Hormone replacement therapy (menopause)

# Overview
Hormone replacement therapy (HRT) is a system of medical treatment for surgically menopausal, perimenopausal and postmenopausal women, based on the assumption that it may prevent discomfort and health problems caused by diminished circulating estrogen and progesterone hormones. The treatment involves a series of drugs designed to artificially boost hormone levels. The main types of hormones involved are estrogens, progesterone or progestins, and sometimes testosterone.
HRT is available in various forms. It generally provides low dosages of one or more estrogens, and often also provides either progesterone or a chemical analogue, called a progestin. Testosterone may also be included. In women who have had a hysterectomy, an estrogen compound is usually given without any progesterone, a therapy referred to as "unopposed estrogen therapy". HRT may be delivered to the body via patches, tablets, creams, troches, IUDs, vaginal rings, gels or, more rarely, by injection. Dosage is often varied cyclically, with estrogens taken daily and progesterone or progestins taken for about two weeks every month or two; a method called "sequentially combined HRT" or scHRT. An alternate method, a constant dosage with both types of hormones taken daily, is called "continuous combined HRT" or ccHRT, and is a more recent innovation. Sometimes an androgen, generally testosterone, is added to treat reduced sexual desire/(libido). It may also treat reduced energy and help reduce osteoporosis after menopause.
HRT is seen as either a short-term relief (often one or two years, usually less than five) from menopausal symptoms (hot flashes, irregular menstruation, fat redistribution etc.) or as a longer term treatment to reduce the risk of osteopenia leading to osteoporosis. Younger women with premature ovarian failure or surgical menopause may use hormone replacement therapy for many years, until the age that natural menopause would be expected to occur.

# Types of Hormone Replacement Therapy
Historically the most commonly prescribed forms of HRT has been proprietary mixtures of conjugated equine estrogens (CEE) as well as progestins that, while not progesterone, approximate its effects. With the passage of time, an increasing number of studies have shown that certain risks are associated with these combinations of progestins and equine estrogens. Because these have been used most commonly and for the longest time, there are many more studies of these forms of hormones than of some of the newer forms with newer delivery systems, and therefore the most is known about these kinds. Whether or not such risks exist with other forms of estrogens and progestins, and other delivery systems, remain to be seen.
Bioidentical forms of human estrogen and progesterone have been very little studied. This distinction is important, because the adverse biological effects of xenoestrogens and progestins revealed by studies of Premarin and PremPro do not necessarily generalize to supplementation with human forms of estrogen and progesterone. For example, a pilot study reported in JAMA by Smith, Heckbert, et al. found clinical evidence that oral conjugated equine estrogens caused clotting, but the other estrogen compound tested in the same study, bioidentical esterified estrogens, does not. Conjugatged equine estrogens were found to be associated with increased venous thrombotic risk. In sharp contrast, the study found that users of esterified estrogen had no increase in venous thrombotic risk.
Additionally, the route of administration may be as important as the type of estrogen administered. For example, in a large study published in the Lancet Scarabin et al. compared effects of oral vs. transdermal (skin patch) estrogen (mainly estradiol-17 beta, the "bioidentical" human estrogen) and found that the oral route was associated with a 3-fold increase in risk of venous clotting disease (thrombophlebitis, pulmonary embolus), whereas the skin patch produced no excess risk. This difference was likely due to the fact that transdermal estrogens are absorbed directly into the bloodstream, while oral estrogens are processed and changed by the liver before release into the blood stream.
Studies finding adverse health effects of equine estrogens and progestins have often been reported, inaccurately, as revealing effects of "estrogen" and "progesterone."  It is important to keep this habitual inaccurate generalization in mind in reviewing press reports. On the other hand, creams, gels, etc. containing "biodentical" hormones custom-prepared by compounding pharmacies are not subject to FDA monitoring or regulation, so that doses delivered and hormone blood levels produced are unpredictable and may be highly variable, and there are fewer large scale studies of these items.
It has become increasingly clear that oral progestin and equine estrogen pills can increase a number of risks, including the risks of exacerbation of existing liver or gallbladder problems and of dangerous blood clots. Long term use of equine estrogens probably also increases the risk of breast cancer. In women with a uterus, therapy with equine estrogen, unopposed by progesterone, is generally acknowledged to increase the risk of uterine cancers in women with intact uterine linings. This proprietary combination can also affect blood triglyceride levels and increase the risk of adverse cardiovascular events. Although HRT with progestins and equine estrogens was once widely thought to promote cardiovascular health in women, on February 4, 2004, the American Heart Association released guidelines stating that it should no longer be considered as an agent to increase heart health or to decrease the chances of cardiovascular disease.
In 2006, results from the large, ongoing, observational Harvard Nurses' study showed that those taking a pill containing a combination of estrogen with methyltestosterone (a synthetic testosterone analogue) had higher risk of breast cancer than those not taking the methyltestosterone. Unfortunately, few or no studies have tested the safety or benefits of human bioidentical testosterone, or of low-dose non-pill administration of testosterone that avoids the first pass through the liver.
Due to the risks and potential problems of progestins and equine estrogens, a number of alternative therapies have been developed, including lifestyle changes, non-hormone drug therapy, and bioidentical hormone replacement therapy. To reduce the risk of osteoporosis without hormones, dietary changes that increase calcium uptake, exercise, and drugs such as biphosphates, selective estrogen receptor modulators, or calcitonin have been tried.

# Bioidentical hormone replacement therapy
Recently, interest in "bioidentical" hormone replacement therapy (BHRT) has risen. This term is used to refer to HRT formulated to contain the three main naturally occurring human estrogens estradiol, estrone, and estriol, as well as to refer to bioidentical human progesterone and sometimes testosterone. As recently as 2004, before the release of the Women's Health Initiative (WHI) studies referenced below, the relative benefits of bioidentical hormones over xenoestrogens and progestins were regarded as not yet established. BHRT is often delivered via topical administration of a cream or gel solution of the hormones to the skin, reducing concerns about adverse liver effects of oral medications. Larger-scale studies are still needed to confirm the relative benefits and safety noted in pilot trials of Bioidentical hormone replacement compared with equine estrogen and oral progestins. While chemically, these hormones are identical to those found in the human body, they cannot replicate the delivery system of those produced by the human body, nor the amounts. The human body contains over 25 different types of estrogen, and estradiol, estrone, and estriol are merely the three most common types. However, the body is able to convert estrogens into different hormones to a certain extent.

# Results of the WHI hormone replacement therapy studies
Clinical medical practice changed rapidly and dramatically with the results of the two parallel WHI studies of postmenopausal HRT. Prior studies were much smaller, and many were studies of women who were electively taking hormones. This self-selected group tended to be comprised of women who were more health-conscious, which was a possible factor to explain why these women tended to be healthier than the average. The WHI studies were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy, postmenopausal women. The WHI estrogen-plus-progestin trial and estrogen-alone trial were both halted early (in July 2002 and February 2004 respectively) because preliminary study results indicated that the health risks of the conjugated equine estrogen and progestin exceeded benefits.
The first report on the halted WHI estrogen-plus-progestin study came out in July 2002. It followed over 16 000 women for an average of 5.2 years, half of which taking a placebo, the other half taking a combination of the progestin medroxyprogesterone acetate and conjugated equine estrogens. The study found statistically signficant 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. 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 the specific proprietary combination of conjugated equine estrogen and progestin studied.
The risks of coronary heart disease varied according to age and years since the onset of menopause. Women aged 50 to 59 using HRT showed a small trend towards lower risk of coronary heart disease, as did women who were within five years of the onset of menopause.
The adverse cardiovascular outcomes may only apply to oral dosing with progestin and equine estrogens, while other types of HRT such as topical estradiol and estriol may not produce the same risks. Results from other studies suggest that when estrogen is administered orally, liver function is altered and the risk of blood clots is increased.
The WHI preliminary results in 2004 found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer and a 2006 update of concluded that use of estrogen-only HRT for 7 years does not increase the risk of breast cancer in postmenopausal women who have had a hysterectomy. The results of the WHI estrogen-alone trial suggest that the progestin used in the WHI estrogen-plus-progestin trial increased the risk for breast cancer above that associated with estrogen alone. Estrogen-alone HRT ("unopposed estrogen") poses unacceptable cancer risks to women who have not previously had a hysterectomy.
After the increased clotting found in the first WHI results was reported in 2002, a large number of women who had been taking the proprietary mixtures of equine estrogens and progestins studied (PremPro) ceased filling their prescriptions. Some simply stopped all hormones, and others switched to bioidentical hormones.  The number of PremPro prescriptions filled was abruptly cut almost in half.

# Effects and outcomes
A randomized controlled trial found HRT may prevent the development of heart disease and reduce the incidence of heart attack in women between 50 and 59, but not for older women. The mechanism may have something to do with the contradictory effects of increasing propensity for clotting, versus improving both "good" and "bad" cholesterol concentrations in the blood (which would have a protective effect). Follow-up studies are being performed which are intended to confirm these finding.
A report citing early findings reported at a American Academy of Neurology meeting, hormone therapy taken soon after menopause may help protect against dementia, even though it raises the risk of mental decline in women who do not take the drugs until they are older. Dementia risk was 1% in women who started HRT early, and 1.7% in women who didn't, (e.g. women who didn't take it seem to have hadon averagea 70% higher relative risk of dementia).

## Breast cancer
HRT is associated with an increased incidence of breast cancer; however, there is conflicting evidence whether this is due to estrogens or progestins or both.
Breast cancer increase may be due to the medroxyprogesterone acetate rather than conjugated equine estrogen (CEE) according to long-term follow-up of the Women's Health Initiative (WHI) randomized controlled trials. Previously reported short-term results of the WHI trial found:
- CEE plus medroxyprogesterone acetate (MPA) for 5.6 years in women without hysterectomy, found increased breast cancer (Hazard ratio: 1.26 95%$ CI: 1.00-1.59). 1 of every 1250 women treated are estimated to have invasive breast cancer. This increase was confirmed in longer term follow-up (Hazard ratio: 1.28; 95% CI: 1.13-1.45)
- Estrogen only in women with prior hysterectomy (41% also had bilateral oophorectomy) found no increased risk of breast cancer although stroke was increased. In this trial, the hazard ratio for breast cancer was 0.77 (95% CI,: 0.59-1.01). Longer term follow up found this reduction to be statistically significant (Hazard ratio: 0.78; 95% CI: 0.65-0.93).
On the other hand, individual participant meta-analysis of long-term non-randomized studies by the  Collaborative Group on Hormonal Factors in Breast Cancer suggest estrogens may increase breast cancer:
- Combination therapy (presumably mostly in women without prior hysterectomy). Significant increase risk of breast cancer starting at great than one year of usage and maybe even with less than one year.
- Estrogen only therapy (presumably mostly in women with prior hysterectomy). Significant increase risk of breast cancer starting at great than one year of usage.
- The Million Women Study, which was included in the meta-analysis, reported findings consistent with the larger meta-analysis Even less than 5 years of estrogen was associated with increased risk of breast cancer.
- Although 45% of the women in this study had a prior hysterectomy are mostly took estrogen only, a subgroup analysis of this was not reported.
In reconciling the results:
- The age at which HRT was received may have been older in the WHI trial (50-79 years old for 5 years) than the non-randomized studies (ages 30 to 70 for 1 to 20 years).
- Current practice may use lower doses of topical estrogen 17-beta estradiol  as well as micronized progesterone rather than medroxyprogesterone acetate. However, long-term studies on this combination are not available.
Summary:
- Among women without prior hysterectomy and bilateral oophorectomy, the WHI trial and the collaborative individual patient meta-analysis both find an increased risk of breast cancer from combination therapy. It is possible that modern regimens of combination therapy in women less than age 60 does not increase the risk of breast cancer, but this question has not been addressed with long term studies.
- Among women with prior hysterectomy and bilateral oophorectomy, the studies conflict and subsequent, published commentary has not provided a reconciliation.

# Contraindications of HRT
Absolute contraindications:
- undiagnosed vaginal bleeding
- severe liver disease
- pregnancy
- Coronary artery disease (CAD)
- venous thrombosis
- Well-differentiated and early endometrial cancer (once treatment for the malignancy is complete, is no longer an absolute contraindication.) Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens.
Relative contraindications:
- Migraine headaches
- personal history of breast cancer
- History of fibroids
- Atypical ductal hyperplasia of the breast
- Active gall bladder disease (Cholangitis, Cholecystitis)