Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of
hormone therapy used to treat
symptoms associated with female
menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
.
These symptoms can include
hot flash
Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...
es,
vaginal atrophy, accelerated skin aging,
vaginal dryness, decreased
muscle mass,
sexual dysfunction
Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction a ...
, and
bone loss or osteoporosis. They are in large part related to the diminished levels of
sex hormone
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effect ...
s that occur during menopause.
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
s and
progestogens are the main hormone drugs used in HRT.
Progesterone is the main female sex hormone that occurs naturally and is also
manufactured
Manufacturing is the creation or production of goods with the help of equipment, labor, machines, tools, and chemical or biological processing or formulation. It is the essence of secondary sector of the economy. The term may refer to a ran ...
into a drug that is used in menopausal hormone therapy.
Although both classes of hormones can have symptomatic benefit, progestogen is specifically added to estrogen regimens, unless the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
has been removed, to avoid the increased risk of endometrial cancer. Unopposed estrogen therapy promotes
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 t ...
and increases the risk of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, while progestogen reduces this risk.
Androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
s like
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
are sometimes used as well.
HRT is available through a variety of different
routes.
The long-term effects of HRT on most organ systems vary by age and time since the last
physiological exposure to hormones, and there can be large differences in individual regimens, factors which have made analyzing effects difficult.
The
Women's Health Initiative
The Women's Health Initiative (WHI) was a series of clinical studies initiated by the U.S. National Institutes of Health (NIH) in 1991, to address major health issues causing morbidity and mortality in postmenopausal women. It consisted of three ...
(WHI) is an ongoing study of over 27,000 women that began in 1991, with the most recent analyses suggesting that, when initiated within 10 years of menopause, HRT reduces all-cause
mortality and risks of coronary disease, osteoporosis, and dementia; after 10 years the beneficial effects on mortality and coronary heart disease are no longer apparent, though there are decreased risks of hip and vertebral fractures and an increased risk of
venous thromboembolism
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
when taken orally.
"Bioidentical" hormone replacement is a development in the 21st century and uses manufactured compounds with "exactly the same chemical and molecular structure as hormones that are produced in the human body."
These are mainly
steroids derived from plants and can be a component of either registered ''pharmaceutical'' or custom-made ''compounded'' preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and formal oversight.
Bioidentical hormone replacement has inadequate
clinical research
Clinical research is a branch of healthcare science that determines the safety and effectiveness ( efficacy) of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treatm ...
to determine its safety and efficacy as of 2017.
The current indications for use from the United States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) include short-term treatment of
menopausal symptoms
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
, such as
vasomotor
Vasomotor refers to actions upon a blood vessel which alter its diameter. More specifically, it can refer to vasodilator action and vasoconstrictor action.
Control Sympathetic innervation
Sympathetic nerve fibers travel around the tunica media of ...
hot flash
Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...
es or
vaginal atrophy, and prevention of
osteoporosis.
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.
The
American College of Obstetrics and Gynecology
The American College of Obstetricians and Gynecologists (ACOG) is a professional association of physicians specializing in obstetrics and gynecology in the United States. Several Latin American countries are also represented within Districts of ...
(ACOG) approves of HRT for symptomatic relief of menopausal symptoms, and advocates its use beyond the age of 65 in appropriate scenarios. The
North American Menopause Society
The North American Menopause Society (NAMS), 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 an ...
(NAMS) 2016 annual meeting mentioned that HRT may have more benefits than risks in women before the age of 60.
A consensus expert opinion published by
The Endocrine Society
The Endocrine Society is a professional, international medical organization in the field of endocrinology and metabolism, founded in 1916 as The Association for the Study of Internal Secretions. The official name of the organization was changed ...
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.
The
American Association of Clinical Endocrinologists
The American Association of Clinical Endocrinology (AACE), formerly known as the American Association of Clinical Endocrinologists, is a professional community of physicians specializing in endocrinology, diabetes, and metabolism. AACE's missio ...
(AACE) has also released position statements approving of HRT when appropriate.
[
Women receiving this treatment are usually ]post-
''Post-'' (stylized in all caps) is the third solo album by American singer-songwriter Jeff Rosenstock. It was released on January 1, 2018, without any promotional lead-up. The album was released on Polyvinyl Record Co. in the United States an ...
, 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'. Premature menopause can occur if the ovaries are surgically removed, as can be done to treat ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...
or uterine cancer
Uterine cancer, also known as womb cancer, includes two types of cancer that develop from the tissues of the uterus. Endometrial cancer forms from the lining of the uterus, and uterine sarcoma forms from the muscles or support tissue of the ut ...
.
Demographically, the vast majority of data available is in postmenopausal American women with concurrent pre-existing conditions and an average age of over 60 years.
Menopausal symptoms
HRT is often given as a short-term relief from menopausal symptoms during perimenopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
. Potential menopausal symptoms include:[
* ]Hot flash
Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...
es – vasomotor symptoms
* Vulvovaginal atrophy – atrophic vaginitis and dryness
* Dyspareunia – painful sexual intercourse due to vaginal atrophy and lack of lubrication
* Bone loss – decreased bone mineral density, which can eventually lead to osteopenia
Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...
, osteoporosis, and associated fractures
Fracture is the separation of an object or material into two or more pieces under the action of stress. The fracture of a solid usually occurs due to the development of certain displacement discontinuity surfaces within the solid. If a displa ...
* Decreased sexual desire
* Defeminization
In developmental biology and zoology, defeminization is an aspect of the process of sexual differentiation by which a potential female-specific structure, function, or behavior is changed by one of the processes of male development. Although the t ...
– diminished feminine fat distribution and accelerated skin aging
The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to ...
* Sleep disturbance
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are tests ...
s and joint pain
Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication.
According to MeSH, ...
The most common of these are loss of sexual drive and vaginal dryness.[Sarrel, P.M. (2000). Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause. Journal of Women's Health and Gender-Based Medicine, 9, 25–32]
Heart disease
The effect of HRT in menopause appears to be divergent, with lower risk of heart disease when started within five years, but no impact after ten. There may be an increase in heart disease if HRT is given twenty years post-menopause. This variability has led some reviews to suggest an absence of significant effect on morbidity
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
. Importantly, there is no difference in long-term mortality from HRT, regardless of age.
A Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health profes ...
suggested that women starting HRT less than 10 years after menopause had lower mortality and coronary heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
, without any strong effect on the risk of stroke and pulmonary embolism
Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...
.[ 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.][
HRT with estrogen and progesterone also improves cholesterol levels. With menopause, HDL decreases, while ]LDL
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
, triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other ...
s and lipoprotein a increase, patterns that reverse with estrogen. Beyond this, HRT improves heart contraction Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of ...
, coronary Coronary () may, as shorthand in English, be used to mean:
* Coronary circulation, the system of arteries and veins in mammals
** Coronary artery disease
**Coronary occlusion
** A myocardial infarction, a heart attack
As adjective
* Referring to ...
blood flow, sugar metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
, and decreases platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
aggregation and plaque formation. HRT may promote 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 first via entering the lymphatic system, then the bloodstream.
Cholesterol from non-hepatic peripheral ti ...
through induction of cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
ABC transporters
The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC tran ...
. HRT also results in a large reduction in the pro-thrombotic lipoprotein a. Studies on cardiovascular disease with testosterone therapy have been mixed, with some suggesting no effect or a mild negative effect, though others have shown an improvement in surrogate markers such as cholesterol, triglycerides and weight. Testosterone has a positive effect on vascular endothelial function and tone with observational studies suggesting that women with lower testosterone may be at greater risk for heart disease. Available studies are limited by small sample size and study design. Low sex hormone binding globulin, which occurs with menopause, is associate with increased body mass index and risk for type 2 diabetes.
Blood clots
Effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism
Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...
may vary with different estrogen and progestogen therapies, and with different doses or method of use.[ Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots,] whereas when used orally, the risk of blood clots and pulmonary embolism is increased.[ Skin and vaginal routes of hormone therapy are not subject to ]first pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...
, and so lack the anabolic
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking ...
effects that oral therapy has on liver synthesis of vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
-dependent clotting factors, possibly explaining why oral therapy may increase blood clot formation.
While a 2018 review found that taking progesterone and estrogen together can decrease this risk, 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.[
The risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary.
]
Stroke
Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause, and that the association is absent or even preventive when given by non-oral routes. Ischemic stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop funct ...
risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy and no difference in mortality at long term follow up. When oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until five years from menopause, cohort studies
A cohort study is a particular form of longitudinal study that samples a cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or graduation), performing ...
in Swedish women have suggested an association with hemorrhagic
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
and ischemic stroke. 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.
Endometrial cancer
In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence. The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease.
Endometrial cancer has been grouped into two forms in the context of hormone replacement. Type 1 is the most common, can be associated with estrogen therapy, and is usually low grade. Type 2 is not related to estrogen stimulation and usually higher grade and poorer in prognosis. The 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 t ...
that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen. 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.
Paradoxically, progestogens do promote the growth of uterine fibroids
Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bl ...
, and a pelvic ultrasound
Medical ultrasound includes diagnostic techniques (mainly imaging techniques) using ultrasound, as well as therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal body structures such as tendons, musc ...
can be performed before beginning HRT to make sure there are no underlying uterine or endometrial lesions.
Androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent.
There is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.
Breast cancer
Studies regarding the association of breast cancer with hormone replacement are inconsistent and vary with type of replacement and time since menopause. While some evaluations suggest an increased risk, in others it is decreased. This inconsistency of effect has been suggested to imply a lack of meaningful impact of HRT on breast cancer risk.
There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone. The risk may be reduced with bioidentical
Bioidentical hormone replacement therapy (BHRT), also known as bioidentical hormone therapy (BHT) or natural hormone therapy, is the use of hormones that are identical on a molecular level with endogenous hormones in hormone replacement therapy. ...
progesterone, though the only prospective study that suggested this was underpowered due to the rarity of breast cancer in the control population. There have been no randomized controlled trials as of 2018. The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of synthetic progestin administration.
The most recent follow up of the Women's Health Initiative participants demonstrated a lower incidence of breast cancer in post-hysterectomy participants taking equine estrogen alone, though the relative risk was increased if estrogen was taken with medroxy-progesterone. Estrogen is usually only given alone in the setting of a hysterectomy due to the increased risk of vaginal bleeding and uterine cancer with unopposed estrogen.
HRT has been more strongly associated with risk of breast cancer in women with lower body mass indices (BMIs). No breast cancer association has been found with BMIs of over 25. 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
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...
, or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate.
Evaluating the response of breast tissue density to HRT using mammography appears to help assessing the degree of breast cancer risk associated with therapy; women with dense or mixed-dense breast tissue
Dense breast tissue, also known as dense breasts, is a condition of the breasts where a higher proportion of the breasts are made up of glandular tissue and fibrous tissue than fatty tissue. Around 40–50% of women have dense breast tissue and o ...
have a higher risk of developing breast cancer than those with low density tissue.
Micronized
Micronization is the process of reducing the average diameter of a solid material's particles. Traditional techniques for micronization focus on mechanical means, such as milling and grinding. Modern techniques make use of the properties of superc ...
progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration.
A retrospective Cox proportional hazards analysis from Richard Neapolitan endorsed the reduced risk breast cancer with conjugated equine estrogen usage alone, but also suggested that conjugated equine estrogen with medroxyprogesterone acetate was associated with a risk reduction in breast cancer and that bioidentical hormone therapy was not associated with a statistically significant effect. There have been no prospective randomized clinical trials comparing the two routes of administration with regards to breast cancer.
For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
s or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
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. In women who are BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
or BRCA2 mutation carriers, HRT does not appear to impact breast cancer risk. The relative number of women using HRT who also obtain regular screening mammograms is higher than that in women who do not use HRT, a factor which has been suggested as contributing to different breast cancer detection rates in the two groups.
With androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association.
Ovarian cancer
HRT is associated with an increased risk of ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...
, with women using HRT having about one additional case of ovarian cancer per 1,000 users. This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT. Regarding the specific subtype
Subtype may refer to:
* Viral subtypes, such as Subtypes of HIV
* Subtyping
In programming language theory, subtyping (also subtype polymorphism or inclusion polymorphism) is a form of type polymorphism in which a subtype is a datatype that is ...
, there may be a higher risk of serous cancer, but no association with clear cell
In histology, a clear cell is a cell that shows a clear cytoplasm when stained with hematoxylin and eosin (H&E).
Normal histology
In the skin, some secretory cells in the epithelium appear as clear cells, and are one of the components of eccrine ...
, endometrioid, or mucinous ovarian cancer. Hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates.
Other malignancies
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
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
or distant sites than colorectal cancer in women not taking hormones. In colorectal cancer survivors, usage of HRT is thought to lead to lower recurrence risk and overall mortality.
Cervical cancer
There appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with HRT and a weak increase in adenocarcinoma. No studies have reported an increased risk of recurrence when HRT is used with cervical cancer survivors.
Sexual function
HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40 and 69 years suggest that 75% of women remain sexually active after menopause. 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
Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
.
Decreased libido and sexual dysfunction are common issues in postmenopausal women, an entity referred to hypoactive sexual desire disorder (HSDD); its signs and symptoms can both be improved by HRT. 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. Decreases in sex hormone-binding globulin
Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...
(SHBG) and inhibin
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual ...
(A and B) also occur. Testosterone is present in women at a lower level than men, peaking at age 30 and declining gradually with age; there is less variation during the menopausal transition relative to estrogen and progesterone.
A global consensus position statement has advised that postmenopausal testosterone replacement to premenopausal levels can be effective for HSDD. Safety information for testosterone treatment is not available beyond two years of continuous therapy however and dosing above physiologic levels is not advised. Testosterone patches have been found to restore sexual desire in post menopausal women. There is insufficient data to evaluate the impact of testosterone replacement on heart disease, breast cancer, with most trials having included women taking concomitant estrogen and progesterone and with testosterone therapy itself being relatively short in duration. In the setting of this limited data, testosterone therapy has not been associated with adverse events.
Not all women are responsive, especially those with preexisting sexual difficulties. 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. It also has been shown to have positive effects on the urinary tract. Estrogen can also reduce vaginal atrophy and increase sexual arousal, frequency and orgasm
Orgasm (from Greek , ; "excitement, swelling") or sexual climax is the sudden discharge of accumulated sexual excitement during the sexual response cycle, resulting in rhythmic, involuntary muscular contractions in the pelvic region chara ...
.
The effectiveness of hormone replacement can decline in some women after long-term use. A number of studies have also found that the combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone. Tibolone
Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated ...
, a synthetic steroid with estrogenic, androgenic, and progestogenic properties that is available in Europe, has the ability to improve mood, libido, and physical symptomatology. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been seen, though it also carries a similar risk profile to conventional HRT.
Neurodegenerative disorders
For prevention, the WHI suggested that HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50 and 55 years. Other studies in perimenopause have shown HRT to be consistently associated with a lower risk of Alzheimer's. With Parkinson's the majority of clinical and epidemiological studies show have demonstrated either no association or inconclusive results. A Danish study suggested an increased risk of Parkinson's with HRT in cyclical dosing schedules.
With regards to treatment, randomized trials have shown that HRT improves executive and attention processes outside of the context of dementia in postmenopausal women, both in those that are asymptomatic and those with mild cognitive impairment. Estrogen replacement appears to improve motor symptoms and activities of daily living in post menopausal women with Parkinson's, with significant improvement of UPDRS scores. Clinical trials have also shown testosterone replacement to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women. DHEA has not been found to improve cognitive performance after menopause. Pre-clinical studies indicate that endogenous estrogen and testosterone are neuroprotective and can prevent brain amyloid deposition.
Muscle and bone
There is a significant decrease in hip fracture
A hip fracture is a break that occurs in the upper part of the femur (thigh bone). Symptoms may include pain around the hip, particularly with movement, and shortening of the leg. Usually the person cannot walk.
They most often occur as a res ...
risk during treatment that to a lesser degree persists after HRT is stopped. It also helps collagen formation, which in turn improves intervertebral disc and bone strength.
Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle. Lower testosterone is associated with lower bone density and higher free testosterone is associated with lower hip fracture rates in older women. Testosterone therapy, which can be used for decreased sexual function, can also increase bone mineral density and muscle mass.
Side effects
Side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
in HRT occur with varying frequency and include:
Common
* Headache
* Upset stomach
Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues.
Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...
, stomach cramp
A cramp is a sudden, involuntary, painful skeletal muscle contraction or overshortening associated with electrical activity; while generally temporary and non-damaging, they can cause significant pain and a paralysis-like immobility of the aff ...
s or bloating
Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, pres ...
* Diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
* Appetite and weight changes
* Changes in sex drive
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...
or performance
* Nervousness
Nervous may refer to:
* nervousness
* Nervous system, a network of cells in an animal's body that coordinates movement and the senses
** Nervous tissue, the cells of the nervous system that work in aggregate to transmit signals
Music
* "Nervous" ...
* Brown or black patches on the skin
* Acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
* 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
Contact lenses, or simply contacts, are thin lenses placed directly on the surface of the eyes. Contact lenses are ocular prosthetic devices used by over 150 million people worldwide, and they can be worn to correct vision or for cosmeti ...
Uncommon
* Double vision
Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often v ...
* Severe abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues.
Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
* Yellowing of skin or eyes
* Severe depression
* Unusual bleeding
* Loss of appetite
* Skin rash
A rash is a change of the human skin which affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...
* Lassitude
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
* Fever
* Dark-colored urine
* Light colored stool
* Chorea
Chorea (or choreia, occasionally) is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term ''chorea'' is derived from the grc, χορεία ("dance"; see choreia), as the quick movem ...
Contraindications
The following are absolute and relative contraindications to HRT:
Absolute contraindications
* Undiagnosed vaginal bleeding
* Severe liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
* Pregnancy
* Severe coronary artery disease
* Aggressive breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
, uterine
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
or ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...
Relative contraindications
* Migraine headaches
* History of breast cancer
* History of ovarian cancer
* Venous thrombosis
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
* History of uterine fibroids
Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bl ...
* Atypical ductal hyperplasia of the breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
* Active gallbladder
In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...
disease ( cholangitis, cholecystitis
Cholecystitis is inflammation of the gallbladder. Symptoms include right upper abdominal pain, pain in the right shoulder, nausea, vomiting, and occasionally fever. Often gallbladder attacks (biliary colic) precede acute cholecystitis. The pai ...
)
* Well-differentiated and early endometrial cancer – once treatment for the malignancy is complete, is no longer an absolute contraindication.
History and research
The extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin
Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the ...
, one of the earlier forms of estrogen to be introduced. From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an eight-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet. It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium. This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera).
Trials
The Women's Health Initiative trials were conducted between 1991 and 2006 and were the first large, double-blind
In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...
, placebo-controlled clinical trials of HRT in healthy women. 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
In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...
disease, and urinary incontinence
Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a large impact on quality of life. It has been identified as an important issue in geri ...
, while benefits include decreased hip fracture
A hip fracture is a break that occurs in the upper part of the femur (thigh bone). Symptoms may include pain around the hip, particularly with movement, and shortening of the leg. Usually the person cannot walk.
They most often occur as a res ...
s, decreased incidence of diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
, and improvement of vasomotor
Vasomotor refers to actions upon a blood vessel which alter its diameter. More specifically, it can refer to vasodilator action and vasoconstrictor action.
Control Sympathetic innervation
Sympathetic nerve fibers travel around the tunica media of ...
symptoms. There is also an increased risk of dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
with HRT in women over 65, though at younger ages it appears to be neuroprotective. After the cessation of HRT, the WHI continued to observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist. Other studies have also suggested an increased risk of ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...
.
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
The Women's Health Initiative (WHI) was a series of clinical studies initiated by the U.S. National Institutes of Health (NIH) in 1991, to address major health issues causing morbidity and mortality in postmenopausal women. It consisted of three ...
(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
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
, 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.
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
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, 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. 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. In 2012, the United States Preventive Task Force
The United States Preventive Services Task Force (USPSTF) is "an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services". ...
(USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits.
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.[
The data published by the WHI suggested supplemental estrogen increased risk of ]venous thromboembolism
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed. 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.
The WHI reported statistically significant increases in rates of breast cancer, coronary heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture
A hip fracture is a break that occurs in the upper part of the femur (thigh bone). Symptoms may include pain around the hip, particularly with movement, and shortening of the leg. Usually the person cannot walk.
They most often occur as a res ...
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." 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. 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.
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.
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.
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.
Available forms
There are five major human steroid hormones: estrogens, progestogens, androgens
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
, mineralocorticoids
Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary min ...
, and glucocorticoids
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
. 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.
In women with intact uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
es, 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
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 t ...
and endometrial cancer. 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:
* Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
s – bioidentical
Bioidentical hormone replacement therapy (BHRT), also known as bioidentical hormone therapy (BHT) or natural hormone therapy, is the use of hormones that are identical on a molecular level with endogenous hormones in hormone replacement therapy. ...
estrogens like estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
and estriol
Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost ...
, animal-derived estrogens like conjugated estrogens
Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the ...
(CEEs), and synthetic estrogens like ethinylestradiol
Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disord ...
* Progestogens – bioidentical progesterone, and progestins (synthetic progestogens) like medroxyprogesterone acetate (MPA), norethisterone, and dydrogesterone
Dydrogesterone, sold under the brand name Duphaston & Dydroboon among others, is a progestin medication which is used for a variety of indications, including threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding, infertil ...
* Androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
s – bioidentical testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
and dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It fun ...
(DHEA), and synthetic anabolic steroids like methyltestosterone
Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low ...
and nandrolone decanoate
Nandrolone decanoate, sold under the brand name Deca-Durabolin among others, is an androgen and anabolic steroid (AAS) medication which is used primarily in the treatment of anemias and wasting syndromes, as well as osteoporosis in menopausal wo ...
Tibolone
Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated ...
– a synthetic medication available in Europe but not the United States– is more effective than placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
but less effective than combination hormone therapy in postmenopausal women. It may have a decreased risk of breast and colorectal cancer, though conversely it can be associated with vaginal bleeding, endometrial cancer, and increase the risk of stroke in women over age 60 years.
Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes.[Estrogen (Vaginal Route)]
from Mayo Clinic / Thomson Healthcare Inc. Portions of this document last updated: 1 November 2011 Sometimes an androgen, generally testosterone, can be added to treat diminished libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act u ...
.
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. Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic. Impact on breast density appears to be similar in both regimen timings.
Route of administration
The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration
A route of administration in pharmacology and toxicology is the way by which a medication, drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance i ...
:
* Oral administration
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are ...
– tablets, capsules
* Transdermal administration
Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery.
The drug is administered in the form of a patch or ointme ...
– patch
Patch or Patches may refer to:
Arts, entertainment and media
* Patch Johnson, a fictional character from ''Days of Our Lives''
* Patch (''My Little Pony''), a toy
* "Patches" (Dickey Lee song), 1962
* "Patches" (Chairmen of the Board song) ...
es, gel
A gel is a semi-solid that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state, although the liquid phase may still dif ...
s, cream
Cream is a dairy product composed of the higher-fat layer skimmed from the top of milk before homogenization. In un-homogenized milk, the fat, which is less dense, eventually rises to the top. In the industrial production of cream, this process ...
s
* Vaginal administration
Intravaginal administration is a route of administration where the substance is applied inside the vagina. Pharmacologically, it has the potential advantage to result in effects primarily in the vagina or nearby structures (such as the vaginal p ...
– tablets, creams, suppositories, ring
Ring may refer to:
* Ring (jewellery), a round band, usually made of metal, worn as ornamental jewelry
* To make a sound with a bell, and the sound made by a bell
:(hence) to initiate a telephone connection
Arts, entertainment and media Film and ...
s
* Intramuscular
Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
or subcutaneous injection – solution
Solution may refer to:
* Solution (chemistry), a mixture where one substance is dissolved in another
* Solution (equation), in mathematics
** Numerical solution, in numerical analysis, approximate solutions within specified error bounds
* Soluti ...
s in vial
A vial (also known as a phial or flacon) is a small glass or plastic vessel or bottle, often used to store medication as liquids, powders or capsules. They can also be used as scientific sample vessels; for instance, in autosampler devices i ...
s or ampoule
An ampoule (also ampul and ampule) is a small sealed vial which is used to contain and preserve a sample, usually a solid or liquid. Ampoules are usually made of glass.
Modern ampoules are most commonly used to contain pharmaceuticals and chem ...
s
* Subcutaneous implant – surgically-inserted pellets placed into fat tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular en ...
* Less commonly sublingual, buccal, intranasal
Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivere ...
, and rectal administration
Rectal administration uses the rectum as a route of administration for medication and other fluids, which are absorbed by the rectum's blood vessels,The rectum has numerous blood vessels available to absorb drugs. and flow into the body's ci ...
, as well as intrauterine devices
More recently developed forms of drug delivery are alleged to have increased local effect lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels. Transdermal and vaginal estrogen, in particular, avoid first pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...
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.
Injectable forms of estradiol exist and have been used occasionally in the past. However, they are rarely used in menopausal hormone therapy in modern times and are no longer recommended. Instead, other non-oral forms of estradiol such as transdermal estradiol are recommended and may be used. Estradiol injectables are generally well-tolerated and convenient, requiring infrequent administration. However, this form of estradiol does not release estradiol at a constant rate and there are very high circulating estradiol levels soon after injection followed by a rapid decline in levels. Injections may also be painful. Examples of estradiol injectables that may be used in menopausal hormone therapy include estradiol valerate
Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and Primiwal E4 and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy fo ...
and estradiol cypionate
Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in cis women, in hormone therapy for trans women, and in ...
. In terms of injectable progestogens, injectable progesterone is associated with pain and injection site reactions as well as a short duration of action requiring very frequent injections, and is similarly not recommended in menopausal hormone therapy.
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. There are, however, FDA approved products containing hormones classified as 'bioidentical'.
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. 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'. The British Menopause Society has issued a consensus statement endorsing the distinction between "compounded" forms (cBHRT), described as unregulated, custom made by specialty pharmacies and subject to heavy marketing and "regulated" pharmaceutical grade forms (rBHRT), which undergo formal oversight by entities such as the FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
and form the basis of most clinical trials. Some practitioners recommending compounded bioidentical HRT also use salivary or serum hormonal testing to monitor response to therapy, a practice not endorsed by current clinical guidelines in the United States and Europe.
Bioidentical hormones in pharmaceuticals may have very limited clinical data, with no randomized controlled prospective trials to date comparing them to their animal derived counterparts. Some pre-clinical data has suggested a decreased risk of venous thromboembolism
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, cardiovascular disease, and breast cancer. As of 2012, guidelines from the North American Menopause Society
The North American Menopause Society (NAMS), 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 an ...
, the Endocrine Society, the International Menopause Society, and the European Menopause and Andropause Society The European Menopause and Andropause Society is an institution that promotes the study, and encourages research, of midlife health.
Mission
EMAS "strives to encourage the study of Menopause and Andropause as well as promote the exchange of resea ...
endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk.
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. The U.S. Congress
The United States Congress is the legislature of the federal government of the United States. It is bicameral, composed of a lower body, the House of Representatives, and an upper body, the Senate. It meets in the U.S. Capitol in Washin ...
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
The Drug Quality and Security Act () is a law that amended the Federal Food, Drug, and Cosmetic Act to grant the Food and Drug Administration more authority to regulate and monitor the manufacturing of compounded drugs. The bill was written in re ...
, authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs, and reinforcing FDCA regulations for traditional compounding. The DQSA and its reinforcement of provision §503A of the FDCA solidifies FDA authority to enforce FDCA regulation of against compounders of bioidentical hormone therapy.
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
The General Pharmaceutical Council (GPhC) is the body responsible for the independent regulation of the pharmacy profession within England, Scotland and Wales, responsible for the regulation of pharmacists, pharmacy technicians and pharmacy premi ...
regulates compounding performed within a pharmacy. All testosterone prescribed in the United Kingdom is bioidentical, with its use supported by the National Health Service
The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
. There is also marketing authorisation for male testosterone products. National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas:
* the use of health technologies withi ...
guideline 1.4.8 states: "consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective". The footnote adds: "at the time of publication (November 2015), testosterone did not have a United Kingdom marketing authorisation for this indication in women. Bioidentical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour."
Society and public perception
Wyeth controversy
Wyeth
Wyeth, LLC was an American pharmaceutical company. The company was founded in Philadelphia, Pennsylvania, in 1860 as ''John Wyeth and Brother''. It was later known, in the early 1930s, as American Home Products, before being renamed to Wyeth in ...
, now a subsidiary of Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
, was a pharmaceutical company
The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate sympto ...
that marketed the HRT products Premarin (CEEs) and Prempro (CEEs + MPA). In 2009, litigation involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications. The documents showed that Wyeth commissioned dozens of ghostwritten
''Ghostwritten'' is the first novel published by English author David Mitchell. Published in 1999, it won the John Llewellyn Rhys Prize and was widely acclaimed. The story takes place mainly around East Asia, but also moves through Russia, B ...
reviews
A review is an evaluation of a publication, product, service, or company or a critical take on current affairs in literature, politics or culture. In addition to a critical evaluation, the review's author may assign the work a rating to indic ...
and commentaries that were published in medical journals to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light. 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. It worked mainly with DesignWrite, a medical writing firm. Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals.
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. The publications defended unsupported cardiovascular "benefits" of its products, downplayed risks such as breast cancer, and promoted off-label
Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...
and unproven uses like prevention of dementia, Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, vision problems
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment ...
, and wrinkle
A wrinkle, also known as a rhytid, is a fold, ridge or crease in an otherwise smooth surface, such as on skin or fabric. Skin wrinkles typically appear as a result of ageing processes such as glycation, habitual sleeping positions, loss of ...
s. In addition, Wyeth emphasized negative messages against the SERM raloxifene
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to ...
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."
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. 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. 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." Similar findings were observed in a 2010 analysis of 114 editorials, reviews, guidelines, and letters by five industry-paid authors. These publications promoted positive themes and challenged and criticized unfavorable trials such as the WHI and MWS. In 2009, Wyeth was acquired by Pfizer in a deal valued at US$68 billion. 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.
According to Fugh-Berman (2010), "Today, despite definitive scientific data to the contrary, many gynecologists still believe that the benefits of RToutweigh the risks in asymptomatic women. This non-evidence–based perception may be the result of decades of carefully orchestrated corporate influence on medical literature." As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS. 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.
Popularity
The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again. Transdermal therapy, in part due to its lack of increase in venous thromboembolism, is now often the first choice for HRT in the United Kingdom. Conjugate equine estrogen, in distinction, has a potentially higher thrombosis risk and is now not commonly used in the UK, replaced by estradiol based compounds with lower thrombosis risk. Oral progestogen combinations such as medroxyprogesterone acetate have changed to dyhydrogesterone, due to a lack of association of the latter with venous clot.
See also
* Hormone therapy
* Androgen replacement therapy
* Transgender hormone therapy
Transgender hormone therapy, also called hormone replacement therapy (HRT) or gender-affirming hormone therapy (GAHT), is a form of hormone therapy in which sex hormones and other hormonal medications are administered to transgender or gender non ...
References
External links
Menopause treatment
Hormone Health Network, The Endocrine Society
Sexual Health and Menopause Online
The North American Menopause Society
Menopause
US Food and Drug Administration
British Menopause Society
{{Androgens and antiandrogens
Endocrine procedures
Life sciences industry
Menopause
Obstetrical and gynaecological procedures
pl:Hormonalna terapia zastępcza