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Hormone replacement therapy

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This article is about hormone replacement therapy in menopause. For other forms, see Hormone therapy.

Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT) or postmenopausal hormone therapy (PHT, PMHT), is a form of hormone therapy used to treat symptoms associated with female menopause.[1][2] These symptoms can include hot flashes, vaginal atrophy, accelerated skin aging, vaginal dryness, decreased muscle mass, sexual dysfunction, and bone loss. They are in large part related to the diminished levels of sex hormones that occur during menopause.[1][2]

The main hormonal medications used in HRT for menopausal symptoms are estrogens and progestogens, among which progesterone is the major naturally-occurring female sex hormone and also a manufactured medication used in menopausal hormone therapy.[1] Though both can have symptomatic benefits, progestogen is specifically added to estrogen regimens when the uterus is still present. Unopposed estrogen therapy promotes endometrial thickening and can increase 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 results of the Women's Health Initiative (WHI) suggest both potential risks and benefits across different organ systems. Long-term follow up of the WHI participants, however, has found no difference in all-cause, cardiovascular, or cancer mortality with HRT.[6] Later studies suggested that risk can differ depending on route of administration.[7] "Bioidentical" hormone replacement – a development in the 21st century using manufactured compounds having "exactly the same chemical and molecular structure as hormones that are produced in the human body",[8] and are based mainly on steroids from plants[9] – has inadequate clinical research to determine its efficacy and safety, as of 2017.[10]

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.[11]

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.[11] The American College of Obstetrics and Gynecology (ACOG) approves of HRT for symptomatic relief of menopausal symptoms,[12] and advocates its use beyond the age of 65 in appropriate scenarios.[13] 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.[14]

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.[15] The American Association of Clinical Endocrinologists (AACE) has also released position statements approving of HRT in appropriate scenarios.[10]

Women receiving this treatment are usually post-, peri-, or surgically 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.

The Women's Health Initiative (WHI) was a study of over 27,000 women beginning in 1991. Successive analyses have found sometimes contradictory results, with the most recent publication in 2017 finding no difference for all cause mortality with HRT.[6] The effects of HRT on most organ systems vary by age and time since the last physiological exposure to hormones, and there can be differences in individual regimens, factors which have made analyzing effects difficult.[6] Demographically, the vast majority of data available is in postmenopausal American women with concurrent pre-existing conditions, and with a mean age of over 60 years.[16]

Menopausal symptoms

Mean number of moderate-to-severe hot flashes per week with placebo and different doses of oral estradiol in a randomized controlled trial of 333 menopausal women.[17][18]

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]

Heart disease

The risks of coronary heart disease with HRT vary depending on age and time since menopause.

The effect of HRT in menopause appears to be divergent, with lower risk when started within five years, but no impact after ten.[23][24][25] There may be an increase in heart disease if HRT is given twenty years post-menopause.[26] There is, however, no actual difference in long-term mortality from HRT, regardless of age.[6]

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.[23] 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.[23]

HRT 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.[27]

Blood clots

Clot in the greater saphenous vein; oral estrogen is associated with increased risk of venous blood clots due to increased liver formation of vitamin K-dependent clotting factors.

Effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism may vary with different estrogen and progestogen therapies, and with different doses or method of use.[16] Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots,[16][28] whereas when used orally, the risk of blood clots and pulmonary embolism is increased.[23] 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.[29] While a 2018 review found that taking progesterone and estrogen together can decrease this risk,[28] 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.[16][23]

Risk of venous thromboembolism (VTE) with hormone therapy and birth control (QResearch/CPRD)
Type Route Medications Odds ratio (95% CITooltip confidence interval)
Menopausal hormone therapy Oral Estradiol alone
    ≤1 mg/day
    >1 mg/day		 1.27 (1.16–1.39)*
1.22 (1.09–1.37)*
1.35 (1.18–1.55)*
Conjugated estrogens alone
    ≤0.625 mg/day
    >0.625 mg/day		 1.49 (1.39–1.60)*
1.40 (1.28–1.53)*
1.71 (1.51–1.93)*
Estradiol/medroxyprogesterone acetate 1.44 (1.09–1.89)*
Estradiol/dydrogesterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.18 (0.98–1.42)
1.12 (0.90–1.40)
1.34 (0.94–1.90)
Estradiol/norethisterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.68 (1.57–1.80)*
1.38 (1.23–1.56)*
1.84 (1.69–2.00)*
Estradiol/norgestrel or estradiol/drospirenone 1.42 (1.00–2.03)
Conjugated estrogens/medroxyprogesterone acetate 2.10 (1.92–2.31)*
Conjugated estrogens/norgestrel
    ≤0.625 mg/day CEEs
    >0.625 mg/day CEEs		 1.73 (1.57–1.91)*
1.53 (1.36–1.72)*
2.38 (1.99–2.85)*
Tibolone alone 1.02 (0.90–1.15)
Raloxifene alone 1.49 (1.24–1.79)*
Transdermal Estradiol alone
   ≤50 μg/day
   >50 μg/day		 0.96 (0.88–1.04)
0.94 (0.85–1.03)
1.05 (0.88–1.24)
Estradiol/progestogen 0.88 (0.73–1.01)
Vaginal Estradiol alone 0.84 (0.73–0.97)
Conjugated estrogens alone 1.04 (0.76–1.43)
Combined birth control Oral Ethinylestradiol/norethisterone 2.56 (2.15–3.06)*
Ethinylestradiol/levonorgestrel 2.38 (2.18–2.59)*
Ethinylestradiol/norgestimate 2.53 (2.17–2.96)*
Ethinylestradiol/desogestrel 4.28 (3.66–5.01)*
Ethinylestradiol/gestodene 3.64 (3.00–4.43)*
Ethinylestradiol/drospirenone 4.12 (3.43–4.96)*
Ethinylestradiol/cyproterone acetate 4.27 (3.57–5.11)*
Notes: (1) Nested case–control studies (2015, 2019) based on data from the QResearch and Clinical Practice Research Datalink (CPRD) databases. (2) Bioidentical progesterone was not included, but is known to be associated with no additional risk relative to estrogen alone. Footnotes: * = Statistically significant (p < 0.01). Sources: See template.

Stroke

Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause,[30] and that the association is absent or even preventive when given by non-oral routes.[7] Ischemic stroke risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy[26] and no difference in mortality at long term follow up.[6] When oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until 5 years from menopause, cohort studies in Swedish women have suggested an association with hemorrhagic and ischemic stroke.[30] 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.[7]

Endometrial cancer

Endometrial cancer can be associated with HRT, particularly in those not taking a progestogen.

In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.[31] The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease.[32]

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 prognosis.[33] The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen.[33] 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.[34]

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.[33]

Research suggests there is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.[35]

Breast cancer

Studies regarding the association of breast cancer with hormone replacement have been mixed and vary with the type of replacement used; some evaluations suggest an increased risk, though in others it is decreased.[36]

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,[37] 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 to date.[36] The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of administration.[38]

The WHI also found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer, though estrogen is usually only given alone in the setting of a hysterectomy due to the effect of unopposed estrogen on the uterus.[39][40]

HRT has been more strongly associated with risk of breast cancer in women with a lower range body mass indices (BMIs). No breast cancer association has been found with BMIs of over 25.[41] 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.[42]

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.[43]

Worldwide epidemiological evidence on breast cancer risk with menopausal hormone therapy (CGHFBC, 2019)
Therapy <5 years 5–14 years 15+ years
Cases RRTooltip Adjusted relative risk (95% CITooltip confidence interval) Cases RRTooltip Adjusted relative risk (95% CITooltip confidence interval) Cases RRTooltip Adjusted relative risk (95% CITooltip confidence interval)
Estrogen alone 1259 1.18 (1.10–1.26) 4869 1.33 (1.28–1.37) 2183 1.58 (1.51–1.67)
    By estrogen
        Conjugated estrogens 481 1.22 (1.09–1.35) 1910 1.32 (1.25–1.39) 1179 1.68 (1.57–1.80)
        Estradiol 346 1.20 (1.05–1.36) 1580 1.38 (1.30–1.46) 435 1.78 (1.58–1.99)
        Estropipate (estrone sulfate) 9 1.45 (0.67–3.15) 50 1.09 (0.79–1.51) 28 1.53 (1.01–2.33)
        Estriol 15 1.21 (0.68–2.14) 44 1.24 (0.89–1.73) 9 1.41 (0.67–2.93)
        Other estrogens 15 0.98 (0.46–2.09) 21 0.98 (0.58–1.66) 5 0.77 (0.27–2.21)
    By route
        Oral estrogens – – 3633 1.33 (1.27–1.38) – –
        Transdermal estrogens – – 919 1.35 (1.25–1.46) – –
        Vaginal estrogens – – 437 1.09 (0.97–1.23) – –
Estrogen and progestogen 2419 1.58 (1.51–1.67) 8319 2.08 (2.02–2.15) 1424 2.51 (2.34–2.68)
    By progestogen
        (Levo)norgestrel 343 1.70 (1.49–1.94) 1735 2.12 (1.99–2.25) 219 2.69 (2.27–3.18)
        Norethisterone acetate 650 1.61 (1.46–1.77) 2642 2.20 (2.09–2.32) 420 2.97 (2.60–3.39)
        Medroxyprogesterone acetate 714 1.64 (1.50–1.79) 2012 2.07 (1.96–2.19) 411 2.71 (2.39–3.07)
        Dydrogesterone 65 1.21 (0.90–1.61) 162 1.41 (1.17–1.71) 26 2.23 (1.32–3.76)
        Progesterone 11 0.91 (0.47–1.78) 38 2.05 (1.38–3.06) 1 –
        Promegestone 12 1.68 (0.85–3.31) 19 2.06 (1.19–3.56) 0 –
        Nomegestrol acetate 8 1.60 (0.70–3.64) 14 1.38 (0.75–2.53) 0 –
        Other progestogens 12 1.70 (0.86–3.38) 19 1.79 (1.05–3.05) 0 –
    By progestogen frequency
        Continuous – – 3948 2.30 (2.21–2.40) – –
        Intermittent – – 3467 1.93 (1.84–2.01) – –
Progestogen alone 98 1.37 (1.08–1.74) 107 1.39 (1.11–1.75) 30 2.10 (1.35–3.27)
    By progestogen
        Medroxyprogesterone acetate 28 1.68 (1.06–2.66) 18 1.16 (0.68–1.98) 7 3.42 (1.26–9.30)
        Norethisterone acetate 13 1.58 (0.77–3.24) 24 1.55 (0.88–2.74) 6 3.33 (0.81–13.8)
        Dydrogesterone 3 2.30 (0.49–10.9) 11 3.31 (1.39–7.84) 0 –
        Other progestogens 8 2.83 (1.04–7.68) 5 1.47 (0.47–4.56) 1 –
Miscellaneous
    Tibolone – – 680 1.57 (1.43–1.72) – –
Notes: Meta-analysis of worldwide epidemiological evidence on menopausal hormone therapy and breast cancer risk by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC). Fully adjusted relative risks for current versus never-users of menopausal hormone therapy. Source: See template.
Risk of breast cancer with menopausal hormone therapy in large observational studies (Mirkin, 2018)
Study Therapy Hazard ratio (95% CITooltip confidence interval)
E3N-EPIC: Fournier et al. (2005) Estrogen alone 1.1 (0.8–1.6)
Estrogen plus progesterone
    Transdermal estrogen
    Oral estrogen		 0.9 (0.7–1.2)
0.9 (0.7–1.2)
No events
Estrogen plus progestin
    Transdermal estrogen
    Oral estrogen		 1.4 (1.2–1.7)
1.4 (1.2–1.7)
1.5 (1.1–1.9)
E3N-EPIC: Fournier et al. (2008) Oral estrogen alone 1.32 (0.76–2.29)
Oral estrogen plus progestogen
    Progesterone
    Dydrogesterone
    Medrogestone
    Chlormadinone acetate
    Cyproterone acetate
    Promegestone
    Nomegestrol acetate
    Norethisterone acetate
    Medroxyprogesterone acetate
Not analyzeda
0.77 (0.36–1.62)
2.74 (1.42–5.29)
2.02 (1.00–4.06)
2.57 (1.81–3.65)
1.62 (0.94–2.82)
1.10 (0.55–2.21)
2.11 (1.56–2.86)
1.48 (1.02–2.16)
Transdermal estrogen alone 1.28 (0.98–1.69)
Transdermal estrogen plus progestogen
    Progesterone
    Dydrogesterone
    Medrogestone
    Chlormadinone acetate
    Cyproterone acetate
    Promegestone
    Nomegestrol acetate
    Norethisterone acetate
    Medroxyprogesterone acetate
1.08 (0.89–1.31)
1.18 (0.95–1.48)
2.03 (1.39–2.97)
1.48 (1.05–2.09)
Not analyzeda
1.52 (1.19–1.96)
1.60 (1.28–2.01)
Not analyzeda
Not analyzeda
E3N-EPIC: Fournier et al. (2014) Estrogen alone 1.17 (0.99–1.38)
Estrogen plus progesterone or dydrogesterone 1.22 (1.11–1.35)
Estrogen plus progestin 1.87 (1.71–2.04)
CECILE: Cordina-Duverger et al. (2013) Estrogen alone 1.19 (0.69–2.04)
Estrogen plus progestogen
    Progesterone
    Progestins
        Progesterone derivatives
        Testosterone derivatives		 1.33 (0.92–1.92)
0.80 (0.44–1.43)
1.72 (1.11–2.65)
1.57 (0.99–2.49)
3.35 (1.07–10.4)
Footnotes: a = Not analyzed, fewer than 5 cases. Sources: See template.
Risk of breast cancer with menopausal hormone therapy by duration in large observational studies (Mirkin, 2018)
Study Therapy Hazard ratio (95% CITooltip confidence interval)
E3N-EPIC: Fournier et al. (2005)a Transdermal estrogen plus progesterone
    <2 years
    2–4 years
    ≥4 years
0.9 (0.6–1.4)
0.7 (0.4–1.2)
1.2 (0.7–2.0)
Transdermal estrogen plus progestin
    <2 years
    2–4 years
    ≥4 years
1.6 (1.3–2.0)
1.4 (1.0–1.8)
1.2 (0.8–1.7)
Oral estrogen plus progestin
    <2 years
    2–4 years
    ≥4 years
1.2 (0.9–1.8)
1.6 (1.1–2.3)
1.9 (1.2–3.2)
E3N-EPIC: Fournier et al. (2008) Estrogen plus progesterone
    <2 years
    2–4 years
    4–6 years
    ≥6 years
0.71 (0.44–1.14)
0.95 (0.67–1.36)
1.26 (0.87–1.82)
1.22 (0.89–1.67)
Estrogen plus dydrogesterone
    <2 years
    2–4 years
    4–6 years
    ≥6 years
0.84 (0.51–1.38)
1.16 (0.79–1.71)
1.28 (0.83–1.99)
1.32 (0.93–1.86)
Estrogen plus other progestogens
    <2 years
    2–4 years
    4–6 years
    ≥6 years
1.36 (1.07–1.72)
1.59 (1.30–1.94)
1.79 (1.44–2.23)
1.95 (1.62–2.35)
E3N-EPIC: Fournier et al. (2014) Estrogens plus progesterone or dydrogesterone
    <5 years
    ≥5 years
1.13 (0.99–1.29)
1.31 (1.15–1.48)
Estrogen plus other progestogens
    <5 years
    ≥5 years
1.70 (1.50–1.91)
2.02 (1.81–2.26)
Footnotes: a = Oral estrogen plus progesterone was not analyzed because there was a low number of women who used this therapy. Sources: See template.

Colorectal cancer

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.[44]

Ovarian cancer

A 2015 meta-analysis found that HRT was associated with an increased risk of ovarian cancer, with women using HRT having about one additional case of ovarian cancer per 1,000 users.[45] This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT.[46] Regarding the specific subtype, there may be a higher risk of serous cancer, but no association with clear cell, endometrioid, or mucinous ovarian cancer.[46]

Sexual function

See also: Testosterone (medication) § Women

HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40–69 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.[47] A major complaint among postmenopausal women is decreased libido and sexual function, and many may seek medical consultation.[5][48] 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] Decrease in sex hormone-binding globulin (SHBG) and inhibin (A and B) also occurs. Testosterone, a hormone more commonly associated with males, is also present in women at a lower level. It peaks at age 30, but declines gradually with age, so there is little variation across the lifetime and during the menopausal transition.[4] With surgical menopause, testosterone declines more sharply and can result in more severe symptoms.[4] HRT can help with sexual difficulties related to pain and lubrication.[5]

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] Reduced vaginal atrophy and increased sexual arousal, frequency and orgasm have also been noted.[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] Findings on a relatively new form of HRT called tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties, suggest that it has the ability to improve mood, libido, and physical symptoms of surgically menopausal women to a greater degree than ERT. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been observed.[5] Tibolone has been used in Europe for almost two decades but is not available North America at this point.[5]

Neurodegenerative disorders

HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50–55 years.[26] HRT can also improve executive and attention processes outside of the context of dementia in postmenopausal women.[49]

Muscle and bone

There is a decrease in hip fractures, which persists after the treatment is stopped, though to a lesser degree.[26][50]

Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle.[51]

Side effects

Some common and uncommon side effects include:[52]

Common

Uncommon

Contraindications

The following are absolute and relative contraindications to HRT:[54]

Absolute contraindications

Relative contraindications

History and research

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.[55][56] 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 8-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet.[55] It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium.[55] This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera).[55]

Trials

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.[55] 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 also is an increased risk of dementia with HRT in women over 65, though when given earlier it appears to be neuroprotective. After the cessation of HRT, the WHI continued observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist.[26] Other studies have also suggested an increased risk of ovarian cancer.[46]

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.[57]

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.[57] 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.[58] 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.[59][60]

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.[57]

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.[61] 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.[62][63]

Neither the WHI nor the MWS differentiated the results for different types of progestogens used. MPA – the type most commonly used in the United States – was the only one examined by the WHI, which in its analysis and conclusions extrapolated the benefits versus risks of MPA to all progestins. This conclusion has since been challenged by several researchers as unjustified and misleading, resulting in unreasonable, unnecessary avoidance by many women of HRT. In addition, subsequent findings released by the WHI showed that all cause mortality was not dramatically different between the groups receiving CEEs, those receiving estrogen and a progestogen, and those not on therapy.[64] In addition, the WHI trial was limited by low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens.[60] The double blinding limited validity of study results due to its effects on patient exclusion criteria. Patients who were experiencing symptoms of the menopausal transition were excluded from the study, meaning that younger women who had only recently experienced menopause were not significantly represented. As a result, while the average age of menopause is age 51, study participants were on average 62 years of age. Demographically, the vast majority were Caucasian, and tended to be slightly overweight and former smokers.

Results of the Women's Health Initiative (WHI) menopausal hormone therapy randomized controlled trials
Clinical outcome Hypothesized
effect on risk 		Estrogen and progestogen
(CEsTooltip conjugated estrogens 0.625 mg/day p.o. + MPATooltip medroxyprogesterone acetate 2.5 mg/day p.o.)
(n = 16,608, with uterus, 5.2–5.6 years follow up) 		Estrogen alone
(CEsTooltip Conjugated estrogens 0.625 mg/day p.o.)
(n = 10,739, no uterus, 6.8–7.1 years follow up)
HRTooltip Hazard ratio 95% CITooltip Confidence interval ARTooltip Attributable risk HRTooltip Hazard ratio 95% CITooltip Confidence interval ARTooltip Attributable risk
Coronary heart disease Decreased 1.24 1.00–1.54 +6 / 10,000 PYs 0.95 0.79–1.15 −3 / 10,000 PYs
Stroke Decreased 1.31 1.02–1.68 +8 / 10,000 PYs 1.37 1.09–1.73 +12 / 10,000 PYs
Pulmonary embolism Increased 2.13 1.45–3.11 +10 / 10,000 PYs 1.37 0.90–2.07 +4 / 10,000 PYs
Venous thromboembolism Increased 2.06 1.57–2.70 +18 / 10,000 PYs 1.32 0.99–1.75 +8 / 10,000 PYs
Breast cancer Increased 1.24 1.02–1.50 +8 / 10,000 PYs 0.80 0.62–1.04 −6 / 10,000 PYs
Colorectal cancer Decreased 0.56 0.38–0.81 −7 / 10,000 PYs 1.08 0.75–1.55 +1 / 10,000 PYs
Endometrial cancer – 0.81 0.48–1.36 −1 / 10,000 PYs – – –
Hip fractures Decreased 0.67 0.47–0.96 −5 / 10,000 PYs 0.65 0.45–0.94 −7 / 10,000 PYs
Total fractures Decreased 0.76 0.69–0.83 −47 / 10,000 PYs 0.71 0.64–0.80 −53 / 10,000 PYs
Total mortality Decreased 0.98 0.82–1.18 −1 / 10,000 PYs 1.04 0.91–1.12 +3 / 10,000 PYs
Global index – 1.15 1.03–1.28 +19 / 10,000 PYs 1.01 1.09–1.12 +2 / 10,000 PYs
Diabetes – 0.79 0.67–0.93 0.88 0.77–1.01
Gallbladder disease Increased 1.59 1.28–1.97 1.67 1.35–2.06
Stress incontinence – 1.87 1.61–2.18 2.15 1.77–2.82
Urge incontinence – 1.15 0.99–1.34 1.32 1.10–1.58
Peripheral artery disease – 0.89 0.63–1.25 1.32 0.99–1.77
Probable dementia Decreased 2.05 1.21–3.48 1.49 0.83–2.66
Abbreviations: CEs = conjugated estrogens. MPA = medroxyprogesterone acetate. p.o. = per oral. HR = hazard ratio. AR = attributable risk. PYs = person–years. CI = confidence interval. Notes: Sample sizes (n) include placebo recipients, which were about half of patients. "Global index" is defined for each woman as the time to earliest diagnosis for coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen plus progestogen group only), hip fractures, and death from other causes. Sources: See template.

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."[65] 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.[66] 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.[67]

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.[68]

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.[69][70][71][72][15][73]

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.[74][75][76]

Available forms

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.[8]

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]

A 2016 review of clinical research on tibolone – a synthetic medication – found it was more effective than placebo and less effective than combination hormone therapy in postmenopausal women, although it may cause bleeding, increase the risk of recurrent breast cancer in women with a history of breast cancer, and increase the risk of stroke in women over age 60 years.[79]

Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes.[80] Sometimes an androgen, generally testosterone, can be added to treat diminished libido.[81][82]

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.

Estrogen dosages for menopausal hormone therapy
Route/form Estrogen Low Standard High
Oral Estradiol 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol valerate 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day 0.9–1.8 mg/day 1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Estropipate 0.75 mg/day 1.5 mg/day 3 mg/day
Estriol 1–2 mg/day 2–4 mg/day 4–8 mg/day
Ethinylestradiola 2.5–10 μg/day 5–20 μg/day –
Nasal spray Estradiol 150 μg/day 300 μg/day 600 μg/day
Transdermal patch Estradiol 25 μg/dayb 50 μg/dayb 100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day 1–1.5 mg/day 2–3 mg/day
Vaginal Estradiol 25 μg/day – –
Estriol 30 μg/day 0.5 mg 2x/week 0.5 mg/day
IMTooltip Intramuscular or SC injection Estradiol valerate – – 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks 3 mg 1x/3–4 weeks 5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week 1 mg 1x/week 1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months 50 mg 1x/6 months 100 mg 1x/6 months
Footnotes: a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.

Route of administration

An intrauterine device is one potential route of administration for 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 transvaginal 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.[83]

Bioidentical hormone therapy

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.[84][85] There are, however, FDA approved products containing hormones classified as 'bioidentical'.[10][8]

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.[84] 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'.[8]

Bioidentical hormones in pharmaceuticals may have health benefits over their animal derived counterparts, including a potentially decreased risk of venous thromboembolism, cardiovascular disease, and breast cancer.[84] 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.[84][86]

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.[84][85] 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.[87]

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. Bio-identical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour."

Society and public perception

Wyeth controversy

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).[88][89] In 2009, litigation involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications.[88][89][90] The documents showed that Wyeth commissioned dozens of ghostwritten reviews and commentaries that were published in medical journals in order to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light.[88][89][90] 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.[90] It worked mainly with DesignWrite, a medical writing firm.[90] Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals.[88]

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.[90] 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.[89] 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."[89]

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.[91] 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.[91] 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."[55] Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors.[55] These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS.[55] In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion.[92][93] 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.[55][90]

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."[89] As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS.[94] 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.[90][55]

Popularity

The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again.[83][95]

Notes

References

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