Hormone replacement therapy (HRT) is a form of hormone therapy used to treat symptoms associated with female menopause.
Menopausal symptoms can include hot flashes, vaginal atrophy, accelerated skin aging, vaginal dryness, decreased muscle mass, sexual dysfunction, and bone loss.
((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.
Menopausal symptoms are in large part related to the diminished levels of sex hormones that occur during menopause.
The main hormonal medications used in HRT for menopausal symptoms are estrogens and progestogens.
Progesterone is the major naturally-occurring female sex hormone and also a manufactured medication used in menopausal hormone therapy.
Both hormones can have symptomatic benefits, progestogen is specifically added to estrogen regimens when the uterus is still present.
Progestogen reduces the risk of unopposed estrogen therapy promoting endometrial thickening that can increase the risk of uterine cancer.
Androgens like testosterone are sometimes used as well as HRT.
Long-term follow up of the WHI participants, however, has found no difference in all-cause, cardiovascular, or cancer mortality with HRT.
The current indications for HRT use from the United States Food and Drug Administration (FDA) include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or vaginal atrophy, and prevention of osteoporosis.
HRT may have more benefits than risks in women before the age of 60.
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.
Estrogen therapy has been shown in several studies to increase BMD from 2% to 7% at all sites and to prevent both vertebral and hip fractures in post menopausal women.
Women receiving HRT are usually post-, peri-, or surgically menopausal.
A 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 or uterine cancer.
The Women’s Health Initiative (WHI) was a study of over 27,000 women beginning in 1991.
Analyses have found sometimes contradictory results, with the most recent publication in 2017 finding no difference for all cause mortality with HRT.
Potential menopausal symptoms include:
Hot flashes – 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, osteoporosis, and associated fractures
Decreased sexual desire
Defeminization – diminished feminine fat distribution and accelerated skin aging
Sleep disturbances and joint pain
The most common of these are loss of sexual drive and vaginal dryness.
The risks of coronary heart disease with the use of HRT is dependent on age and time since menopause: with lower risk when started within five years, but no impact after ten.
There is no difference in long-term mortality from HRT, regardless of age.
A Cochrane review suggested that women starting HRT less than 10 years after menopause had lower mortality and coronary heart disease, without any strong effect on the risk of stroke and pulmonary embolism.
Women starting therapy more than 10 years after menopause showed little effect on mortality and coronary heart disease, but an increased risk of stroke.
HRT also improves cholesterol levels:With menopause, HDL decreases, while LDL, triglycerides and lipoprotein a increase.
These patterns are reversed with estrogen.
HRT improves heart contraction, coronary blood flow, sugar metabolism, decreases platelet aggregation and plaque formation.
Estrogen is associated with increased risk of venous blood clots due to increased liver formation of vitamin K-dependent clotting factors.
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, and so lack the anabolic effects that oral therapy has on liver synthesis of vitamin K-dependent clotting factors.
This explains why oral therapy may increase risk of thromboembolism.
There is an increased risk of blood clots and pulmonary embolism when estrogen and progestogen are combined.
Studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause.
But the association is absent or even preventive when HRT is given by non-oral routes.
Ischemic stroke 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 5 years from menopause, there is a suggested association with hemorrhagic and ischemic stroke.
Although oral estrogen increased risk of stroke, absorption through the skin had no impact, and vaginal estrogen actually had a decreased risk in another study.
Endometrial cancer can be associated with HRT, particularly in those not taking a progestogen.
In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.
Progesterone therapy should be at least 14 days per cycle to prevent endometrial disease.
Endometrial cancer has two forms in the context of hormone replacement: Type 1 the most common, can be associated with estrogen therapy, and is usually low grade.
Type 2 is not related to estrogen stimulation and usually higher grade and poorer prognosis.
Endometrial hyperplasia that leads to endometrial cancer due to estrogen stimulation can be prevented by concomitant administration of progestogen.
Progestogens promote the growth of uterine fibroids.
The association of breast cancer with hormone replacement have been mixed:
some evaluations suggest an increased risk, though in others it is decreased.
There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone.
The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of administration.
The WHI also found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer, though estrogen is usually only given alone in the setting of a hysterectomy due to the effect of unopposed estrogen on the uterus.
HRT has been more strongly associated with risk of breast cancer in women with a lower range body mass indices (BMIs):
No breast cancer association has been found with BMIs of over 25.
For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects: bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen for local symptoms.
Observational studies of systemic HRT after breast cancer are generally positive.
In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer.
Yet, the colorectal cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones.
HRT associated ovarian cancer risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT.
HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause.
75% of women remain sexually active after menopause.
Because of increased life spans, women today are living one third or more of their lives in a postmenopausal state.
Therefore, it is a period during which healthy sexuality can be integral to their quality of life.
Postmenopausal women have decreased libido and sexual function, related to hormonal changes taking place during this period: decrease in estrogen and an increase in follicle-stimulating hormone.
The majority of change in menopause occurs during the late perimenopausal and postmenopausal stages.
With menopause there is a decrease in sex hormone-binding globulin (SHBG) and inhibin (A and B).
Testosterone, is present in women at a lower level than in men
Testosterone peaks at age 30, but declines gradually with age, so there is little variation across the lifetime and during the menopausal transition.
HRT can help with sexual difficulties related to pain and lubrication, as adding estrogen can restore vaginal cells, pH levels, and blood flow to the vagina.
HRT with estrogen improves sexually related pain or discomfort as its most responsive component.
Estrogen improves urinary tract function, vaginal atrophy, sexual arousal, and orgasm rate.
Hormone replacement effectiveness can decline in some women after long-term use.
The combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone.
HRT with ((tibilone)), a synthetic steroid with estrogenic, androgenic, and progestogenic properties, has the ability to improve mood, libido, and physical symptoms of surgically menopausal women to a greater degree than ERT.
Improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been observed.
HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50–55 years.
HRT can also improve executive and attention processes outside of the context of dementia in postmenopausal women.
HRT decreases hip fractures.
Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle.
Hormone replacement therapy in the form of estrogen and androgen side effects:
Headache
Stomach cramps or bloating
Diarrhea
Appetite and weight changes
Changes in sex drive or performance
Nervousness
Brown or black patches on the skin
Acne
Swelling due to fluid retention
Changes in menstrual flow
Breast tenderness, enlargement, or discharge
Sudden difficulty wearing contact lenses
Uncomm side effects:
Double vision
Abdominal pain
Jaundice
Depression
Unusual bleeding
Loss of appetite
Skin rash
Lassitude
Fever
Dark-colored urine
Light colored stool
Chorea
Absolute contraindications to HRT
Undiagnosed vaginal bleeding
Severe liver disease
Pregnancy
Severe coronary artery disease
Breast, uterine or ovarian cancer
Relative contraindications
Migraines
History of breast cancer
History of ovarian cancer
Venous thrombosis
History of uterine fibroids
Atypical ductal hyperplasia of the breast
Active gallbladder disease
The Women’s Health Initiative trials were conducted between 1991 and 2006: double-blind, placebo-controlled clinical trials of HRT in healthy women.
During the time of hormone therapy, there are increases in invasive breast cancer, stroke and lung clots.
Other risks: increased endometrial cancer, gallbladder disease, and urinary incontinence.
HRT benefits include: decreased hip fractures, decreased incidence of diabetes, and improvement of vasomotor symptoms.
There also is an increased risk of dementia with HRT in women over 65, though when given earlier it appears to be neuroprotective.
With the cessation of HRT, the WHI continued observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist.
Other studies have also suggested an increased risk of ovarian cancer.
Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier, between age 50 to 59, but higher when begun after age 60.
In older patients, there was an apparent increased incidence of breast cancer, heart attacks, venous thrombosis, and stroke, although a reduced incidence of colorectal cancer and bone fracture.
Some of the WHI findings were found in a larger national study done in the United Kingdom, known as the Million Women Study (MWS).
In 2012, the United States Preventive Task Force (USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits.
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, that is, 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.
The WHI 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 study recommended that women with non-surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk.
Supplemental estrogen increased risk of venous thromboembolism and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed.
Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women.
Results of the Women’s Health Initiative (WHI) menopausal hormone therapy randomized controlled trials
Effects on risk-Estrogen and progestogen
(CEs 0.625 mg/day p.o. + MPA 2.5 mg/day p.o.)
The WHI reported statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli, and statistically significant decreases in rates of hip fracture and colorectal cancer.
Estrogen plus progestin also increases the risks of dementia.
Studies on post hysterectomy women who 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 when 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.
In women with intact uteruses, estrogens are almost always given in combination with progestogens, as long-term unopposed estrogen therapy is associated with a markedly increased risk of endometrial hyperplasia and endometrial cancer.
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.
Specific types of hormone replacement include:
Estrogens – bioidentical estrogens like estradiol and estriol, animal-derived estrogens like conjugated estrogens (CEEs), and synthetic estrogens like ethinylestradiol
Progestogens – bioidentical progesterone, and progestins (synthetic progestogens) like medroxyprogesterone acetate (MPA), norethisterone, and dydrogesterone
Androgens – testosterone and dehydroepiandrosterone (DHEA), and synthetic anabolic steroids like methyltestosterone and nandrolone decanoate
Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes.
Sometimes an androgen, generally testosterone, can be added to treat diminished libido.
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.
The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration.
Oral administration – tablets, capsules
Transdermal administration – patches, gels, creams
Vaginal administration – tablets, creams, suppositories, rings
Intramuscular or subcutaneous injection – solutions in vials or ampoules
Subcutaneous implant – surgically-inserted pellets placed into fat tissue
Less commonly sublingual, buccal, intranasal, and rectal administration, as well as intrauterine devices.
Newly developed forms of drug delivery are alleged to have increased local effects, lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels.
Transdermal and transvaginal estrogens avoid first pass metabolism through the liver,
This in turn prevents an increase in clotting factors and accumulation of anti-estrogenic metabolites, resulting in fewer adverse side effects, particularly with regard to cardiovascular disease and stroke.
Bioidentical hormones can be used in either pharmaceutical or compounded preparations.
Bioidentical hormones in pharmaceuticals may have health benefits over their animal derived counterparts, including a potentially decreased risk of venous thromboembolism, cardiovascular disease, and breast cancer.