Lambrinoudaki, I; Michalaki, M; Eftekhari-Nader, S; Pasquali, R; Peppa, M; Tzanela, M; Vassilatou, E; Vryonidou, A (June 2017). "Mechanisms in Endocrinology: Aging and anti-aging: a Combo-Endocrinology overview". European Journal of Endocrinology. 176 (6): R283–R308. doi:10.1530/EJE-16-1061. PMID 28264815.
  92. ^ Vest, RS; Pike, CJ (February 2013). "Gender, sex steroid hormones, and Alzheimer's disease". Hormones and Behavior. 63 (2): 301–7. doi:10.1016/j.yhbeh.2012.04.006. PMC 3413783. PMID 22554955.
  93. ^ Pike, CJ; Carroll, JC; Rosario, ER; Barron, AM (July 2009). "Protective actions of sex steroid hormones in Alzheimer's disease". Frontiers in Neuroendocrinology. 30 (2): 239–58. doi:10.1016/j.yfrne.2009.04.015. PMC 2728624. PMID 19427328.
  94. ^ MacLennan, AH (August 2011). "HRT in difficult circumstances: are there any absolute contraindications?". Climacteric. 14 (4): 409–17. doi:10.3109/13697137.2010.543496. PMID 21355685. S2CID 25426141.
  95. ^ a b c d e f g h i j Fugh-Berman, Adriane (2015). "The Science of Marketing: How Pharmaceutical Companies Manipulated Medical Discourse on Menopause". Women's Reproductive Health. 2 (1): 18–23. doi:10.1080/23293691.2015.1039448. ISSN 2329-3691.
  96. ^ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 205–. ISBN 978-92-832-1291-1.
  97. ^ a b c Writing Group for the Women's Health Initiative Investigators (2002). "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial". JAMA. 288 (3): 321–333. doi:10.1001/jama.288.3.321. PMID 12117397.
  98. ^ Chlebowski RT, Kuller LH, Prentice RL, Stefanick ML, Manson JE, Gass M, et al. (February 2009). "Breast cancer after use of estrogen plus progestin in postmenopausal women". The New England Journal of Medicine. 360 (6): 573–87. doi:10.1056/NEJMoa0807684. PMC 3963492. PMID 19196674.
  99. ^ Kreatsoulas, C.; Anand, S. S. (2013). "Menopausal hormone therapy for the primary prevention of chronic conditions. U.S. Preventive Services Task Force Recommendation Statement" (PDF). Polskie Archiwum Medycyny Wewnetrznej. 123 (3): 112–117. PMID 23396275.
  100. ^ Nelson, H. D.; Walker, M.; Zakher, B.; Mitchell, J. (2012). "Menopausal hormone therapy for the primary prevention of chronic conditions: A systematic review to update the U.S. Preventive Services Task Force recommendations". Annals of Internal Medicine. 157 (2): 104–113. doi:10.7326/0003-4819-157-2-201207170-00466. PMID 22786830.
  101. ^ George, James L.; Colman, Robert W.; Goldhaber, Samuel Z.; Victor J. Marder (2006). Hemostasis and thrombosis: basic principles and clinical practice. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 1239. ISBN 978-0-7817-4996-1.
  102. ^ Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (2011). "Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic Testing and Molecular Biomarkers. 15 (1–2): 11–5. doi:10.1089/gtmb.2010.0106. PMID 21117950.
  103. ^ Chlebowski, R. T.; Anderson, G. L. (2015). "Menopausal hormone therapy and breast cancer mortality: clinical implications". Therapeutic Advances in Drug Safety. 6 (2): 45–56. doi:10.1177/2042098614568300. ISSN 2042-0986. PMC 4406918. PMID 25922653.
  104. ^ Mazzucco AE, Santoro E, DeSoto M, Lee JH (December 2010). "Hormone Therapy and Menopause". National Research Center for Women and Families.
  105. ^ Gina Kolata (19 April 2007). "Sharp Drop in Rates of Breast Cancer Holds". New York Times.
  106. ^ Roni Caryn Rabin (28 August 2007). "For a Low-Dose Hormone, Take Your Pick". New York Times. Many women seeking natural remedies have turned to compounding pharmacies, which use bioidentical hormones that are chemically synthesized but with the same molecular structure as hormones produced by a woman's body.
  107. ^ John Gever (5 April 2011). "New WHI Estrogen Analysis Shows Lower Breast Ca Risk". MedPageToday.
  108. ^ Salpeter, S. R.; Cheng, J.; Thabane, L.; Buckley, N. S.; Salpeter, E. E. (2009). "Bayesian Meta-analysis of Hormone Therapy and Mortality in Younger Postmenopausal Women". The American Journal of Medicine. 122 (11): 1016–1022.e1. doi:10.1016/j.amjmed.2009.05.021. PMID 19854329.
  109. ^ Anderson, G. L.; Chlebowski, R. T.; Rossouw, J. E.; Rodabough, R. J.; McTiernan, A.; Margolis, K. L.; Aggerwal, A.; David Curb, J. D.; Hendrix, S. L.; Allan Hubbell, F. A.; Khandekar, J.; Lane, D. S.; Lasser, N.; Lopez, A. M.; Potter, J.; Ritenbaugh, C. (2006). "Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin". Maturitas. 55 (2): 103–115. doi:10.1016/j.maturitas.2006.05.004. PMID 16815651.
  110. ^ Hulley, S.; Grady, D.; Bush, T.; Furberg, C.; Herrington, D.; Riggs, B.; Vittinghoff, E. (1998). "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group". JAMA: The Journal of the American Medical Association. 280 (7): 605–613. doi:10.1001/jama.280.7.605. PMID 9718051.
  111. ^ Salpeter, S. R.; Walsh, J. M. E.; Greyber, E.; Ormiston, T. M.; Salpeter, E. E. (2004). "Mortality associated with hormone replacement therapy in younger and older women". Journal of General Internal Medicine. 19 (7): 791–804. doi:10.1111/j.1525-1497.2004.30281.x. PMC 1492478. PMID 15209595.
  112. ^ Grodstein, F.; Stampfer, M. J.; Colditz, G. A.; Willett, W. C.; Manson, J. E.; Joffe, M.; Rosner, B.; Fuchs, C.; Hankinson, S. E.; Hunter, D. J.; Hennekens, C. H.; Speizer, F. E. (1997). "Postmenopausal Hormone Therapy and Mortality". New England Journal of Medicine. 336 (25): 1769–1775. doi:10.1056/NEJM199706193362501. PMID 9187066.
  113. ^ Bethea CL (February 2011). "MPA: Medroxy-Progesterone Acetate Contributes to Much Poor Advice for Women". Endocrinology. 152 (2): 343–345. doi:10.1210/en.2010-1376. PMC 3037166. PMID 21252179.
  114. ^ Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Miller VM, Naftolin F, Santoro N (March 2005). "KEEPS: The Kronos Early Estrogen Prevention Study". Climacteric. 8 (1): 3–12. doi:10.1080/13697130500042417. PMID 15804727. S2CID 37219662.
  115. ^ Dominus, Susan (1 February 2023). "Women Have Been Misled About Menopause". The New York Times. ISSN 0362-4331. Retrieved 7 February 2023. No research has yet followed women who start in their 50s and stay on continuously into their 60s.
  116. ^ Morley JE, Perry HM (May 2003). "Androgens and women at the menopause and beyond". J. Gerontol. A Biol. Sci. Med. Sci. 58 (5): M409–16. doi:10.1093/gerona/58.5.M409. PMID 12730248.
  117. ^ Garefalakis M, Hickey M (2008). "Role of androgens, progestins and tibolone in the treatment of menopausal symptoms: a review of the clinical evidence". Clin Interv Aging. 3 (1): 1–8. doi:10.2147/CIA.S1043. PMC 2544356. PMID 18488873.
  118. ^ Formoso, G; Perrone, E; Maltoni, S; Balduzzi, S; Wilkinson, J; Basevi, V; Marata, AM; Magrini, N; D'Amico, R; Bassi, C; Maestri, E (12 October 2016). "Short-term and long-term effects of tibolone in postmenopausal women". The Cochrane Database of Systematic Reviews. 10 (10): CD008536. doi:10.1002/14651858.CD008536.pub3. ISSN 1469-493X. PMC 6458045. PMID 27733017.
  119. ^ Cummings, SR; Ettinger, B; Delmas, PD; Kenemans, P; Stathopoulos, V; Verweij, P; Mol-Arts, M; Kloosterboer, L; Mosca, L; Christiansen, C; Bilezikian, J; Kerzberg, EM; Johnson, S; Zanchetta, J; Grobbee, DE; Seifert, W; Eastell, R; LIFT Trial, Investigators. (14 August 2008). "The effects of tibolone in older postmenopausal women". The New England Journal of Medicine. 359 (7): 697–708. doi:10.1056/NEJMoa0800743. PMC 3684062. PMID 18703472.
  120. ^ Estrogen (Vaginal Route) from Mayo Clinic / Thomson Healthcare Inc. Portions of this document last updated: 1 November 2011
  121. ^ Somboonporn, W; Davis, S; Seif, MW; Bell, R (19 October 2005). "Testosterone for peri- and postmenopausal women". The Cochrane Database of Systematic Reviews (4): CD004509. doi:10.1002/14651858.CD004509.pub2. PMID 16235365. S2CID 21619940.
  122. ^ North American Menopause, Society. (2005). "The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society". Menopause. 12 (5): 496–511, quiz 649. doi:10.1097/01.gme.0000177709.65944.b0. PMID 16145303. S2CID 5122078.
  123. ^ Drapier-Faure, E; Azoulay, C; Abramovici, Y (July 2005). "[Acceptability of continuous combined versus cyclical HRT: a French multicentric randomized clinical study]". Gynécologie, obstétrique & fertilité. 33 (7–8): 498–504. doi:10.1016/j.gyobfe.2005.04.024. PMID 16005674.
  124. ^ Feeley, KM; Wells, M (June 2001). "Hormone replacement therapy and the endometrium". Journal of Clinical Pathology. 54 (6): 435–40. doi:10.1136/jcp.54.6.435. PMC 1731456. PMID 11376015.
  125. ^ Junkermann, H; von Holst, T; Lang, E; Rakov, V (14 February 2005). "Influence of different HRT regimens on mammographic density". Maturitas. 50 (2): 105–10. doi:10.1016/j.maturitas.2004.04.008. PMID 15653007.
  126. ^ a b Beck, KL; Anderson, MC; Kirk, JK (August 2017). "Transdermal estrogens in the changing landscape of hormone replacement therapy". Postgraduate Medicine. 129 (6): 632–636. doi:10.1080/00325481.2017.1334507. PMID 28540770. S2CID 205452835.
  127. ^ a b c d e f g Yoo JW, Lee CH (May 2006). "Drug delivery systems for hormone therapy". J Control Release. 112 (1): 1–14. doi:10.1016/j.jconrel.2006.01.021. PMID 16530874.
  128. ^ a b c d Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
  129. ^ Martin, K. A.; Barbieri, R. L.; Crowley, W. F. Jr. (24 September 2021). "Preparations for menopausal hormone therapy". UpToDate. Retrieved 2 February 2022. Not recommended. Depot estrogen—Estrogen is also available in some, but not all, countries as long-acting (three to four weeks) injections of either estradiol cypionate or estradiol valerate. Given the other effective estrogen options, we do not use this approach (table 1).
  130. ^ Unfer V, Casini ML, Marelli G, Costabile L, Gerli S, Di Renzo GC (August 2005). "Different routes of progesterone administration and polycystic ovary syndrome: a review of the literature". Gynecol Endocrinol. 21 (2): 119–27. doi:10.1080/09513590500170049. PMID 16109599. S2CID 24890723.
  131. ^ a b "FDA Takes Action Against Compounded Menopause Hormone Therapy Drugs". FDA. 9 January 2008. Retrieved 17 February 2009.
  132. ^ Panay, N; Medical Advisory Council of the British Menopause, Society. (June 2019). "BMS – Consensus statement: Bioidentical HRT". Post Reproductive Health. 25 (2): 61–63. doi:10.1177/2053369119841844. PMID 31192760. S2CID 189816648.
  133. ^ Cirigliano, M (June 2007). "Bioidentical hormone therapy: a review of the evidence". Journal of Women's Health. 16 (5): 600–31. doi:10.1089/jwh.2006.0311. PMID 17627398.
  134. ^ Simon JA (July 2014). "What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead?". Menopause. 21 (7): 769–83. doi:10.1097/GME.0000000000000169. PMID 24398406. S2CID 30292136.
  135. ^ a b Pinkerton, JV; Pickar, JH (February 2016). "Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy". Menopause. 23 (2): 215–23. doi:10.1097/GME.0000000000000523. PMC 4927324. PMID 26418479.
  136. ^ a b c d Singer, Natasha (4 August 2009). "Medical Papers by Ghostwriters Pushed Therapy". The New York Times. Retrieved 13 July 2018.
  137. ^ a b c d e f Fugh-Berman AJ (September 2010). "The haunting of medical journals: how ghostwriting sold "HRT"". PLOS Med. 7 (9): e1000335. doi:10.1371/journal.pmed.1000335. PMC 2935455. PMID 20838656.
  138. ^ a b c d e f g Steve Kent May; Steve May (20 January 2012). Case Studies in Organizational Communication: Ethical Perspectives and Practices: Ethical Perspectives and Practices. SAGE. pp. 197–. ISBN 978-1-4129-8309-9.
  139. ^ a b Miller VM, Harman SM (November 2017). "An update on hormone therapy in postmenopausal women: mini-review for the basic scientist". Am. J. Physiol. Heart Circ. Physiol. 313 (5): H1013–H1021. doi:10.1152/ajpheart.00383.2017. PMC 5792205. PMID 28801526.
  140. ^ Sorkin, Andrew Ross; Wilson, Duff (25 January 2009). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times.
  141. ^ "Pfizer Sizes Up: Closes $68B Wyeth Deal". CNBC. 19 October 2009.
  142. ^ Tao M, Teng Y, Shao H, Wu P, Mills EJ (2011). "Knowledge, perceptions and information about hormone therapy (HT) among menopausal women: a systematic review and meta-synthesis". PLOS ONE. 6 (9): e24661. Bibcode:2011PLoSO...624661T. doi:10.1371/journal.pone.0024661. PMC 3174976. PMID 21949743.
  143. ^ "Hormone therapy for brain performance: No effect, whether started early or late". www.sciencedaily.com.
  144. ^ Davies, M; Hamoda, H; British Menopause Society Medical Advisory, Council. (11 February 2019). "Hormone replacement therapy: changes in prescribing practice". BMJ (Clinical Research Ed.). 364: l633. doi:10.1136/bmj.l633. PMID 30745316. S2CID 73435897.

External links edit

  • Menopause treatment, Hormone Health Network, The Endocrine Society
  • Sexual Health and Menopause Online, The North American Menopause Society
  • Menopause, US Food and Drug Administration
  • British Menopause Society

February 15, 2024
hormone, replacement, therapy, this, article, about, hormone, replacement, therapy, menopause, transgender, applications, transgender, hormone, therapy, other, forms, hormone, therapy, also, known, menopausal, hormone, therapy, postmenopausal, hormone, therapy. This article is about hormone replacement therapy in menopause For transgender applications see Transgender hormone therapy For other forms see Hormone 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 1 2 Effects of menopause can include symptoms such as hot flashes accelerated skin aging vaginal dryness decreased muscle mass and complications such as osteoporosis bone loss sexual dysfunction and vaginal atrophy They are mostly caused by low levels of female sex hormones e g estrogens that occur during menopause 1 2 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 1 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 3 4 Androgens like testosterone are sometimes used as well 5 HRT is available through a variety of different routes 1 2 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 6 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 7 8 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 9 These are mainly steroids derived from plants 10 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 11 Bioidentical hormone replacement has inadequate clinical research to determine its safety and efficacy as of 2017 12 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 13 Contents 1 Medical uses 1 1 Menopausal symptoms 1 2 Sexual function 1 3 Muscle and bone 2 Side effects 2 1 Common 2 2 Uncommon 2 3 Heart disease 2 4 Blood clots 2 5 Stroke 2 6 Endometrial cancer 2 7 Breast cancer 2 8 Ovarian cancer 2 9 Other cancers 2 9 1 Colorectal cancer 2 9 2 Cervical cancer 2 10 Neurodegenerative disorders 3 Contraindications 3 1 Absolute contraindications 3 2 Relative contraindications 4 History and research 4 1 Trials 5 Available forms 5 1 Continuous versus cyclic 5 2 Route of administration 5 3 Bioidentical hormone therapy 5 3 1 Compounding 6 Society and culture 6 1 Wyeth controversy 6 2 Popularity 7 See also 8 References 9 External linksMedical uses editApproved 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 13 The American College of Obstetrics and Gynecology ACOG approves of HRT for symptomatic relief of menopausal symptoms 14 and advocates its use beyond the age of 65 in appropriate scenarios 15 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 16 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 17 The American Association of Clinical Endocrinologists AACE has also released position statements approving of HRT when appropriate 12 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 4 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 18 Menopausal symptoms edit nbsp Symptoms of menopauseHRT is often given as a short term relief from menopausal symptoms during perimenopause 19 Potential menopausal symptoms include 1 2 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 20 21 Sleep disturbances and joint painThe most common of these are loss of sexual drive and vaginal dryness 4 22 Sexual function edit See also Testosterone medication Women nbsp Atrophy of vaginal mucosa that occurs with menopauseHRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause Epidemiological surveys of women between 40 and 69 years suggest that 75 of women remain sexually active after menopause 4 With increasing life spans women today are living one third or more of their lives in a postmenopausal state a period during which healthy sexuality can be integral to their quality of life 23 Decreased libido and sexual dysfunction are common issues in postmenopausal women an entity referred to hypoactive sexual desire disorder HSDD its signs and symptoms can both be improved by HRT 5 24 Several hormonal changes take place during this period including a decrease in estrogen and an increase in follicle stimulating hormone For most women the majority of change occurs during the late perimenopausal and postmenopausal stages 4 Decreases in sex hormone binding globulin SHBG and inhibin A and B also occur Testosterone is present in women at a lower level than men peaking at age 30 and declining gradually with age there is less variation during the menopausal transition relative to estrogen and progesterone 4 A global consensus position statement has advised that postmenopausal testosterone replacement to premenopausal levels can be effective for HSDD Safety information for testosterone treatment is not available beyond two years of continuous therapy however and dosing above physiologic levels is not advised 25 Testosterone patches have been found to restore sexual desire in post menopausal women 26 There is insufficient data to evaluate the impact of testosterone replacement on heart disease breast cancer with most trials having included women taking concomitant estrogen and progesterone and with testosterone therapy itself being relatively short in duration In the setting of this limited data testosterone therapy has not been associated with adverse events 25 Not all women are responsive especially those with preexisting sexual difficulties 22 Estrogen replacement can restore vaginal cells pH levels and blood flow to the vagina all of which tend to deteriorate at the onset of menopause Pain or discomfort with sex appears to be the most responsive component to estrogen 22 It also has been shown to have positive effects on the urinary tract 22 Estrogen can also reduce vaginal atrophy and increase sexual arousal frequency and orgasm 22 The effectiveness of hormone replacement can decline in some women after long term use 22 A number of studies have also found that the combined effects of estrogen androgen replacement therapy can increase libido and arousal over estrogen alone 22 Tibolone a synthetic steroid with estrogenic androgenic and progestogenic properties that is available in Europe has the ability to improve mood libido and physical symptomatology In various placebo controlled studies improvements in vasomotor symptoms emotional response sleep disturbances physical symptoms and sexual desire have been seen though it also carries a similar risk profile to conventional HRT 5 Muscle and bone edit There is a significant decrease in hip fracture risk during treatment that to a lesser degree persists after HRT is stopped 27 28 It also helps collagen formation which in turn improves intervertebral disc and bone strength 29 Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle 30 Lower testosterone is associated with lower bone density and higher free testosterone is associated with lower hip fracture rates in older women 31 Testosterone therapy which can be used for decreased sexual function can also increase bone mineral density and muscle mass 25 Side effects editSide effects in HRT occur with varying frequency and include 32 Common edit Headache Upset stomach stomach cramps or bloating Diarrhea Appetite and weight changes Changes in sex drive or performance Nervousness Brown or black patches on the skin Acne Swelling of hands feet or lower legs due to fluid retention Changes in menstrual flow Breast tenderness enlargement or discharge Sudden difficulty wearing contact lensesUncommon edit Double vision Severe abdominal pain Yellowing of skin or eyes Severe depression Unusual bleeding Loss of appetite Skin rash Lassitude Fever Dark colored urine Light colored stool Chorea 33 Heart disease edit nbsp 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 34 35 36 For women who are in early menopause and have no issues with their cardiovascular health HRT comes with a low risk of adverse cardiovascular events 37 There may be an increase in heart disease if HRT is given twenty years post menopause 38 This variability has led some reviews to suggest an absence of significant effect on morbidity 39 Importantly there is no difference in long term mortality from HRT regardless of age 40 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 34 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 34 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 41 HRT also results in a large reduction in the pro thrombotic lipoprotein a 42 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 43 44 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 45 Blood clots edit nbsp 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 18 Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina there is a lower risk of blood clots 18 46 whereas when used orally the risk of blood clots and pulmonary embolism is increased 47 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 48 While a 2018 review found that taking progesterone and estrogen together can decrease this risk 46 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 18 47 The risk of venous thromboembolism may be reduced with bioidentical preparations though research on this is only preliminary 49 Stroke edit Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause 50 and that the association is absent or even preventive when given by non oral routes 8 Ischemic stroke risk was increased during the time of intervention in the WHI with no significant effect after the cessation of therapy 27 and no difference in mortality at long term follow up 6 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 50 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 8 Endometrial cancer edit nbsp 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 51 The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease 52 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 53 The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen 53 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 54 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 53 Androgens do not stimulate endometrial proliferation in post menopausal women and appear to inhibit the proliferation induced by estrogen to a certain extent 55 There is insufficient high quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer 56 Breast cancer edit In general hormone replacement therapy to treat menopause is associated with only a small increased risk of breast cancer 57 58 59 The level of risk also depends on the type of HRT the duration of the treatment and the age of the person Oestrogen only HRT taken by people who had a hysterectomy comes with an extremely low level of breast cancer risk The most commonly taken combined HRT oestrogen and progestogen is linked to a small risk of breast cancer This risk is lower for women in their 50s and higher for older women The risk increases with the duration of HRT When HRT is taken for a year or less there is no increased risk of breast cancer HRT taken for more than 5 years comes with an increased risk but the risk reduces after the therapy is stopped 58 59 There is a non statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone 6 The risk may be reduced with bioidentical progesterone 60 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 61 The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of synthetic progestin administration 62 63 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 64 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 65 66 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 67 It has been suggested by some that the absence of significant effect in some of these studies could be due to selective prescription to overweight women who have higher baseline estrone or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate 68 Evaluating the response of breast tissue density to HRT using mammography appears to help assessing the degree of breast cancer risk associated with therapy women with dense or mixed dense breast tissue have a higher risk of developing breast cancer than those with low density tissue 69 Micronized progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration 70 For women who previously have had breast cancer it is recommended to first consider other options for menopausal effects such as bisphosphonates or selective estrogen receptor modulators SERMs for osteoporosis cholesterol lowering agents and aspirin for cardiovascular disease and vaginal estrogen for local symptoms Observational studies of systemic HRT after breast cancer are generally reassuring If HRT is necessary after breast cancer estrogen only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy 71 In women who are BRCA1 or BRCA2 mutation carriers HRT does not appear to impact breast cancer risk 72 The relative number of women using HRT who also obtain regular screening mammograms is higher than that in women who do not use HRT a factor which has been suggested as contributing to different breast cancer detection rates in the two groups 73 With androgen therapy pre clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association 74 Ovarian cancer edit HRT is associated with an increased risk of ovarian cancer with women using HRT having about one additional case of ovarian cancer per 1 000 users 75 This risk is decreased when progestogen therapy is given concomitantly as opposed to estrogen alone and also decreases with increasing time since stopping HRT 76 Regarding the specific subtype there may be a higher risk of serous cancer but no association with clear cell endometrioid or mucinous ovarian cancer 76 Hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates 77 Other cancers edit Colorectal cancer edit In the WHI women who took combined estrogen progesterone therapy had a lower risk of getting colorectal cancer However the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones 78 In colorectal cancer survivors usage of HRT is thought to lead to lower recurrence risk and overall mortality 79 Cervical cancer edit There appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with HRT and a weak increase in adenocarcinoma No studies have reported an increased risk of recurrence when HRT is used with cervical cancer survivors 80 Neurodegenerative disorders edit For prevention the WHI suggested that HRT may increase risk of dementia if initiated after 65 years of age but have a neutral outcome or be neuroprotective for those between 50 and 55 years 27 Other studies in perimenopause have shown HRT to be consistently associated with a lower risk of Alzheimer s 81 82 With Parkinson s the majority of clinical and epidemiological studies show have demonstrated either no association 83 84 or inconclusive results 81 85 A Danish study suggested an increased risk of Parkinson s with HRT in cyclical dosing schedules 86 With regards to treatment randomized trials have shown that HRT improves executive and attention processes outside of the context of dementia in postmenopausal women both in those that are asymptomatic and those with mild cognitive impairment 87 88 89 Estrogen replacement appears to improve motor symptoms and activities of daily living in post menopausal women with Parkinson s with significant improvement of UPDRS scores 90 Clinical trials have also shown testosterone replacement to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women 91 DHEA has not been found to improve cognitive performance after menopause 31 Pre clinical studies indicate that endogenous estrogen and testosterone are neuroprotective and can prevent brain amyloid deposition 92 93 Contraindications editThe following are absolute and relative contraindications to HRT 94 Absolute contraindications edit Undiagnosed vaginal bleeding Severe liver disease Pregnancy Severe coronary artery disease Aggressive breast uterine or ovarian cancerRelative contraindications edit Migraine headaches History of breast cancer History of ovarian cancer Venous thrombosis History of uterine fibroids Atypical ductal hyperplasia of the breast Active gallbladder disease cholangitis cholecystitis Well differentiated and early endometrial cancer once treatment for the malignancy is complete is no longer an absolute contraindication History and research editThe extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin one of the earlier forms of estrogen to be introduced 95 96 From that time until the mid 1970s estrogen was administered without a supplemental progestogen Beginning in 1975 studies began to show that without a progestogen unopposed estrogen therapy with Premarin resulted in an eight fold increased risk of endometrial cancer eventually causing sales of Premarin to plummet 95 It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium 95 This led to the development of combined estrogen progestogen therapy most commonly with a combination of conjugated equine estrogen Premarin and medroxyprogesterone Provera 95 Trials edit The Women s Health Initiative trials were conducted between 1991 and 2006 and were the first large double blind placebo controlled clinical trials of HRT in healthy women 95 Their results were both positive and negative suggesting that during the time of hormone therapy itself there are increases in invasive breast cancer stroke and lung clots Other risks include increased endometrial cancer gallbladder disease and urinary incontinence while benefits include decreased hip fractures decreased incidence of diabetes and improvement of vasomotor symptoms There is also an increased risk of dementia with HRT in women over 65 though at younger ages it appears to be neuroprotective After the cessation of HRT the WHI continued to observe its participants and found that most of these risks and benefits dissipated though some elevation in breast cancer risk did persist 27 Other studies have also suggested an increased risk of ovarian cancer 76 The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its Data Monitoring Committee DMC due to perceived health risks though this occurred a full year after the data suggesting increased risk became manifest In 2004 the arm of the WHI in which post hysterectomy patients were being treated with estrogen alone was also closed by the DMC Clinical medical practice changed based upon two parallel Women s Health Initiative WHI studies of HRT Prior studies were smaller and many were of women who electively took hormonal therapy One portion of the parallel studies followed over 16 000 women for an average of 5 2 years half of whom took placebo while the other half took a combination of CEEs and MPA Prempro This WHI estrogen plus progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined CEEs and progestins exceeded their benefits The first report on the halted WHI estrogen plus progestin study came out in July 2002 97 Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier between age 50 to 59 but higher when begun after age 60 In older patients there was an apparent increased incidence of breast cancer heart attacks venous thrombosis and stroke although a reduced incidence of colorectal cancer and bone fracture At the time The WHI recommended that women with non surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks 97 Some of the WHI findings were again found in a larger national study done in the United Kingdom known as the Million Women Study MWS As a result of these findings the number of women taking HRT dropped precipitously 98 In 2012 the United States Preventive Task Force USPSTF concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits 99 100 In 2002 when the first WHI follow up study was published with HRT in post menopausal women both older and younger age groups had a slightly higher incidence of breast cancer and both heart attack and stroke were increased in older patients although not in younger participants Breast cancer was increased in women treated with estrogen and a progestin but not with estrogen and progesterone or estrogen alone Treatment with unopposed estrogen i e an estrogen alone without a progestogen is contraindicated if the uterus is still present due to its proliferative effect on the endometrium The WHI also found a reduced incidence of colorectal cancer when estrogen and a progestogen were used together and most importantly a reduced incidence of bone fractures Ultimately the study found disparate results for all cause mortality with HRT finding it to be lower when HRT was begun during ages 50 59 but higher when begun after age 60 The authors of the study recommended that women with non surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk 97 The data published by the WHI suggested supplemental estrogen increased risk of venous thromboembolism and breast cancer but was protective against osteoporosis and colorectal cancer while the impact on cardiovascular disease was mixed 101 These results were later supported in trials from the United Kingdom but not in more recent studies from France and China Genetic polymorphism appears to be associated with inter individual variability in metabolic response to HRT in postmenopausal women 102 103 The WHI reported statistically significant increases in rates of breast cancer coronary heart disease strokes and pulmonary emboli The study also found statistically significant decreases in rates of hip fracture and colorectal cancer A year after the study was stopped in 2002 an article was published indicating that estrogen plus progestin also increases the risks of dementia 104 The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits The results were almost universally reported as risks and problems associated with HRT in general rather than with Prempro the specific proprietary combination of CEEs and MPA studied After the increased clotting found in the first WHI results was reported in 2002 the number of Prempro prescriptions filled reduced by almost half Following the WHI results a large percentage of HRT users opted out of them which was quickly followed by a sharp drop in breast cancer rates The decrease in breast cancer rates has continued in subsequent years 105 An unknown number of women started taking alternatives to Prempro such as compounded bioidentical hormones though researchers have asserted that compounded hormones are not significantly different from conventional hormone therapy 106 The other portion of the parallel studies featured women who were post hysterectomy and so received either placebo progestogen or CEEs alone This group did not show the risks demonstrated in the combination hormone study and the estrogen only study was not halted in 2002 However in February 2004 it too was halted While there was a 23 decreased incidence of breast cancer in the estrogen only study participants risks of stroke and pulmonary embolism were increased slightly predominantly in patients who began HRT over the age of 60 107 Several other large studies and meta analyses have reported reduced mortality for HRT in women younger than age 60 or within 10 years of menopause and a debatable or absent effect on mortality in women over 60 108 109 110 111 17 112 Though research thus far has been substantial further investigation is needed to fully understand differences in effect for different types of HRT and lengths of time since menopause 113 114 29 As of 2023 update for example no trial has studied women who begin taking HRT around age 50 and continue taking it for longer than 10 years 115 Available forms editSee also Sex hormonal agent and List of sex hormonal medications available in the United States There are five major human steroid hormones estrogens progestogens androgens mineralocorticoids and glucocorticoids Estrogens and progestogens are the two most often used in menopause They are available in a wide variety of FDA approved and non FDA approved formulations 9 In women with intact uteruses estrogens are almost always given in combination with progestogens as long term unopposed estrogen therapy is associated with a markedly increased risk of endometrial hyperplasia and endometrial cancer 1 2 Conversely in women who have undergone a hysterectomy or do not have a uterus a progestogen is not required and estrogen can be used alone There are many combined formulations which include both estrogen and progestogen Specific types of hormone replacement include 1 2 Estrogens bioidentical estrogens like estradiol and estriol animal derived estrogens like conjugated estrogens CEEs and synthetic estrogens like ethinylestradiol Progestogens bioidentical progesterone and progestins synthetic progestogens like medroxyprogesterone acetate MPA norethisterone and dydrogesterone Androgens bioidentical testosterone and dehydroepiandrosterone DHEA and synthetic anabolic steroids like methyltestosterone and nandrolone decanoate 116 117 Tibolone a synthetic medication available in Europe but not the United States is more effective than placebo but less effective than combination hormone therapy in postmenopausal women It may have a decreased risk of breast and colorectal cancer though conversely it can be associated with vaginal bleeding endometrial cancer and increase the risk of stroke in women over age 60 years 118 119 Vaginal estrogen can improve local atrophy and dryness with fewer systemic effects than estrogens delivered by other routes 120 Sometimes an androgen generally testosterone can be added to treat diminished libido 121 122 Continuous versus cyclic edit Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle with estrogens taken daily and progestogens taken for about two weeks every month or every other month a schedule referred to as cyclic or sequentially combined Alternatively continuous combined HRT can be given with a constant daily hormonal dosage 123 Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic 124 Impact on breast density appears to be similar in both regimen timings 125 Route of administration edit nbsp An intrauterine device can be used to receive HRT The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration 1 2 Oral administration tablets capsules Transdermal administration patches gels creams Vaginal administration tablets creams suppositories rings Intramuscular or subcutaneous injection solutions in vials or ampoules Subcutaneous implant surgically inserted pellets placed into fat tissue Less commonly sublingual buccal intranasal and rectal administration as well as intrauterine devicesMore recently developed forms of drug delivery are alleged to have increased local effect lower dosing fewer side effects and constant rather than cyclical serum hormone levels 1 2 Transdermal and vaginal estrogen in particular avoid first pass metabolism through the liver This in turn prevents an increase in clotting factors and accumulation of anti estrogenic metabolites resulting in fewer adverse side effects particularly with regard to cardiovascular disease and stroke 126 Injectable forms of estradiol exist and have been used occasionally in the past 127 128 However they are rarely used in menopausal hormone therapy in modern times and are no longer recommended 127 129 Instead other non oral forms of estradiol such as transdermal estradiol are recommended and may be used 127 Estradiol injectables are generally well tolerated and convenient requiring infrequent administration 127 128 However this form of estradiol does not release estradiol at a constant rate and there are very high circulating estradiol levels soon after injection followed by a rapid decline in levels 127 Injections may also be painful 127 Examples of estradiol injectables that may be used in menopausal hormone therapy include estradiol valerate and estradiol cypionate 127 128 In terms of injectable progestogens injectable progesterone is associated with pain and injection site reactions as well as a short duration of action requiring very frequent injections and is similarly not recommended in menopausal hormone therapy 130 128 Bioidentical hormone therapy edit Main article Bioidentical hormone therapy Bioidentical hormone therapy BHT is the usage of hormones that are chemically identical to those produced in the body Although proponents of BHT claim advantages over non bioidentical or conventional hormone therapy the FDA does not recognize the term bioidentical hormone stating there is no scientific evidence that these hormones are identical to their naturally occurring counterparts 11 131 There are however FDA approved products containing hormones classified as bioidentical 12 9 Bioidentical hormones can be used in either pharmaceutical or compounded preparations with the latter generally not recommended by regulatory bodies due to their lack of standardization and regulatory oversight 11 Most classifications of bioidentical hormones do not take into account manufacturing source or delivery method of the products and so describe both non FDA approved compounded products and FDA approved pharmaceuticals as bioidentical 9 The British Menopause Society has issued a consensus statement endorsing the distinction between compounded forms cBHRT described as unregulated custom made by specialty pharmacies and subject to heavy marketing and regulated pharmaceutical grade forms rBHRT which undergo formal oversight by entities such as the FDA and form the basis of most clinical trials 132 Some practitioners recommending compounded bioidentical HRT also use salivary or serum hormonal testing to monitor response to therapy a practice not endorsed by current clinical guidelines in the United States and Europe 133 Bioidentical hormones in pharmaceuticals may have very limited clinical data with no randomized controlled prospective trials to date comparing them to their animal derived counterparts Some pre clinical data has suggested a decreased risk of venous thromboembolism cardiovascular disease and breast cancer 11 As of 2012 guidelines from the North American Menopause Society the Endocrine Society the International Menopause Society and the European Menopause and Andropause Society endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk 11 134 Compounding edit Compounding for HRT is generally discouraged by the FDA and medical industry in the United States due to a lack of regulation and standardized dosing 11 131 The U S Congress did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the Federal Food Drug and Cosmetic Act FDCA but they have encountered obstacles in this role since that time After 64 patient deaths and 750 harmed patients from a 2012 meningitis outbreak due to contaminated steroid injections Congress passed the 2013 Drug Quality and Security Act authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs and reinforcing FDCA regulations for traditional compounding 135 The DQSA and its reinforcement of provision 503A of the FDCA solidifies FDA authority to enforce FDCA regulation of against compounders of bioidentical hormone therapy 135 In the United Kingdom on the other hand compounding is a regulated activity The Medicines and Healthcare products Regulatory Agency regulates compounding performed under a Manufacturing Specials license and the General Pharmaceutical Council regulates compounding performed within a pharmacy All testosterone prescribed in the United Kingdom is bioidentical with its use supported by the National Health Service There is also marketing authorisation for male testosterone products National Institute for Health and Care Excellence guideline 1 4 8 states consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective The footnote adds at the time of publication November 2015 testosterone did not have a United Kingdom marketing authorisation for this indication in women Bioidentical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour Society and culture editWyeth controversy edit See also Medical ghostwriter Wyeth now a subsidiary of Pfizer was a pharmaceutical company that marketed the HRT products Premarin CEEs and Prempro CEEs MPA 136 137 In 2009 litigation involving Wyeth resulted in the release of 1 500 documents that revealed practices concerning its promotion of these medications 136 137 138 The documents showed that Wyeth commissioned dozens of ghostwritten reviews and commentaries that were published in medical journals to promote unproven benefits of its HRT products downplay their harms and risks and cast competing therapies in a negative light 136 137 138 Starting in the mid 1990s and continuing for over a decade Wyeth pursued an aggressive publication plan strategy to promote its HRT products through the use of ghostwritten publications 138 It worked mainly with DesignWrite a medical writing firm 138 Between 1998 and 2005 Wyeth had 26 papers promoting its HRT products published in scientific journals 136 These favorable publications emphasized the benefits and downplayed the risks of its HRT products especially the misconception of the association of its products with breast cancer 138 The publications defended unsupported cardiovascular benefits of its products downplayed risks such as breast cancer and promoted off label and unproven uses like prevention of dementia Parkinson s disease vision problems and wrinkles 137 In addition Wyeth emphasized negative messages against the SERM raloxifene for osteoporosis instructed writers to stress the fact that alternative therapies have increased in usage since the WHI even though there is little evidence that they are effective or safe called into question the quality and therapeutic equivalence of approved generic CEE products and made efforts to spread the notion that the unique risks of CEEs and MPA were a class effect of all forms of menopausal HRT Overall these data indicate that the benefit risk analysis that was reported in the Women s Health Initiative can be generalized to all postmenopausal hormone replacement therapy products 137 Following the publication of the WHI data in 2002 the stock prices for the pharmaceutical industry plummeted and huge numbers of women stopped using HRT 139 The stocks of Wyeth which supplied the Premarin and Prempro that were used in the WHI trials decreased by more than 50 and never fully recovered 139 Some of their articles in response promoted themes such as the following the WHI was flawed the WHI was a controversial trial the population studied in the WHI was inappropriate or was not representative of the general population of menopausal women results of clinical trials should not guide treatment for individuals observational studies are as good as or better than randomized clinical trials animal studies can guide clinical decision making the risks associated with hormone therapy have been exaggerated the benefits of hormone therapy have been or will be proven and the recent studies are an aberration 95 Similar findings were observed in a 2010 analysis of 114 editorials reviews guidelines and letters by five industry paid authors 95 These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS 95 In 2009 Wyeth was acquired by Pfizer in a deal valued at US 68 billion 140 141 Pfizer a company that produces Provera and Depo Provera MPA and has also engaged in medical ghostwriting continues to market Premarin and Prempro which remain best selling medications 95 138 According to Fugh Berman 2010 Today despite definitive scientific data to the contrary many gynecologists still believe that the benefits of HRT outweigh the risks in asymptomatic women This non evidence based perception may be the result of decades of carefully orchestrated corporate influence on medical literature 137 As many as 50 of physicians have expressed skepticism about large trials like the WHI and HERS 142 The positive perceptions of many physicians of HRT in spite of large trials showing risks that potentially outweigh any benefits may be due to the efforts of pharmaceutical companies like Wyeth 138 95 Popularity edit The 1990s showed a dramatic decline in prescription rates though more recently they have begun to rise again 126 143 Transdermal therapy in part due to its lack of increase in venous thromboembolism is now often the first choice for HRT in the United Kingdom Conjugate equine estrogen in distinction has a potentially higher thrombosis risk and is now not commonly used in the UK replaced by estradiol based compounds with lower thrombosis risk Oral progestogen combinations such as medroxyprogesterone acetate have changed to dyhydrogesterone due to a lack of association of the latter with venous clot 144 See also editAndrogen replacement therapy Hormone therapy Transgender hormone therapyReferences edit a b c d e f g h i Stuenkel CA Davis SR Gompel A Lumsden MA Murad MH Pinkerton JV Santen RJ November 2015 Treatment of Symptoms of the Menopause An Endocrine Society Clinical Practice Guideline PDF J Clin Endocrinol Metab 100 11 3975 4011 doi 10 1210 jc 2015 2236 PMID 26444994 a b c d e f g h Santen RJ Allred DC Ardoin SP Archer DF Boyd N Braunstein GD Burger HG Colditz GA Davis SR Gambacciani M Gower BA Henderson VW Jarjour WN Karas RH Kleerekoper M Lobo RA Manson JE Marsden J Martin KA Martin L Pinkerton JV Rubinow DR Teede H Thiboutot DM Utian WH July 2010 Postmenopausal hormone therapy an Endocrine Society scientific statement J Clin Endocrinol Metab 95 7 Suppl 1 s1 s66 doi 10 1210 jc 2009 2509 PMC 6287288 PMID 20566620 Shuster Lynne T Rhodes Deborah J Gostout Bobbie S Grossardt Brandon R Rocca Walter A 2010 Premature menopause or early menopause Long term health consequences Maturitas 65 2 161 166 doi 10 1016 j maturitas 2009 08 003 ISSN 0378 5122 PMC 2815011 PMID 19733988 a b c d e f Eden KJ Wylie KR 1 July 2009 Quality of sexual life and menopause Women s Health 6 4 385 396 doi 10 2217 WHE 09 24 PMID 19586430 a b c Ziaei S Moghasemi M Faghihzadeh S 2010 Comparative effects of conventional hormone replacement therapy and tibolone on climacteric symptoms and sexual dysfunction in postmenopausal women Climacteric 13 3 147 156 doi 10 1016 j maturitas 2006 04 014 PMID 16730929 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link a b c Manson JE Aragaki AK Rossouw JE Anderson GL Prentice RL LaCroix AZ Chlebowski RT Howard BV Thomson CA Margolis KL Lewis CE Stefanick ML Jackson RD Johnson KC Martin LW Shumaker SA Espeland MA Wactawski Wende J WHI Investigators 12 September 2017 Menopausal Hormone Therapy and Long term All Cause and Cause Specific Mortality The Women s Health Initiative Randomized Trials JAMA 318 10 927 938 doi 10 1001 jama 2017 11217 PMC 5728370 PMID 28898378 Langer RD Hodis HN Lobo RA Allison MA February 2021 Hormone replacement therapy where are we now Climacteric 24 1 3 10 doi 10 1080 13697137 2020 1851183 PMID 33403881 S2CID 230783545 a b c Lokkegaard E Nielsen LH Keiding N August 2017 Risk of Stroke With Various Types of Menopausal Hormone Therapies A National Cohort Study Stroke 48 8 2266 2269 doi 10 1161 STROKEAHA 117 017132 PMID 28626058 S2CID 207579406 a b c d Files JA Ko MG Pruthi S July 2011 Bioidentical hormone therapy Mayo Clinic Proceedings 86 7 673 80 quiz 680 doi 10 4065 mcp 2010 0714 PMC 3127562 PMID 21531972 Bioidentical hormones Cleveland Clinic 12 December 2012 a b c d e f Conaway E March 2011 Bioidentical hormones an evidence based review for primary care providers J Am Osteopath Assoc 111 3 153 64 PMID 21464264 a b c Cobin RH Goodman NF AACE Reproductive Endocrinology Scientific Committee 1 July 2017 Position Statement on Menopause 2017 Update PDF Endocrine Practice 23 7 869 880 doi 10 4158 EP171828 PS PMID 28703650 Archived from the original PDF on 1 March 2019 Retrieved 1 March 2019 a b USPTF Consensus Statement 2012 Archived from the original on 30 May 2013 Retrieved 14 May 2013 Lewis Ricki ACOG Revises Guidelines on Treating Menopause Symptoms login medscape com Medscape Retrieved 4 March 2019 Hormone Therapy and Heart Disease ACOG www acog org Committee on Gynecologic Practice Retrieved 4 March 2019 Medscape www medscape com a b Santen RJ Utian WH 2010 Executive Summary Postmenopausal Hormone Therapy An Endocrine Society Scientific Statement J Clin Endocrinol Metab 95 S1 S66 Supplement 1 s1 s66 doi 10 1210 jc 2009 2509 PMC 6287288 PMID 20566620 a b c d Marjoribanks Jane Farquhar Cindy Roberts Helen Lethaby Anne Lee Jasmine 17 January 2017 Long term hormone therapy for perimenopausal and postmenopausal women The Cochrane Database of Systematic Reviews 1 1 CD004143 doi 10 1002 14651858 CD004143 pub5 ISSN 1469 493X PMC 6465148 PMID 28093732 Menopause treatments National Health Service United Kingdom 2019 Retrieved 23 February 2018 Raine Fenning NJ Brincat MP Muscat Baron Y 2003 Skin aging and menopause implications for treatment Am J Clin Dermatol 4 6 371 8 doi 10 2165 00128071 200304060 00001 PMID 12762829 S2CID 20392538 Zouboulis CC Makrantonaki E June 2012 Hormonal therapy of intrinsic aging Rejuvenation Res 15 3 302 12 doi 10 1089 rej 2011 1249 PMID 22533363 a b c d e f g Sarrel P M 2000 Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause Journal of Women s Health and Gender Based Medicine 9 25 32 Miller M M Franklin K B J 1999 Theoretical basis for the benefit of postmenopausal estrogen substitution Experimental Gerontology 34 5 587 604 doi 10 1016 S0531 5565 99 00032 7 PMID 10530785 S2CID 43031351 Gonzalez M Viagara G Caba F Molina E 2004 Sexual function menopause and hormone replacement therapy HRT The European Menopause Journal 48 4 411 420 doi 10 1016 j maturitas 2003 10 005 PMID 15283933 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link a b c Davis SR Baber R Panay N Bitzer J Perez SC Islam RM Kaunitz AM Kingsberg SA Lambrinoudaki I Liu J Parish SJ Pinkerton J Rymer J Simon JA Vignozzi L Wierman ME September 2019 Global Consensus Position Statement on the Use of Testosterone Therapy for Women The Journal of Sexual Medicine 16 9 1331 1337 doi 10 1016 j jsxm 2019 07 012 hdl 2158 1176450 PMID 31488288 S2CID 201845588 Johansen N Linden Hirschberg A Moen MH August 2020 The role of testosterone in menopausal hormone treatment What is the evidence Acta Obstetricia et Gynecologica Scandinavica 99 8 966 969 doi 10 1111 aogs 13819 PMID 32027015 S2CID 211050248 a b c d Manson JE Chlebowski RT Stefanick ML Aragaki AK Rossouw JE Prentice RL Anderson G Howard BV Thomson CA LaCroix AZ Wactawski Wende J Jackson RD Limacher M Margolis KL Wassertheil Smoller S Beresford SA Cauley JA Eaton CB Gass M Hsia J Johnson KC Kooperberg C Kuller LH Lewis CE Liu S Martin LW Ockene JK O Sullivan MJ Powell LH Simon MS Van Horn L Vitolins MZ Wallace RB 2 October 2013 Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women s Health Initiative randomized trials JAMA 310 13 1353 68 doi 10 1001 jama 2013 278040 PMC 3963523 PMID 24084921 Zhu L Jiang X Sun Y Shu W April 2016 Effect of hormone therapy on the risk of bone fractures a systematic review and meta analysis of randomized controlled trials Menopause 23 4 461 70 doi 10 1097 GME 0000000000000519 PMID 26529613 S2CID 26110755 a b Studd J March 2010 Ten reasons to be happy about hormone replacement therapy a guide for patients Menopause Int 16 1 44 6 doi 10 1258 mi 2010 010001 PMID 20424287 S2CID 33414205 Tiidus PM August 2011 Benefits of estrogen replacement for skeletal muscle mass and function in post menopausal females evidence from human and animal studies The Eurasian Journal of Medicine 43 2 109 14 doi 10 5152 eajm 2011 24 PMC 4261347 PMID 25610174 a b Shifren JL Davis SR August 2017 Androgens in postmenopausal women a review Menopause 24 8 970 979 doi 10 1097 GME 0000000000000903 PMID 28609390 S2CID 39876534 Deleruyelle LJ 2017 Menopausal Symptom Relief and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and or Progestin Hormone Replacement Therapy Part 3 International Journal of Pharmaceutical Compounding 21 1 6 16 PMID 28346192 Suchowersky O Muthipeedika J December 2005 A case of late onset chorea Nat Clin Pract Neurol 1 2 113 6 doi 10 1038 ncpneuro0052 PMID 16932507 S2CID 11410333 a b c Boardman HM Hartley L Eisinga A Main C Roque i Figuls M Bonfill Cosp X Gabriel Sanchez R Knight B 10 March 2015 Hormone therapy for preventing cardiovascular disease in post menopausal women The Cochrane Database of Systematic Reviews 2015 3 CD002229 doi 10 1002 14651858 CD002229 pub4 hdl 20 500 12105 9999 ISSN 1469 493X PMC 10183715 PMID 25754617 S2CID 22188456 Hodis HN Mack WJ Henderson VW Shoupe D Budoff MJ Hwang Levine J Li Y Feng M Dustin L Kono N Stanczyk FZ Selzer RH Azen SP ELITE Research Group 31 March 2016 Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol The New England Journal of Medicine 374 13 1221 31 doi 10 1056 NEJMoa1505241 PMC 4921205 PMID 27028912 Writing Group on Behalf of Workshop Consensus October 2009 Aging menopause cardiovascular disease and HRT International Menopause Society Consensus Statement Climacteric 12 5 368 77 doi 10 1080 13697130903195606 PMID 19811229 S2CID 218865937 Committee Opinion No 565 Hormone Therapy and Heart Disease Obstetrics amp Gynecology 121 6 1407 1410 June 2013 doi 10 1097 01 AOG 0000431053 33593 2d ISSN 0029 7844 PMID 23812486 S2CID 30775537 Manson JE Chlebowski RT Stefanick ML Aragaki AK Rossouw JE Prentice RL Anderson G Howard BV Thomson CA LaCroix AZ Wactawski Wende J Jackson RD Limacher M Margolis KL Wassertheil Smoller S Beresford SA Cauley JA Eaton CB Gass M Hsia J Johnson KC Kooperberg C Kuller LH Lewis CE Liu S Martin LW Ockene JK O Sullivan MJ Powell LH Simon MS Van Horn L Vitolins MZ Wallace RB 2 October 2013 Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women s Health Initiative randomized trials JAMA 310 13 1353 68 doi 10 1001 jama 2013 278040 PMC 3963523 PMID 24084921 Saeaib N Peeyananjarassri K Liabsuetrakul T Buhachat R Myriokefalitaki E 28 January 2020 Hormone replacement therapy after surgery for epithelial ovarian cancer The Cochrane Database of Systematic Reviews 1 1 CD012559 doi 10 1002 14651858 CD012559 pub2 PMC 7027384 PMID 31989588 Manson JE Aragaki AK Rossouw JE Anderson GL Prentice RL LaCroix AZ Chlebowski RT Howard BV Thomson CA Margolis KL Lewis CE Stefanick ML Jackson RD Johnson KC Martin LW Shumaker SA Espeland MA Wactawski Wende J WHI Investigators 12 September 2017 Menopausal Hormone Therapy and Long term All Cause and Cause Specific Mortality The Women s Health Initiative Randomized Trials JAMA 318 10 927 938 doi 10 1001 jama 2017 11217 PMC 5728370 PMID 28898378 Darabi M Rabbani M Ani M Zarean E Panjehpour M Movahedian A 2011 Increased leukocyte ABCA1 gene expression in post menopausal women on hormone replacement therapy Gynecological Endocrinology 27 9 701 705 doi 10 3109 09513590 2010 507826 PMID 20807164 S2CID 203464 Gregersen I Hoibraaten E Holven KB Lovdahl L Ueland T Mowinckel MC Dahl TB Aukrust P Halvorsen B Sandset PM December 2019 Effect of hormone replacement therapy on atherogenic lipid profile in postmenopausal women Thrombosis Research 184 1 7 doi 10 1016 j thromres 2019 10 005 hdl 10852 75276 PMID 31677448 Spoletini I Vitale C Pelliccia F Fossati C Rosano GM December 2014 Androgens and cardiovascular disease in postmenopausal women a systematic review Climacteric 17 6 625 34 doi 10 3109 13697137 2014 887669 PMID 24559253 S2CID 33413274 Davis SR Baber R Panay N Bitzer J Perez SC Islam RM Kaunitz AM Kingsberg SA Lambrinoudaki I Liu J Parish SJ Pinkerton J Rymer J Simon JA Vignozzi L Wierman ME September 2019 Global Consensus Position Statement on the Use of Testosterone Therapy for Women The Journal of Sexual Medicine 16 9 1331 1337 doi 10 1016 j jsxm 2019 07 012 hdl 2158 1176450 PMID 31488288 S2CID 201845588 Shifren JL Davis SR August 2017 Androgens in postmenopausal women a review Menopause 24 8 970 979 doi 10 1097 GME 0000000000000903 PMID 28609390 S2CID 39876534 a b Scarabin P Y August 2018 Progestogens and venous thromboembolism in menopausal women an updated oral versus transdermal estrogen meta analysis Climacteric 21 4 341 345 doi 10 1080 13697137 2018 1446931 ISSN 1473 0804 PMID 29570359 S2CID 4229701 a b Boardman HM Hartley L Eisinga A Main C Roque i Figuls M Bonfill Cosp X Gabriel Sanchez R Knight B 10 March 2015 Hormone therapy for preventing cardiovascular disease in post menopausal women The Cochrane Database of Systematic Reviews 2015 3 CD002229 doi 10 1002 14651858 CD002229 pub4 hdl 20 500 12105 9999 ISSN 1469 493X PMC 10183715 PMID 25754617 S2CID 22188456 Olie V R Canonico M Scarabin P Y 2010 Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women Current Opinion in Hematology 17 5 457 463 doi 10 1097 MOH 0b013e32833c07bc PMID 20601871 S2CID 205827003 Rott H 2014 Prevention and treatment of venous thromboembolism during HRT current perspectives International Journal of General Medicine 7 433 40 doi 10 2147 IJGM S46310 PMC 4155999 PMID 25210472 a b Carrasquilla GD Frumento P Berglund A Borgfeldt C Bottai M Chiavenna C Eliasson M Engstrom G Hallmans G Jansson JH Magnusson PK Nilsson PM Pedersen NL Wolk A Leander K November 2017 Postmenopausal hormone therapy and risk of stroke A pooled analysis of data from population based cohort studies PLOS Med 14 11 e1002445 doi 10 1371 journal pmed 1002445 PMC 5693286 PMID 29149179 Chlebowski RT Anderson GL Sarto GE Haque R Runowicz CD Aragaki AK Thomson CA Howard BV Wactawski Wende J Chen C Rohan TE Simon MS Reed SD Manson JE March 2016 Continuous Combined Estrogen Plus Progestin and Endometrial Cancer The Women s Health Initiative Randomized Trial Journal of the National Cancer Institute 108 3 djv350 doi 10 1093 jnci djv350 PMC 5072373 PMID 26668177 Archer DF 2001 The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women Menopause 8 4 245 51 doi 10 1097 00042192 200107000 00005 PMID 11449081 S2CID 38526018 a b c Kim JJ Kurita T Bulun SE February 2013 Progesterone action in endometrial cancer endometriosis uterine fibroids and breast cancer Endocrine Reviews 34 1 130 62 doi 10 1210 er 2012 1043 PMC 3565104 PMID 23303565 Young Robert Arlan F Jr Fuller Fuller Arlan F Michael V Seiden 2004 Uterine cancer Hamilton Ont B C Decker ISBN 978 1 55009 163 2 Zang H Sahlin L Masironi B Eriksson E Linden Hirschberg A June 2007 Effects of testosterone treatment on endometrial proliferation in postmenopausal women The Journal of Clinical Endocrinology and Metabolism 92 6 2169 75 doi 10 1210 jc 2006 2171 PMID 17341565 Endometrial cancer risk was lower in women who used continuous combined HRT than in non users Evidence based Obstetrics amp Gynecology 8 1 2 68 69 March 2006 doi 10 1016 j ebobgyn 2006 01 011 ISSN 1361 259X Collaborative Group on Hormonal Factors in Breast Cancer September 2019 Type and timing of menopausal hormone therapy and breast cancer risk individual participant meta analysis of the worldwide epidemiological evidence Lancet 394 10204 1159 1168 doi 10 1016 S0140 6736 19 31709 X PMC 6891893 PMID 31474332 a b Risk of breast cancer with HRT depends on therapy type and duration NIHR Evidence National Institute for Health and Care Research 20 December 2021 doi 10 3310 alert 48575 a b Vinogradova Y Coupland C Hippisley Cox J October 2020 Use of hormone replacement therapy and risk of breast cancer nested case control studies using the QResearch and CPRD databases BMJ 371 m3873 doi 10 1136 bmj m3873 PMC 7592147 PMID 33115755 Fournier A S Berrino F Clavel Chapelon F O 2007 Unequal risks for breast cancer associated with different hormone replacement therapies Results from the E3N cohort study Breast Cancer Research and Treatment 107 1 103 111 doi 10 1007 s10549 007 9523 x PMC 2211383 PMID 17333341 Zeng Z Jiang X Li X Wells A Luo Y Neapolitan R 2018 Conjugated equine estrogen and medroxyprogesterone acetate are associated with decreased risk of breast cancer relative to bioidentical hormone therapy and controls PLOS ONE 13 5 e0197064 Bibcode 2018PLoSO 1397064Z doi 10 1371 journal pone 0197064 PMC 5955567 PMID 29768475 Beral V Reeves G Bull D Green J Million Women Study Collaborators 16 February 2011 Breast cancer risk in relation to the interval between menopause and starting hormone therapy Journal of the National Cancer Institute 103 4 296 305 doi 10 1093 jnci djq527 PMC 3039726 PMID 21278356 a href Template Cite journal html title Template Cite journal cite journal a first5 has generic name help Letendre I Lopes P 2012 Menopause et risques carcinologiques Journal de Gynecologie Obstetrique et Biologie de la Reproduction 41 7 F33 F37 doi 10 1016 j jgyn 2012 09 006 PMID 23062839 Chlebowski RT Anderson GL Aragaki AK Manson JE Stefanick ML Pan K Barrington W Kuller LH Simon MS Lane D Johnson KC Rohan TE Gass MLS Cauley JA Paskett ED Sattari M Prentice RL 28 July 2020 Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long term Follow up of the Women s Health Initiative Randomized Clinical Trials JAMA 324 4 369 380 doi 10 1001 jama 2020 9482 PMC 7388026 PMID 32721007 Anderson G L Limacher M Assaf A R Bassford T Beresford S A Black H Bonds D Brunner R Brzyski R Caan B Chlebowski R Curb D Gass M Hays J Heiss G Hendrix S Howard B V Hsia J Hubbell A Jackson R Johnson K C Judd H Kotchen J M Kuller L Lacroix A Z Lane D Langer R D Lasser N Lewis C E Manson J 2004 Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy The Women s Health Initiative Randomized Controlled Trial JAMA The Journal of the American Medical Association 291 14 1701 1712 doi 10 1001 jama 291 14 1701 PMID 15082697 Stefanick ML Anderson GL Margolis KL et al 2006 Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy JAMA 295 14 1647 57 doi 10 1001 jama 295 14 1647 PMID 16609086 Association between hormone replacement therapy use and breast cancer risk varies by race ethnicity body mass index and breast density JNCI Journal of the National Cancer Institute 105 18 2013 doi 10 1093 jnci djt264 ISSN 0027 8874 In turn citing Hou N Hong S Wang W Olopade O I Dignam J J Huo D 2013 Hormone Replacement Therapy and Breast Cancer Heterogeneous Risks by Race Weight and Breast Density JNCI Journal of the National Cancer Institute 105 18 1365 1372 doi 10 1093 jnci djt207 ISSN 0027 8874 PMC 3776262 PMID 24003037 Kuhl H Schneider H P G 2013 Progesterone promoter or inhibitor of breast cancer Climacteric 16 Suppl 1 54 68 doi 10 3109 13697137 2013 768806 PMID 23336704 S2CID 20808536 Azam S Lange T Huynh S Aro AR von Euler Chelpin M Vejborg I Tjonneland A Lynge E Andersen ZJ June 2018 Hormone replacement therapy mammographic density and breast cancer risk a cohort study Cancer Causes amp Control 29 6 495 505 doi 10 1007 s10552 018 1033 0 PMC 5938298 PMID 29671181 Stute P Wildt L Neulen J April 2018 The impact of micronized progesterone on breast cancer risk a systematic review Climacteric 21 2 111 122 doi 10 1080 13697137 2017 1421925 PMID 29384406 S2CID 3642971 Management of the menopause after breast cancer Archived 7 April 2016 at archive today from The Royal Australian and New Zealand College of Obstetricians and Gynaecologists College Statement C Gyn 15 1st Endorsed February 2003 Current November 2011 Review November 2014 Gordhandas S Norquist BM Pennington KP Yung RL Laya MB Swisher EM April 2019 Hormone replacement therapy after risk reducing salpingo oophorectomy in patients with BRCA1 or BRCA2 mutations a systematic review of risks and benefits Gynecologic Oncology 153 1 192 200 doi 10 1016 j ygyno 2018 12 014 PMID 30661763 S2CID 58593390 Heinig M Schwarz S Haug U 16 February 2021 Self selection for mammography screening according to use of hormone replacement therapy A systematic literature review Cancer Epidemiology 71 Pt A 101812 doi 10 1016 j canep 2020 101812 PMID 33608235 S2CID 231970420 Kotsopoulos J Narod SA January 2012 Androgens and breast cancer Steroids 77 1 2 1 9 doi 10 1016 j steroids 2011 10 002 PMID 22015396 S2CID 32022318 Collaborative Group on Epidemiological Studies of Ovarian Cancer 12 February 2015 Menopausal hormone use and ovarian cancer risk individual participant meta analysis of 52 epidemiological studies The Lancet 385 9980 1835 1842 doi 10 1016 S0140 6736 14 61687 1 PMC 4427760 PMID 25684585 a b c Shi LF Wu Y Li CY April 2016 Hormone therapy and risk of ovarian cancer in postmenopausal women a systematic review and meta analysis Menopause 23 4 417 24 doi 10 1097 GME 0000000000000550 PMID 26506499 S2CID 32195397 Guidozzi F December 2013 Estrogen therapy in gynecological cancer survivors Climacteric 16 6 611 7 doi 10 3109 13697137 2013 806471 PMID 23952524 S2CID 38122562 Menopausal Hormone Therapy and Cancer Risk www cancer org Retrieved 4 March 2019 Jang YC Huang HL Leung CY 9 December 2019 Association of hormone replacement therapy with mortality in colorectal cancer survivor a systematic review and meta analysis BMC Cancer 19 1 1199 doi 10 1186 s12885 019 6428 0 PMC 6902524 PMID 31818262 Vargiu V Amar ID Rosati A Dinoi G Turco LC Capozzi VA Scambia G Villa P 25 November 2020 Hormone replacement therapy and cervical cancer a systematic review of the literature Climacteric 24 2 120 127 doi 10 1080 13697137 2020 1826426 PMID 33236658 S2CID 227166430 a b Dye RV Miller KJ Singer EJ Levine AJ 2012 Hormone replacement therapy and risk for neurodegenerative diseases International Journal of Alzheimer s Disease 2012 258454 doi 10 1155 2012 258454 PMC 3324889 PMID 22548198 Campdelacreu J November 2014 Parkinson disease and Alzheimer disease environmental risk factors Neurologia Barcelona Spain 29 9 541 9 doi 10 1016 j nrl 2012 04 001 PMID 22703631 Nicoletti A Nicoletti G Arabia G Annesi G De Mari M Lamberti P Grasso L Marconi R Epifanio A Morgante L Cozzolino A Barone P Quattrone A Zappia M December 2011 Reproductive factors and Parkinson s disease a multicenter case control study Movement Disorders 26 14 2563 6 doi 10 1002 mds 23951 PMID 21956541 S2CID 40143658 Noyce AJ Bestwick JP Silveira Moriyama L Hawkes CH Giovannoni G Lees AJ Schrag A December 2012 Meta analysis of early nonmotor features and risk factors for Parkinson disease Annals of Neurology 72 6 893 901 doi 10 1002 ana 23687 PMC 3556649 PMID 23071076 Wang P Li J Qiu S Wen H Du J 2015 Hormone replacement therapy and Parkinson s disease risk in women a meta analysis of 14 observational studies Neuropsychiatric Disease and Treatment 11 59 66 doi 10 2147 NDT S69918 PMC 4317144 PMID 25657580 Rugbjerg K Christensen J Tjonneland A Olsen JH April 2013 Exposure to estrogen and women s risk for Parkinson s disease a prospective cohort study in Denmark Parkinsonism amp Related Disorders 19 4 457 60 doi 10 1016 j parkreldis 2013 01 008 PMID 23402992 Yoon BK Chin J Kim JW Shin MH Ahn S Lee DY Seo SW Na DL August 2018 Menopausal hormone therapy and mild cognitive impairment a randomized placebo controlled trial Menopause 25 8 870 876 doi 10 1097 GME 0000000000001140 PMID 29846283 S2CID 44174553 Rasgon NL Geist CL Kenna HA Wroolie TE Williams KE Silverman DH 2014 Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia PLOS ONE 9 3 e89095 Bibcode 2014PLoSO 989095R doi 10 1371 journal pone 0089095 PMC 3951184 PMID 24622517 Schmidt R Fazekas F Reinhart B Kapeller P Fazekas G Offenbacher H Eber B Schumacher M Freidl W November 1996 Estrogen replacement therapy in older women a neuropsychological and brain MRI study Journal of the American Geriatrics Society 44 11 1307 13 doi 10 1111 j 1532 5415 1996 tb01400 x PMID 8909345 S2CID 22921797 Parkinson Study Group POETRY Investigators December 2011 A randomized pilot trial of estrogen replacement therapy in post menopausal women with Parkinson s disease Parkinsonism amp Related Disorders 17 10 757 60 doi 10 1016 j parkreldis 2011 07 007 PMID 21824799 Diamanti Kandarakis E Dattilo M Macut D Duntas L Gonos ES Goulis DG Gantenbein CK Kapetanou M Koukkou E Lambrinoudaki I Michalaki M Eftekhari Nader S Pasquali R Peppa M Tzanela M Vassilatou E Vryonidou A June 2017 Mechanisms in Endocrinology Aging and anti aging a Combo Endocrinology overview European Journal of Endocrinology 176 6 R283 R308 doi 10 1530 EJE 16 1061 PMID 28264815 Vest RS Pike CJ February 2013 Gender sex steroid hormones and Alzheimer s disease Hormones and Behavior 63 2 301 7 doi 10 1016 j yhbeh 2012 04 006 PMC 3413783 PMID 22554955 Pike CJ Carroll JC Rosario ER Barron AM July 2009 Protective actions of sex steroid hormones in Alzheimer s disease Frontiers in Neuroendocrinology 30 2 239 58 doi 10 1016 j yfrne 2009 04 015 PMC 2728624 PMID 19427328 MacLennan AH August 2011 HRT in difficult circumstances are there any absolute contraindications Climacteric 14 4 409 17 doi 10 3109 13697137 2010 543496 PMID 21355685 S2CID 25426141 a b c d e f g h i j Fugh Berman Adriane 2015 The Science of Marketing How Pharmaceutical Companies Manipulated Medical Discourse on Menopause Women s Reproductive Health 2 1 18 23 doi 10 1080 23293691 2015 1039448 ISSN 2329 3691 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans World Health Organization International Agency for Research on Cancer 2007 Combined Estrogen progestogen Contraceptives and Combined Estrogen progestogen Menopausal Therapy World Health Organization pp 205 ISBN 978 92 832 1291 1 a b c Writing Group for the Women s Health Initiative Investigators 2002 Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women s Health Initiative Randomized Controlled Trial JAMA 288 3 321 333 doi 10 1001 jama 288 3 321 PMID 12117397 Chlebowski RT Kuller LH Prentice RL Stefanick ML Manson JE Gass M et al February 2009 Breast cancer after use of estrogen plus progestin in postmenopausal women The New England Journal of Medicine 360 6 573 87 doi 10 1056 NEJMoa0807684 PMC 3963492 PMID 19196674 Kreatsoulas C Anand S S 2013 Menopausal hormone therapy for the primary prevention of chronic conditions U S Preventive Services Task Force Recommendation Statement PDF Polskie Archiwum Medycyny Wewnetrznej 123 3 112 117 PMID 23396275 Nelson H D Walker M Zakher B Mitchell J 2012 Menopausal hormone therapy for the primary prevention of chronic conditions A systematic review to update the U S Preventive Services Task Force recommendations Annals of Internal Medicine 157 2 104 113 doi 10 7326 0003 4819 157 2 201207170 00466 PMID 22786830 George James L Colman Robert W Goldhaber Samuel Z Victor J Marder 2006 Hemostasis and thrombosis basic principles and clinical practice Hagerstown MD Lippincott Williams amp Wilkins pp 1239 ISBN 978 0 7817 4996 1 Darabi M Ani M Panjehpour M Rabbani M Movahedian A Zarean E 2011 Effect of estrogen receptor b A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy Genetic Testing and Molecular Biomarkers 15 1 2 11 5 doi 10 1089 gtmb 2010 0106 PMID 21117950 Chlebowski R T Anderson G L 2015 Menopausal hormone therapy and breast cancer mortality clinical implications Therapeutic Advances in Drug Safety 6 2 45 56 doi 10 1177 2042098614568300 ISSN 2042 0986 PMC 4406918 PMID 25922653 Mazzucco AE Santoro E DeSoto M Lee JH December 2010 Hormone Therapy and Menopause National Research Center for Women and Families Gina Kolata 19 April 2007 Sharp Drop in Rates of Breast Cancer Holds New York Times Roni Caryn Rabin 28 August 2007 For a Low Dose Hormone Take Your Pick New York Times Many women seeking natural remedies have turned to compounding pharmacies which use bioidentical hormones that are chemically synthesized but with the same molecular structure as hormones produced by a woman s body John Gever 5 April 2011 New WHI Estrogen Analysis Shows Lower Breast Ca Risk MedPageToday Salpeter S R Cheng J Thabane L Buckley N S Salpeter E E 2009 Bayesian Meta analysis of Hormone Therapy and Mortality in Younger Postmenopausal Women The American Journal of Medicine 122 11 1016 1022 e1 doi 10 1016 j amjmed 2009 05 021 PMID 19854329 Anderson G L Chlebowski R T Rossouw J E Rodabough R J McTiernan A Margolis K L Aggerwal A David Curb J D Hendrix S L Allan Hubbell F A Khandekar J Lane D S Lasser N Lopez A M Potter J Ritenbaugh C 2006 Prior hormone therapy and breast cancer risk in the Women s Health Initiative randomized trial of estrogen plus progestin Maturitas 55 2 103 115 doi 10 1016 j maturitas 2006 05 004 PMID 16815651 Hulley S Grady D Bush T Furberg C Herrington D Riggs B Vittinghoff E 1998 Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women Heart and Estrogen progestin Replacement Study HERS Research Group JAMA The Journal of the American Medical Association 280 7 605 613 doi 10 1001 jama 280 7 605 PMID 9718051 Salpeter S R Walsh J M E Greyber E Ormiston T M Salpeter E E 2004 Mortality associated with hormone replacement therapy in younger and older women Journal of General Internal Medicine 19 7 791 804 doi 10 1111 j 1525 1497 2004 30281 x PMC 1492478 PMID 15209595 Grodstein F Stampfer M J Colditz G A Willett W C Manson J E Joffe M Rosner B Fuchs C Hankinson S E Hunter D J Hennekens C H Speizer F E 1997 Postmenopausal Hormone Therapy and Mortality New England Journal of Medicine 336 25 1769 1775 doi 10 1056 NEJM199706193362501 PMID 9187066 Bethea CL February 2011 MPA Medroxy Progesterone Acetate Contributes to Much Poor Advice for Women Endocrinology 152 2 343 345 doi 10 1210 en 2010 1376 PMC 3037166 PMID 21252179 Harman SM Brinton EA Cedars M Lobo R Manson JE Merriam GR Miller VM Naftolin F Santoro N March 2005 KEEPS The Kronos Early Estrogen Prevention Study Climacteric 8 1 3 12 doi 10 1080 13697130500042417 PMID 15804727 S2CID 37219662 Dominus Susan 1 February 2023 Women Have Been Misled About Menopause The New York Times ISSN 0362 4331 Retrieved 7 February 2023 No research has yet followed women who start in their 50s and stay on continuously into their 60s Morley JE Perry HM May 2003 Androgens and women at the menopause and beyond J Gerontol A Biol Sci Med Sci 58 5 M409 16 doi 10 1093 gerona 58 5 M409 PMID 12730248 Garefalakis M Hickey M 2008 Role of androgens progestins and tibolone in the treatment of menopausal symptoms a review of the clinical evidence Clin Interv Aging 3 1 1 8 doi 10 2147 CIA S1043 PMC 2544356 PMID 18488873 Formoso G Perrone E Maltoni S Balduzzi S Wilkinson J Basevi V Marata AM Magrini N D Amico R Bassi C Maestri E 12 October 2016 Short term and long term effects of tibolone in postmenopausal women The Cochrane Database of Systematic Reviews 10 10 CD008536 doi 10 1002 14651858 CD008536 pub3 ISSN 1469 493X PMC 6458045 PMID 27733017 Cummings SR Ettinger B Delmas PD Kenemans P Stathopoulos V Verweij P Mol Arts M Kloosterboer L Mosca L Christiansen C Bilezikian J Kerzberg EM Johnson S Zanchetta J Grobbee DE Seifert W Eastell R LIFT Trial Investigators 14 August 2008 The effects of tibolone in older postmenopausal women The New England Journal of Medicine 359 7 697 708 doi 10 1056 NEJMoa0800743 PMC 3684062 PMID 18703472 Estrogen Vaginal Route from Mayo Clinic Thomson Healthcare Inc Portions of this document last updated 1 November 2011 Somboonporn W Davis S Seif MW Bell R 19 October 2005 Testosterone for peri and postmenopausal women The Cochrane Database of Systematic Reviews 4 CD004509 doi 10 1002 14651858 CD004509 pub2 PMID 16235365 S2CID 21619940 North American Menopause Society 2005 The role of testosterone therapy in postmenopausal women position statement of The North American Menopause Society Menopause 12 5 496 511 quiz 649 doi 10 1097 01 gme 0000177709 65944 b0 PMID 16145303 S2CID 5122078 Drapier Faure E Azoulay C Abramovici Y July 2005 Acceptability of continuous combined versus cyclical HRT a French multicentric randomized clinical study Gynecologie obstetrique amp fertilite 33 7 8 498 504 doi 10 1016 j gyobfe 2005 04 024 PMID 16005674 Feeley KM Wells M June 2001 Hormone replacement therapy and the endometrium Journal of Clinical Pathology 54 6 435 40 doi 10 1136 jcp 54 6 435 PMC 1731456 PMID 11376015 Junkermann H von Holst T Lang E Rakov V 14 February 2005 Influence of different HRT regimens on mammographic density Maturitas 50 2 105 10 doi 10 1016 j maturitas 2004 04 008 PMID 15653007 a b Beck KL Anderson MC Kirk JK August 2017 Transdermal estrogens in the changing landscape of hormone replacement therapy Postgraduate Medicine 129 6 632 636 doi 10 1080 00325481 2017 1334507 PMID 28540770 S2CID 205452835 a b c d e f g Yoo JW Lee CH May 2006 Drug delivery systems for hormone therapy J Control Release 112 1 1 14 doi 10 1016 j jconrel 2006 01 021 PMID 16530874 a b c d Kuhl H August 2005 Pharmacology of estrogens and progestogens influence of different routes of administration Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 Martin K A Barbieri R L Crowley W F Jr 24 September 2021 Preparations for menopausal hormone therapy UpToDate Retrieved 2 February 2022 Not recommended Depot estrogen Estrogen is also available in some but not all countries as long acting three to four weeks injections of either estradiol cypionate or estradiol valerate Given the other effective estrogen options we do not use this approach table 1 Unfer V Casini ML Marelli G Costabile L Gerli S Di Renzo GC August 2005 Different routes of progesterone administration and polycystic ovary syndrome a review of the literature Gynecol Endocrinol 21 2 119 27 doi 10 1080 09513590500170049 PMID 16109599 S2CID 24890723 a b FDA Takes Action Against Compounded Menopause Hormone Therapy Drugs FDA 9 January 2008 Retrieved 17 February 2009 Panay N Medical Advisory Council of the British Menopause Society June 2019 BMS Consensus statement Bioidentical HRT Post Reproductive Health 25 2 61 63 doi 10 1177 2053369119841844 PMID 31192760 S2CID 189816648 Cirigliano M June 2007 Bioidentical hormone therapy a review of the evidence Journal of Women s Health 16 5 600 31 doi 10 1089 jwh 2006 0311 PMID 17627398 Simon JA July 2014 What if the Women s Health Initiative had used transdermal estradiol and oral progesterone instead Menopause 21 7 769 83 doi 10 1097 GME 0000000000000169 PMID 24398406 S2CID 30292136 a b Pinkerton JV Pickar JH February 2016 Update on medical and regulatory issues pertaining to compounded and FDA approved drugs including hormone therapy Menopause 23 2 215 23 doi 10 1097 GME 0000000000000523 PMC 4927324 PMID 26418479 a b c d Singer Natasha 4 August 2009 Medical Papers by Ghostwriters Pushed Therapy The New York Times Retrieved 13 July 2018 a b c d e f Fugh Berman AJ September 2010 The haunting of medical journals how ghostwriting sold HRT PLOS Med 7 9 e1000335 doi 10 1371 journal pmed 1000335 PMC 2935455 PMID 20838656 a b c d e f g Steve Kent May Steve May 20 January 2012 Case Studies in Organizational Communication Ethical Perspectives and Practices Ethical Perspectives and Practices SAGE pp 197 ISBN 978 1 4129 8309 9 a b Miller VM Harman SM November 2017 An update on hormone therapy in postmenopausal women mini review for the basic scientist Am J Physiol Heart Circ Physiol 313 5 H1013 H1021 doi 10 1152 ajpheart 00383 2017 PMC 5792205 PMID 28801526 Sorkin Andrew Ross Wilson Duff 25 January 2009 Pfizer Agrees to Pay 68 Billion for Rival Drug Maker Wyeth The New York Times Pfizer Sizes Up Closes 68B Wyeth Deal CNBC 19 October 2009 Tao M Teng Y Shao H Wu P Mills EJ 2011 Knowledge perceptions and information about hormone therapy HT among menopausal women a systematic review and meta synthesis PLOS ONE 6 9 e24661 Bibcode 2011PLoSO 624661T doi 10 1371 journal pone 0024661 PMC 3174976 PMID 21949743 Hormone therapy for brain performance No effect whether started early or late www sciencedaily com Davies M Hamoda H British Menopause Society Medical Advisory Council 11 February 2019 Hormone replacement therapy changes in prescribing practice BMJ Clinical Research Ed 364 l633 doi 10 1136 bmj l633 PMID 30745316 S2CID 73435897 External links editMenopause treatment Hormone Health Network The Endocrine Society Sexual Health and Menopause Online The North American Menopause Society Menopause US Food and Drug Administration British Menopause Society Retrieved from https en wikipedia org w index php title Hormone replacement therapy amp oldid 1193557883, wikipedia, wiki, book, books, library,

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