Hormone replacement therapy
Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of
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
Medical uses
Approved uses of HRT in the United States include short-term treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and prevention of osteoporosis.
A consensus expert opinion published by
Women receiving this treatment are usually
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
HRT is often given as a short-term relief from menopausal symptoms during
- Hot flashes – vasomotor symptoms
- dryness
- Dyspareunia – painful sexual intercourse due to vaginal atrophy and lack of lubrication
- bone mineral density, which can eventually lead to osteopenia, osteoporosis, and associated fractures
- Decreased sexual desire
- Sleep disturbances and joint pain
The most common of these are
Sexual function
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
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.
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
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
Common
- Headache
- 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 lenses
Uncommon
- 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]
Health effects
Heart disease
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.
A
HRT with estrogen and progesterone also improves
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.[44][45] 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 associated with increased body mass index and risk for type 2 diabetes.[46]
Blood clots
Effects of hormone replacement therapy on
While a 2018 review found that taking progesterone and estrogen together can decrease this risk,[47] 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][48]
The risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary.[50]
Stroke
Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause,
Endometrial cancer
In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.[52] The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease.[53]
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.[54] The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen.[54] 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.[55]
Paradoxically, progestogens do promote the growth of
Androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent.[56]
There is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.[57]
Breast cancer
In general, hormone replacement therapy to treat menopause is associated with only a small increased risk of breast cancer.[58][59][60] 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.[59][60]
There is a
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 medroxyprogesterone.[65] 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.[66][67]
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.[68] 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.[69]
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.[70]
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.[71]
For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as
With androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association.[75]
Ovarian cancer
HRT is associated with an increased risk of
Other cancers
Colorectal cancer
In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting
Cervical cancer
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.[81]
Neurodegenerative disorders
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.[82][83] With Parkinson's the majority of clinical and epidemiological studies show have demonstrated either no association[84][85] or inconclusive results.[82][86] A Danish study suggested an increased risk of Parkinson's with HRT in cyclical dosing schedules.[87]
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.[88][89][90] 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.[91] Clinical trials have also shown testosterone replacement to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women.[92] 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.[93][94]
Contraindications
The following are absolute and relative contraindications to HRT:[95]
Absolute contraindications
- Undiagnosed vaginal bleeding
- Severe liver disease
- Pregnancy
- Severe coronary artery disease
- Aggressive breast, uterine or ovarian cancer
Relative contraindications
- Migraine headaches
- History of breast cancer
- History of ovarian cancer
- Venous thrombosis
- History of uterine fibroids
- Atypical ductal hyperplasia of the breast
- Active cholangitis, cholecystitis)
- Well-differentiated and early endometrial cancer – once treatment for the malignancy is complete, is no longer an absolute contraindication.
History and research
The extraction of CEEs from the urine of pregnant
Trials
The Women's Health Initiative trials were conducted between 1991 and 2006 and were the first large,
The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its
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,
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.[98]
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.[102] 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.[103][104]
The WHI reported
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.[106] 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.[107]
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.[108]
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.[109][110][111][112][17][113]
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.[114][115][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.[116]
Available forms
There are five major human steroid hormones: estrogens, progestogens,
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]
- synthetic estrogens like ethinylestradiol
- 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[117][118]
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.[119][120]
Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes.[121] Sometimes an androgen, generally testosterone, can be added to treat diminished libido.[122][123]
Continuous versus cyclic
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.[124] Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic.[125] Impact on breast density appears to be similar in both regimen timings.[126]
Route of administration
The medications used in menopausal HRT are available in numerous different
- Oral administration – tablets, capsules
- gels, creams
- Vaginal administration – tablets, creams, suppositories, rings
- Subcutaneous implant – surgically-inserted pellets placed into fat tissue
- Less commonly intranasal, and rectal administration, as well as intrauterine devices
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.
Injectable forms of estradiol exist and have been used occasionally in the past.[128][129] However, they are rarely used in menopausal hormone therapy in modern times and are no longer recommended.[128][130] Instead, other non-oral forms of estradiol such as transdermal estradiol are recommended and may be used.[128] Estradiol injectables are generally well-tolerated and convenient, requiring infrequent administration.[128][129] 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.[128] Injections may also be painful.[128] Examples of estradiol injectables that may be used in menopausal hormone therapy include estradiol valerate and estradiol cypionate.[128][129] 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.[131][129]
Bioidentical hormone therapy
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.[133] 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.[134]
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
Compounding
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.
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
Wyeth controversy
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.
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.[140] 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.[140] 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."[96] Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors.[96] These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS.[96] In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion.[141][142] 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.[96][139]
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."[138] As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS in a 2011 survey.[143] 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, according to May and May (2012) and Fugh-Berman (2015).[139][96]
Popularity
The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again.[127][144] 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.[145]
See also
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External links
- 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