Hormone replacement therapy (menopause)
Encyclopedia
Hormone replacement therapy (HRT) is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal
women. It is based on the idea that the treatment may prevent discomfort caused by diminished circulating oestrogen and progesterone
hormone
s, or in the case of the surgically or prematurely menopausal, that it may prolong life and may reduce incidence of dementia. It involves the use of one or more of a group of medications designed to artificially boost hormone levels. The main types of hormones involved are oestrogens, progesterone
or progestin
s, and sometimes testosterone
. It often referred to as "treatment" rather than therapy.
, an oestrogen 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, IUD
s, vaginal ring
s, gels or, more rarely, by injection. For example, vaginally administered estrogens
include those given by intravaginal tablets, creams and rings, and can have more effect on atrophic vaginitis
with less systemic effects.
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 diminished libido
. It may also treat reduced energy and help reduce osteoporosis after menopause.
HRT is often given as a short-term relief (often one or two years, usually less than five) from menopausal symptoms (hot flashes, irregular menstruation, fat redistribution etc.). 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.
Attitudes towards HRT changed in 2002 following the announcement by the Women's Health Initiative
of the National Institutes of Health
that those receiving the treatment (Prempro) in the main part of their study had a larger incidence of breast cancer
, heart attacks and stroke
s. The WHI findings were reconfirmed in a larger national study done in the UK, known as The Million Women Study
. As a result of these findings, the number of women taking hormone treatment dropped precipitously. As a result of these findings, the Women's Health Initiative recommended that women with normal rather than surgical menopause should take the lowest feasible dose of HRT for the shortest possible time to avoid these risks.
is one such CEE), estrogens derived from the urine of pregnant mares, have been a common prescribed form of HRT, as well as progestin
s. As the most common and longest-prescribed type of HRT, the majority of studies of HRT involve CEE. More recent forms of drug delivery have been researched, including suppositories, subdermal implants, skin patches and gels rather than pills or injections, which allow more local effect, lower doses, fewer side effects and a constant rather than cyclical level of hormones within the blood. Comparisons between a pill and transdermal patch
suggests that when estrogens are taken orally the risks of thrombophlebitis
and pulmonary embolism
are increased, an effect which is not seen in with transdermal administration (this effect refers only to patches that contain estradiol for hormone replacement, and has no bearing on the patches used for birth control, which contain ethinyl estradiol). Transdermal drugs enter the bloodstream directly and unlike oral estrogens are not modified by the liver before being absorbed (modification by the liver is believed to be the reason for the increased risks). Once considered protective of the cardiovascular system, the large-scale, randomized, placebo controlled studies in the Women's Health Initiative
found that conventional hormone therapy with CEE actually increased the risk of heart disease, strokes, emboli and breast cancer while offering only mild protection against osteoporosis
and colorectal cancer
. Unopposed estrogen (the supplementation of endogenous estrogens without a progestagen
) can also result in endometrial hyperplasia
, a precursor to endometrial cancer
. 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 this type of cancer.
HRT may also be effective at reversing the effects of aging on muscle and/or promoting reverse cholesterol transport
(RCT) via the induction of cholesterol
ABC transporters.
Women have also pursued alternative interventions which do not involve estrogen supplementation. Due to the risks and potential problems of progestins and equine estrogens, a number of alternative therapies have been presented, including lifestyle changes and phytoestrogens
(plants and food supplements believed to alleviate the symptoms of menopause due to estrogen-like compounds). However, systemic reviews of the research on phytoestrogens demonstrated that these compounds are not effective. Bioidentical hormone replacement therapy
has also been inaccurately promoted as a panacea
and an alternative to conventional HRT, but bioidentical hormones are derived from the same sources as nonbioidentical molecules, have been used in FDA-approved drugs for many years, lack a research base demonstrating their risks or benefits, are expected to have the same risks and benefits as conventional HRT, and frequently associated with the expensive, unnecessary and potentially dangerous practice of compounding
.
According to a 2007 presentation at an 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 had—on average—a 70% higher relative risk
of dementia). This is consistent with research that hormone therapy improves executive and attention processes in postmenopausal women. It is also supported by research upon monkeys that were given ovariectomies to imitate the effect of menopause and then estrogen therapies. This showed replacement treated compared to nontreated monkeys had long term improved prefrontal cortex executive abilities on the Wisconsin card sort task.
Another recent randomized controlled trial
found HRT may actually 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). Followup studies are being performed which are intended to confirm these findings. The increased risk of breast cancer remains.
A recent large well-designed randomized controlled trial recently showed that increased breast cancer risk applies only to those women who take progesterone analogues (as was done in the WHI) but not to those taking progesterone itself
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 composed 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 PremPro, a combination of the progestin
medroxyprogesterone acetate
and conjugated equine estrogens
. The study found statistically significant
increases in rates of breast cancer
, coronary heart disease
, stroke
s 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." http://www.center4research.org/hrt072002.html 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 conjugated equine estrogen and progestin studied.
The increase in risks of coronary heart disease
in the PremPro arm of the study 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 the progestin and equine estrogens in Prempro, 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 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.
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. The number of Prempro prescriptions filled was abruptly cut almost in half. A number of women started taking alternatives to Prempro, such as bioidentical hormones. A sharp drop in breast cancer rates was observed following these changes, and held steady in subsequent years.
and saliva testing
to determine, and adjust a woman's hormone levels (the latter two practices are extremely controversial - compounding has not demonstrated any benefits and presents risks of uncertain dosing, potency and possible contamination; saliva testing is considered to have no merit due to the natural fluctuations in hormone levels and the lack of support for a specific dosage of hormones being ideal). Proponents also claim that BHRT can offer advantages beyond those typical of traditional HRT, though there is no evidence to support these claims. The United States Food and Drug Administration states that BHRT is expected to present the same risks and benefits of non-bioidentical HRT, but that traditional products have been researched to quantify these risks and benefits, and are produced by manufacturers with stringent purity and potency standards.
Uncommon symptoms
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
women. It is based on the idea that the treatment may prevent discomfort caused by diminished circulating oestrogen and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, or in the case of the surgically or prematurely menopausal, that it may prolong life and may reduce incidence of dementia. It involves the use of one or more of a group of medications designed to artificially boost hormone levels. The main types of hormones involved are oestrogens, progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
or progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
s, and sometimes testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
. It often referred to as "treatment" rather than therapy.
Overview
HRT is available in various forms. It generally provides low dosages of one or more oestrogens, and often also provides either progesterone or a chemical analogues, called a progestin. Testosterone may also be included. In women who have had a hysterectomyHysterectomy
A hysterectomy is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total or partial...
, an oestrogen 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, IUD
Intrauterine device
A copper IUD is a type of intrauterine device. Most IUDs have a plastic T- or U-shaped frame which is wrapped in copper wire, with the exception of Gynefix, which is a plastic string with several copper beads, affixed to the fundus of the uterus...
s, vaginal ring
Vaginal ring
Vaginal rings are polymeric drug delivery devices designed to provide controlled release of drugs for intravaginal administration over extended periods of time. The ring is inserted into the vagina and provides contraception protection...
s, gels or, more rarely, by injection. For example, vaginally administered estrogens
Vaginally administered estrogens
Vaginally administered estrogens are estrogens that are delivered by intravaginal administration, thereby exerting their effects mainly in the nearby tissue, with more limited systemic effects compared to orally administered estrogens....
include those given by intravaginal tablets, creams and rings, and can have more effect on atrophic vaginitis
Atrophic vaginitis
Atrophic vaginitis is an inflammation of the vagina due to the thinning and shrinking of the tissues, as well as decreased lubrication...
with less systemic effects.
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
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
, generally testosterone, is added to treat diminished libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
. It may also treat reduced energy and help reduce osteoporosis after menopause.
HRT is often given as a short-term relief (often one or two years, usually less than five) from menopausal symptoms (hot flashes, irregular menstruation, fat redistribution etc.). Younger women with premature ovarian failure
Premature ovarian failure
Premature Ovarian Failure , also known as premature ovarian insufficiency, primary ovarian insufficiency , premature menopause, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40...
or surgical menopause
Oophorectomy
Oophorectomy is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term has been traditionally used in basic science research describing the surgical removal of ovaries in laboratory animals...
may use hormone replacement therapy for many years, until the age that natural menopause would be expected to occur.
Attitudes towards HRT changed in 2002 following the announcement by the Women's Health Initiative
Women's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
of the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
that those receiving the treatment (Prempro) in the main part of their study had a larger incidence of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, heart attacks and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s. The WHI findings were reconfirmed in a larger national study done in the UK, known as The Million Women Study
The Million Women Study
The Million Women Study is a study of women’s health analyzing data from more than one million women aged 50 and over conducted by UK researchers. It is a collaborative project between Cancer Research UK and the National Health Service , with additional funding from the Medical Research Council...
. As a result of these findings, the number of women taking hormone treatment dropped precipitously. As a result of these findings, the Women's Health Initiative recommended that women with normal rather than surgical menopause should take the lowest feasible dose of HRT for the shortest possible time to avoid these risks.
Risks and benefits
Proprietary mixtures of conjugated equine estrogens (CEE, PremarinPremarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
is one such CEE), estrogens derived from the urine of pregnant mares, have been a common prescribed form of HRT, as well as progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
s. As the most common and longest-prescribed type of HRT, the majority of studies of HRT involve CEE. More recent forms of drug delivery have been researched, including suppositories, subdermal implants, skin patches and gels rather than pills or injections, which allow more local effect, lower doses, fewer side effects and a constant rather than cyclical level of hormones within the blood. Comparisons between a pill and transdermal patch
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
suggests that when estrogens are taken orally the risks of thrombophlebitis
Thrombophlebitis
Thrombophlebitis is phlebitis related to a thrombus . When it occurs repeatedly in different locations, it is known as "Thrombophlebitis migrans" or "migrating thrombophlebitis".-Signs and symptoms:...
and pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
are increased, an effect which is not seen in with transdermal administration (this effect refers only to patches that contain estradiol for hormone replacement, and has no bearing on the patches used for birth control, which contain ethinyl estradiol). Transdermal drugs enter the bloodstream directly and unlike oral estrogens are not modified by the liver before being absorbed (modification by the liver is believed to be the reason for the increased risks). Once considered protective of the cardiovascular system, the large-scale, randomized, placebo controlled studies in the Women's Health Initiative
Women's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
found that conventional hormone therapy with CEE actually increased the risk of heart disease, strokes, emboli and breast cancer while offering only mild protection against osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
and colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. Unopposed estrogen (the supplementation of endogenous estrogens without a progestagen
Progestagen
Progestogens are a group of hormones including progesterone.The progestogens are one of the five major classes of steroid hormones, in addition to the estrogens, androgens, mineralocorticoids, and glucocorticoids. All progestogens are characterized by their basic 21-carbon skeleton, called a...
) can also result in endometrial hyperplasia
Endometrial hyperplasia
Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus.Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of the progesterone-like hormones which ordinarily...
, a precursor to endometrial cancer
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
. The extensive use of high-dose estrogens for birth control
Birth control
Birth control is an umbrella term for several techniques and methods used to prevent fertilization or to interrupt pregnancy at various stages. Birth control techniques and methods include contraception , contragestion and abortion...
in the 1970s is thought to have resulted in a significant increase in the incidence of this type of cancer.
HRT may also be effective at reversing the effects of aging on muscle and/or promoting reverse cholesterol transport
Reverse cholesterol transport
Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma....
(RCT) via the induction of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
ABC transporters.
Women have also pursued alternative interventions which do not involve estrogen supplementation. Due to the risks and potential problems of progestins and equine estrogens, a number of alternative therapies have been presented, including lifestyle changes and phytoestrogens
Phytoestrogens
Phytoestrogens are plant-derived xenoestrogens functioning as the primary female sex hormone not generated within the endocrine system but consumed by eating phytoestrogonic plants...
(plants and food supplements believed to alleviate the symptoms of menopause due to estrogen-like compounds). However, systemic reviews of the research on phytoestrogens demonstrated that these compounds are not effective. Bioidentical hormone replacement therapy
Bioidentical hormone replacement therapy
Bioidentical hormone replacement therapy , also known as bioidentical hormone therapy or natural hormone therapy, is a poorly-defined term referring to the use of hormones that are identical, on a molecular level, with endogenous hormones in hormone replacement therapy...
has also been inaccurately promoted as a panacea
Panacea (medicine)
The panacea , named after the Greek goddess of healing, Panacea, also known as panchrest, was supposed to be a remedy that would cure all diseases and prolong life indefinitely...
and an alternative to conventional HRT, but bioidentical hormones are derived from the same sources as nonbioidentical molecules, have been used in FDA-approved drugs for many years, lack a research base demonstrating their risks or benefits, are expected to have the same risks and benefits as conventional HRT, and frequently associated with the expensive, unnecessary and potentially dangerous practice of compounding
Compounding
Compounding is the mixing of drugs by a compounding pharmacist to fit the unique needs of a patient...
.
According to a 2007 presentation at an American Academy of Neurology
American Academy of Neurology
The American Academy of Neurology is a professional society for neurologists and neuroscientists. As a medical specialty society it was established in 1949 by A.B. Baker of the University of Minnesota to advance the art and science of neurology, and thereby promote the best possible care for...
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 had—on average—a 70% higher relative risk
Relative risk
In statistics and mathematical epidemiology, relative risk is the risk of an event relative to exposure. Relative risk is a ratio of the probability of the event occurring in the exposed group versus a non-exposed group....
of dementia). This is consistent with research that hormone therapy improves executive and attention processes in postmenopausal women. It is also supported by research upon monkeys that were given ovariectomies to imitate the effect of menopause and then estrogen therapies. This showed replacement treated compared to nontreated monkeys had long term improved prefrontal cortex executive abilities on the Wisconsin card sort task.
Another recent randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
found HRT may actually prevent the development of heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
and reduce the incidence of heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
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
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
concentrations in the blood (which would have a protective effect). Followup studies are being performed which are intended to confirm these findings. The increased risk of breast cancer remains.
A recent large well-designed randomized controlled trial recently showed that increased breast cancer risk applies only to those women who take progesterone analogues (as was done in the WHI) but not to those taking progesterone itself
Results of the WHI hormone replacement therapy studies
Clinical medical practice changed rapidly and dramatically with the results of the two parallel WHIWomen's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
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 composed 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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
, the other half taking PremPro, a combination of the progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
medroxyprogesterone acetate
Medroxyprogesterone
Medroxyprogesterone is a pregnane that acts as a progestin. An acylated derivative, medroxyprogesterone 17-acetate is clinically used as a drug. Compared to MPA, MP is approximately 100 fold less potent as a progestin...
and conjugated equine estrogens
Premarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
. The study found statistically significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
increases in rates of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, coronary heart disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s and pulmonary emboli
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
. The study also found statistically significant decreases in rates of hip fracture
Hip fracture
A hip fracture is a femoral fracture that occurs in the proximal end of the femur , near the hip.The term "hip fracture" is commonly used to refer to four different fracture patterns and is often due to osteoporosis; in the vast majority of cases, a hip fracture is a fragility fracture due to a...
and colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia." http://www.center4research.org/hrt072002.html 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 conjugated equine estrogen and progestin studied.
The increase in risks of coronary heart disease
Coronary disease
Coronary disease refers to the failure of coronary circulation to supply adequate circulation to cardiac muscle and surrounding tissue. It is already the most common form of disease affecting the heart and an important cause of premature death in Europe, the Baltic states, Russia, North and South...
in the PremPro arm of the study 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 the progestin and equine estrogens in Prempro, while other types of HRT such as topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...
estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
and estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
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 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
Hysterectomy
A hysterectomy is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total or partial...
. 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.
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. The number of Prempro prescriptions filled was abruptly cut almost in half. A number of women started taking alternatives to Prempro, such as bioidentical hormones. A sharp drop in breast cancer rates was observed following these changes, and held steady in subsequent years.
Bioidentical hormone replacement therapy
Bioidentical hormone replacement therapy refers to the use of hormones that are chemically identical to those produced in a woman's body, though they are also associated with the practices of pharmaceutical compoundingCompounding
Compounding is the mixing of drugs by a compounding pharmacist to fit the unique needs of a patient...
and saliva testing
Saliva testing
Saliva testing is a diagnostic technique that involves laboratory analysis of saliva to identify markers of endocrine, immunologic, inflammatory, infectious, and other types of conditions. Saliva is a useful biological fluid for assaying steroid hormones such as cortisol, genetic material like...
to determine, and adjust a woman's hormone levels (the latter two practices are extremely controversial - compounding has not demonstrated any benefits and presents risks of uncertain dosing, potency and possible contamination; saliva testing is considered to have no merit due to the natural fluctuations in hormone levels and the lack of support for a specific dosage of hormones being ideal). Proponents also claim that BHRT can offer advantages beyond those typical of traditional HRT, though there is no evidence to support these claims. The United States Food and Drug Administration states that BHRT is expected to present the same risks and benefits of non-bioidentical HRT, but that traditional products have been researched to quantify these risks and benefits, and are produced by manufacturers with stringent purity and potency standards.
Absolute contraindications
- Undiagnosed vaginal bleeding
- Severe liver diseaseLiver diseaseLiver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
- PregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
- Coronary artery disease (CAD)
- Venous thrombosisVenous thrombosisA venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. (Thrombosis is a medical term for blood clotting (Haemostasis) occurring in the wrong place, i.e...
- Well-differentiated and early endometrial cancerEndometrial cancerEndometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
(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
- MigraineMigraineMigraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
headaches - Personal history of breast cancer
- Personal history of ovarian cancer
- History of uterine fibroidsUterine fibroidsA uterine fibroid is a benign tumor that originates from the smooth muscle layer and the accompanying connective tissue of the uterus.Fibroids are the most common benign tumors in...
- Atypical ductal hyperplasiaHyperplasiaHyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
of the breastBreastThe breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues... - Active gallbladderGallbladderIn vertebrates the gallbladder is a small organ that aids mainly in fat digestion and concentrates bile produced by the liver. In humans the loss of the gallbladder is usually easily tolerated....
disease (cholangitis, cholecystitisCholecystitis-Signs and symptoms:Cholecystitis usually presents as a pain in the right upper quadrant. This is known as biliary colic. This is initially intermittent, but later usually presents as a constant, severe pain. During the initial stages, the pain may be felt in an area totally separate from the site...
)
Side effects
Common symptoms- HeadacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
- Upset stomach, stomach cramps or bloatingBloatingBloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...
- DiarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
- AppetiteAppetiteThe appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
and weight changes - Changes in sex driveLibidoLibido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
or performance - NervousnessAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
- Brown or black patches on the skin
- AcneAcneAcne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...
- 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 symptoms
- Double visionDouble visionDouble vision refers to diplopia, the perception of two images from a single object.Double vision may also refer to:- Music :* Double Vision * Double Vision...
- Severe abdominal painAbdominal painAbdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
- Yellowing of skin or eyes
- Severe depression
- Unusual bleeding
- Loss of appetite
- Skin rash
- Laxitude
- Fever
- Dark-colored urine
- Light colored stool
- ChoreaChorea (disease)Choreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία , see choreia , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term...
See also
- AndropauseAndropauseAndropause or male menopause, sometimes colloquially called "man-opause" is a name that has been given to a menopause-like condition in aging men...
- CastrationCastrationCastration is any action, surgical, chemical, or otherwise, by which a male loses the functions of the testicles or a female loses the functions of the ovaries.-Humans:...
- EstrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
- European Menopause and Andropause SocietyEuropean Menopause and Andropause SocietyThe European Menopause and Andropause Society is a medical association focused on the study and treatment of the climacteric in men and women...
- Hormones
- Life extensionLife extensionLife extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...
- Male lactationMale lactationMale lactation in zoology means production of milk from mammary glands in the presence of physiological stimuli connected with nursing infants. It is well documented in the Dayak fruit bat.The term male lactation is not used in human medicine...
- North American Menopause SocietyNorth American Menopause SocietyThe North American Menopause Society , founded in 1989, is a nonprofit multidisciplinary organization with the mission of promoting the health and quality of life of women during midlife and beyond through an understanding of menopause and healthy aging. Based in Cleveland, Ohio, NAMS has over...
- OophorectomyOophorectomyOophorectomy is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term has been traditionally used in basic science research describing the surgical removal of ovaries in laboratory animals...
- OsteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
- ProgesteroneProgesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
- ProlactinProlactinProlactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...