Encephalopathy (/ɛnˌsɛfəˈlɒpəθi/; from Ancient Greek: ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome has many possible organic and inorganic causes.
Types
There are many types of encephalopathy. Some examples include:
Mitochondrial encephalopathy:
Metabolic disorder caused by dysfunction of mitochondrial DNA. Can
affect many body systems, particularly the brain and nervous system.
Neonatal encephalopathy
(hypoxic-ischemic encephalopathy): An obstetric form, often occurring
due to lack of oxygen in bloodflow to brain-tissue of the fetus during
labour or delivery.
Salmonella
encephalopathy: A form of encephalopathy caused by food poisoning
(especially out of peanuts and rotten meat) often resulting in permanent
brain damage and nervous system disorders.
HIV encephalopathy (encephalopathy associated with HIV infection and AIDS, characterized by atrophy and ill-defined white matter hyperintensity).
Sepsis-associated
encephalopathy (this type can occur in the setting of apparent sepsis,
trauma, severe burns, or trauma, even without clear identification of an
infection).
Early infantile epileptic encephalopathy (acquired or congenital abnormal cortical development).
Early myoclonic epileptic encephalopathy (possibly due to metabolic disorders).
Gluten
encephalopathy: Focal abnormalities of the white matter (generally area
of low perfusion) are appreciated through magnetic resonance. Migraine
is the most common symptom reported.
BRAT1 Encephalopathy: An ultra-rare autosomal recessive neonatal encephalopathy.
The hallmark of encephalopathy is an altered mental state or delirium. Characteristic of the altered mental state is impairment of the cognition, attention, orientation, sleep–wake cycle and consciousness. An altered state of consciousness may range from failure of selective attention to drowsiness. Hypervigilance may be present; with or without: cognitive deficits, headache, epileptic seizures, myoclonus (involuntary twitching of a muscle or group of muscles) or asterixis ("flapping tremor" of the hand when wrist is extended).
Depending on the type and severity of encephalopathy, common
neurological symptoms are loss of cognitive function, subtle personality
changes, and an inability to concentrate. Other neurological signs may
include dysarthria, hypomimia, problems with movements (they can be clumsy or slow), ataxia, tremor. Other neurological signs may include involuntary grasping and sucking motions, nystagmus (rapid, involuntary eye movement), jactitation (restlessness while in bed), and respiratory abnormalities such as Cheyne-Stokes respiration (cyclic waxing and waning of tidal volume), apneustic respirations and post-hypercapnicapnea. Focal neurological deficits are less common.
Diagnosis is frequently clinical. That is, no set of tests give
the diagnosis, but the entire presentation of the illness with
nonspecific test results informs the experienced clinician of the
diagnosis.
Treatment
Treatment varies according to the type and severity of the encephalopathy. Anticonvulsants
may be prescribed to reduce or halt any seizures. Changes to diet and
nutritional supplements may help some people. In severe cases, dialysis or organ replacement surgery may be needed.
Treating
the underlying cause of the disorder may improve or reverse symptoms.
However, in some cases, the encephalopathy may cause permanent
structural changes and irreversible damage to the brain. These permanent
deficits can be considered a form of stable dementia. Some encephalopathies can be fatal.
Terminology
Encephalopathy
is a difficult term because it can be used to denote either a disease
or finding (i.e., an observable sign in a person).
When referring to a finding, encephalopathy refers to permanent (or degenerative)
brain injury, or a reversible one. It can be due to direct injury to
the brain, or illness remote from the brain. The individual findings
that cause a clinician to refer to a person as having encephalopathy
include intellectual disability, irritability, agitation, delirium,
confusion, somnolence, stupor, coma and psychosis. As such, describing a
person as having a clinical picture of encephalopathy is not a very
specific description.
When referring to a disease, encephalopathy refers to a wide
variety of brain disorders with very different etiologies, prognoses and
implications. For example, prion diseases, all of which cause transmissible spongiform encephalopathies,
are invariably fatal, but other encephalopathies are reversible and can
have a number of causes including nutritional deficiencies and toxins.
Estrogens and progestogens are the main hormone drugs used in HRT. Progesterone is the main female sex hormone that occurs naturally and is also manufactured 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 has been removed, to avoid the increased risk of endometrial cancer. Unopposed estrogen therapy promotes endometrial hyperplasia and increases the risk of cancer, while progestogen reduces this risk. Androgens like testosterone 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
(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 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 to determine its safety and efficacy as of 2017.
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 (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 (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
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 (AACE) has also released position statements approving of HRT when appropriate.
Women receiving this treatment are usually post-, peri-, or surgically induced 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 or uterine cancer.
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
Symptoms of menopause
HRT is often given as a short-term relief from menopausal symptoms during perimenopause. Potential menopausal symptoms include:
Atrophy of vaginal mucosa that occurs with menopause
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.
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 (SHBG) and inhibin
(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.
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,
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.
Muscle and bone
There is a significant decrease in hip fracture 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 HRT occur with varying frequency and include:
The risks of coronary heart disease with HRT vary depending on age and time since menopause.
The effect of HRT in menopause appears to be divergent, with lower
risk of heart disease when started within five years, but no impact
after ten.
For women who are in early menopause and have no issues with their
cardiovascular health, HRT comes with a low risk of adverse
cardiovascular events. 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. Importantly, 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.
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.
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 associated with increased body mass index and risk for type 2 diabetes.
Blood clots
Clot in the greater saphenous vein; oral estrogen is associated with increased risk of venous blood clots due to increased liver formation of vitamin K-dependent clotting factors.
Effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism may vary with different estrogen and progestogen therapies, and with different doses or method of use.
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, and so lack the anabolic effects that oral therapy has on liver synthesis of vitamin K-dependent clotting factors, possibly explaining why oral therapy may increase blood clot formation.
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 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 in Swedish women have suggested an association with hemorrhagic 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
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. 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 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, and a pelvic ultrasound 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
In general, hormone replacement therapy to treat menopause is associated with only a small increased risk of breast cancer. The level of risk also depends on the type of HRT, the duration of the treatment and the age of the person. Oestrogen-only HRT, taken by people who had a hysterectomy, comes with an extremely low level of breast cancer risk. The most commonly taken combined HRT (oestrogen and progestogen)
is linked to a small risk of breast cancer. This risk is lower for
women in their 50s and higher for older women. The risk increases with
the duration of HRT. When HRT is taken for a year or less, there is no
increased risk of breast cancer. HRT taken for more than 5 years comes
with an increased risk but the risk reduces after the therapy is
stopped.
There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progestogens. The risk may be reduced with bioidentical 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
medroxyprogesterone.
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, 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 have a higher risk of developing breast cancer than those with low density tissue.
Micronized
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.
For women who previously have had breast cancer, it is
recommended to first consider other options for menopausal effects, such
as bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen
for local symptoms. Observational studies of systemic HRT after breast
cancer are generally reassuring. If HRT is necessary after breast
cancer, estrogen-only therapy or estrogen therapy with a progestogen may
be safer options than combined systemic therapy. In women who are BRCA1 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, 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, there may be a higher risk of serous cancer, but no association with clear cell, 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 cancers
Colorectal cancer
In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer. However, the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones. 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.
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.
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, 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, 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 disease, and urinary incontinence, while benefits include decreased hip fractures, decreased incidence of diabetes, and improvement of vasomotor symptoms. There is also an increased risk of dementia
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.
The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its Data Monitoring Committee
(DMC) due to perceived health risks, though this occurred a full year
after the data suggesting increased risk became manifest. In 2004, the
arm of the WHI in which post-hysterectomy patients were being treated
with estrogen alone was also closed by the DMC. Clinical medical
practice changed based upon two parallel Women's Health Initiative
(WHI) studies of HRT. Prior studies were smaller, and many were of
women who electively took hormonal therapy. One portion of the parallel
studies followed over 16,000 women for an average of 5.2 years, half of
whom took placebo,
while the other half took a combination of CEEs and MPA (Prempro). This
WHI estrogen-plus-progestin trial was stopped prematurely in 2002
because preliminary results suggested risks of combined CEEs and
progestins exceeded their benefits. The first report on the halted WHI
estrogen-plus-progestin study came out in July 2002.
Initial data from the WHI in 2002 suggested mortality to be lower
when HRT was begun earlier, between age 50 to 59, but higher when begun
after age 60. In older patients, there was an apparent increased
incidence of breast cancer, heart attacks, venous thrombosis, and stroke, although a reduced incidence of colorectal cancer and bone fracture.
At the time, The WHI recommended that women with non-surgical menopause
take the lowest feasible dose of HRT for the shortest possible time to
minimize associated risks. 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
(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 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, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer.
"A year after the study was stopped in 2002, an article was published
indicating that estrogen plus progestin also increases the risks of
dementia."
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. As of 2023, for example, no trial has studied women who begin taking HRT around age 50 and continue taking it for longer than 10 years.
There are five major human steroid hormones: estrogens, progestogens, androgens, mineralocorticoids, and glucocorticoids.
Estrogens and progestogens are the two most often used in menopause.
They are available in a wide variety of FDA approved and
non–FDA-approved formulations.
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. There are many combined formulations which include both estrogen and progestogen.
Tibolone – a synthetic medication available in Europe but not the United States– is more effective than placebo
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. Sometimes an androgen, generally testosterone, can be added to treat diminished libido.
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
An intrauterine device can be used to receive HRT.
The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration:
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
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 and estradiol cypionate.
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
(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 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.
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 did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the Federal Food, Drug, and Cosmetic Act
(FDCA), but they have encountered obstacles in this role since that
time. After 64 patient deaths and 750 harmed patients from a 2012
meningitis outbreak due to contaminated steroid injections, Congress
passed the 2013 Drug Quality and Security Act,
authorizing creation by the FDA of a voluntary registration for
facilities that manufactured compounded drugs, and reinforcing FDCA
regulations for traditional compounding.
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
regulates compounding performed within a pharmacy. All testosterone
prescribed in the United Kingdom is bioidentical, with its use supported
by the National Health Service. There is also marketing authorisation for male testosterone products. National Institute for Health and Care Excellence
guideline 1.4.8 states: "consider testosterone supplementation for
menopausal women with low sexual desire if HRT alone is not effective".
The footnote adds: "at the time of publication (November 2015),
testosterone did not have a United Kingdom marketing authorisation for
this indication in women. Bioidentical progesterone is used in IVF
treatment and for pregnant women who are at risk of premature labour."
Wyeth, now a subsidiary of Pfizer, was a pharmaceutical company 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 ghostwrittenreviews 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 and unproven uses like prevention of dementia, Parkinson's disease, vision problems, and wrinkles. In addition, Wyeth emphasized negative messages against the SERM raloxifene
for osteoporosis, instructed writers to stress the fact that
"alternative therapies have increased in usage since the WHI even though
there is little evidence that they are effective or safe...", called
into question the quality and therapeutic equivalence of approved
generic CEE products, and made efforts to spread the notion that the
unique risks of CEEs and MPA were a class effect of all forms of
menopausal HRT: "Overall, these data indicate that the benefit/risk
analysis that was reported in the Women's Health Initiative can be
generalized to all postmenopausal hormone replacement therapy products."
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 [HRT] outweigh the risks in asymptomatic women. This
non-evidence–based perception may be the result of decades of carefully
orchestrated corporate influence on medical literature." As many as 50% of physicians have expressed skepticism about large trials like the WHI and HERS in a 2011 survey.
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, according to May
and May (2012) and Fugh-Berman (2015).
Popularity
The 1990s showed a dramatic decline in prescription rates, though more recently they have begun to rise again.[129][146]
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.
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