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Some findings of the WHI were reconfirmed in a larger national study done in the UK, known as [[The Million Women Study]], leading to a reduction in the number of post-menopausal women on hormone replacement therapy.<ref>{{cite pmid|19196674}}</ref> The authors of the WHI recommended that women with normal rather than surgical menopause should take the lowest feasible dose of HRT for the shortest possible time to minimize their reported risks.<ref name = JAMA/> The [[United States Preventive Services Task Force]] also concluded that potential risks of long term therapy outweigh benefits.<ref>{{cite pmid|22786830}}</ref>
Some findings of the WHI were reconfirmed in a larger national study done in the UK, known as [[The Million Women Study]], leading to a reduction in the number of post-menopausal women on hormone replacement therapy.<ref>{{cite pmid|19196674}}</ref> The authors of the WHI recommended that women with normal rather than surgical menopause should take the lowest feasible dose of HRT for the shortest possible time to minimize their reported risks.<ref name = JAMA/> The [[United States Preventive Services Task Force]] also concluded that potential risks of long term therapy outweigh benefits.<ref>{{cite pmid|22786830}}</ref>


These recommendations have not held up with further data analysis however. Later studies released by the WHI showed that all cause mortality was not dramatically different between the groups receiving conjugated equine estrogen (CEE), those receiving estrogen and progesterone, and those not on HRT at all. Specifically, the [[relative risk]] for all-cause mortality were 1.04 ([[confidence interval]] 0.88–1.22) in the CEE-alone trial and 1.00 (CI, 0.83–1.19) in the estrogen plus progesterone trial.<ref>{{cite pmid|17405972}}</ref> Further In an analysis that pooled data from both trials, post-menopausal HRT was associated with a significant reduction in mortality (RR, 0.70; CI, 0.51–0.96) among women ages 50 to 59 yr. This would represent five fewer deaths per 1000 women per 5 yr of therapy. A robust [[Bayesian]] [[meta-analysis]] from 19 [[randomized clinical trial]]s reported similar data with a RR of mortality of 0.73 (CI, 0.52–0.96) in women younger than age 60.<ref>{{cite pmid|19854329}}</ref> However, MHT had minimal effect among those between 60 and 69 yr of age (RR, 1.05; CI, 0.87–1.26) and was associated with a borderline significant increase in mortality among those ages 70 to 79 yr (RR, 1.14; CI, 0.94 –1.37; P for trend � 0.06).<ref>{{cite pmid|16815651}}</ref><ref name="endocrine">{{cite journal |last1= Santen |first1= RJ|last2=Utian |first2=WH |year= 2010|title=Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement |journal=J Clin Endocrinol Metab |volume= 95 S1–S66 |issue=Supplement 1 |pages= |publisher= |doi= |url=http://www.endo-society.org/journals/scientificstatements/upload/jc-2009-2509v1.pdf |accessdate=Feb 7, 2013}}</ref>
These recommendations have not held up with further data analysis however. Later studies released by the WHI showed that all cause mortality was not dramatically different between the groups receiving conjugated equine estrogen (CEE), those receiving estrogen and progesterone, and those not on HRT at all. Specifically, the [[relative risk]] for all-cause mortality were 1.04 ([[confidence interval]] 0.88–1.22) in the CEE-alone trial and 1.00 (CI, 0.83–1.19) in the estrogen plus progesterone trial.<ref>{{cite pmid|17405972}}</ref> Further In an analysis that pooled data from both trials, post-menopausal HRT was associated with a significant reduction in mortality (RR, 0.70; CI, 0.51–0.96) among women ages 50 to 59 yr. This would represent five fewer deaths per 1000 women per 5 yr of therapy. A robust [[Bayesian]] [[meta-analysis]] from 19 [[randomized clinical trial]]s reported similar data with a RR of mortality of 0.73 (CI, 0.52–0.96) in women younger than age 60.<ref>{{cite pmid|19854329}}</ref> However, MHT had minimal effect among those between 60 and 69 years of age (RR, 1.05; CI, 0.87–1.26) and was associated with a borderline significant increase in mortality in those between 70 to 79 years of age (RR, 1.14; CI, 0.94 –1.37; P for trend < 0.06).<ref>{{cite pmid|16815651}}</ref> Similarly, in the HERS trial, with participants having a mean age of 66.7 yr, MHT did not reduce in total mortality (RR, 1.08; CI, 0.84 –1.38). <ref>{{Cite pmid|9718051 }}</ref> A 2003 meta-analysis of
30 randomized trials of menopausal HRT in relation to mortality showed that it was associated with a nearly 40% reduction in mortality in trials in which participants had a mean age of less than 60 yr or were within 10 yr of menopause onset but was unrelated to mortality in the other trials. <ref>{{Cite pmid|15209595 }}</ref> The findings in the younger age groups were similar to those in the observational [[Nurses Health Study]] (RR for mortality, 0.63; CI, 0.56 – 0.70).<ref>{{Cite pmid|9187066 }}</ref><ref name="endocrine">{{cite journal |last1= Santen |first1= RJ|last2=Utian |first2=WH |year= 2010|title=Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement |journal=J Clin Endocrinol Metab |volume= 95 S1–S66 |issue=Supplement 1 |pages= |publisher= |doi= |url=http://www.endo-society.org/journals/scientificstatements/upload/jc-2009-2509v1.pdf |accessdate=Feb 7, 2013}}</ref>


The relatively benign risk profile of HRT was confirmed in a consensus expert opinion published by the [[The Endocrine Society]], which states that when taken during perimenopause, or the initial years of menopause, hormonal therapy carries significantly fewer risks than previously published, and can reduce all cause mortality in the appropriate patient scenario.<ref name="endocrine"/>
The relatively benign risk profile of HRT was confirmed in a consensus expert opinion published by the [[The Endocrine Society]], which states that when taken during perimenopause, or the initial years of menopause, hormonal therapy carries significantly fewer risks than previously published, and can reduce all cause mortality in the appropriate patient scenario.<ref name="endocrine"/>

Revision as of 12:59, 8 February 2013

Hormone replacement therapy

Hormone replacement therapy (HRT) in menopause is medical treatment in surgically menopausal, perimenopausal and postmenopausal women. Its goal is to mitigate discomfort caused by diminished circulating estrogen and progesterone hormones in menopause. In those with premature or surgically induced menopause, it may also prolong life and may reduce incidence of dementia.[1] The main hormones involved are estrogen, progesterone and progestin.

There have been a number of large scale cross sectional and cohort studies on the effects of hormone replacement in menopause, with the largest conducted in the United States, the United Kingdom and China. Demographically, the vast majority of data available is about post-menopausal American women with at least some degree of co-morbidity, and the mean participant age in most studies is over 60 years.[2] In July of 2002 the Women's Health Initiative of the National Institutes of Health published the largest randomized control trial to date on the effects of hormonal replacement therapy in post-menopausal women. The study found disparate results for all cause mortality with hormone replacement, finding it to be lower when HRT was begun earlier, between age 50-59, but higher when begun after age 60. Both age groups had a slightly higher incidence of breast cancer, while heart attacks and strokes were increased in older patients, although not significantly higher in the younger group. Progesterone is the major anabolic hormone for breast tissue, and accordingly breast cancer was not increased in patients who were on estrogen therapy alone after hysterectomy. Sole therapy with estrogen is contraindicated if the uterus is still present due to the proliferative effect of hormone on the endometrial lining. The WHI also found a reduced incidence of colorectal cancer when estrogen and progesterone were used together, and most importantly, bone fractures. Ultimately, all cause mortality was lower for HRT than a menopausal hormonal profile when therapy was begun in the 50s, but not after age 60.[3]

Some findings of the WHI were reconfirmed in a larger national study done in the UK, known as The Million Women Study, leading to a reduction in the number of post-menopausal women on hormone replacement therapy.[4] The authors of the WHI recommended that women with normal rather than surgical menopause should take the lowest feasible dose of HRT for the shortest possible time to minimize their reported risks.[3] The United States Preventive Services Task Force also concluded that potential risks of long term therapy outweigh benefits.[5]

These recommendations have not held up with further data analysis however. Later studies released by the WHI showed that all cause mortality was not dramatically different between the groups receiving conjugated equine estrogen (CEE), those receiving estrogen and progesterone, and those not on HRT at all. Specifically, the relative risk for all-cause mortality were 1.04 (confidence interval 0.88–1.22) in the CEE-alone trial and 1.00 (CI, 0.83–1.19) in the estrogen plus progesterone trial.[6] Further In an analysis that pooled data from both trials, post-menopausal HRT was associated with a significant reduction in mortality (RR, 0.70; CI, 0.51–0.96) among women ages 50 to 59 yr. This would represent five fewer deaths per 1000 women per 5 yr of therapy. A robust Bayesian meta-analysis from 19 randomized clinical trials reported similar data with a RR of mortality of 0.73 (CI, 0.52–0.96) in women younger than age 60.[7] However, MHT had minimal effect among those between 60 and 69 years of age (RR, 1.05; CI, 0.87–1.26) and was associated with a borderline significant increase in mortality in those between 70 to 79 years of age (RR, 1.14; CI, 0.94 –1.37; P for trend < 0.06).[8] Similarly, in the HERS trial, with participants having a mean age of 66.7 yr, MHT did not reduce in total mortality (RR, 1.08; CI, 0.84 –1.38). [9] A 2003 meta-analysis of 30 randomized trials of menopausal HRT in relation to mortality showed that it was associated with a nearly 40% reduction in mortality in trials in which participants had a mean age of less than 60 yr or were within 10 yr of menopause onset but was unrelated to mortality in the other trials. [10] The findings in the younger age groups were similar to those in the observational Nurses Health Study (RR for mortality, 0.63; CI, 0.56 – 0.70).[11][12]

The relatively benign risk profile of HRT was confirmed in a consensus expert opinion published by the The Endocrine Society, which states that when taken during perimenopause, or the initial years of menopause, hormonal therapy carries significantly fewer risks than previously published, and can reduce all cause mortality in the appropriate patient scenario.[12]

Historical treatment

The first clinical usage of hormone replacement therapy in the setting of menopause began in the 1950s, with the administered estrogen purified from the urine of pregnant mares. From that time until 1975, estrogen was administered without supplemental progesterone or progestin. A study from Kaiser Permanente by Dr. Harry Ziel demonstrated that in the absence of progesterone, patients were at increased risk of endometrial cancer with unopposed estrogen therapy. After this, progestin was supplemented in women who had not received surgical hysterectomy, to reduce the incidence of endometrial hyperplasia and cancer. This was followed by the Women's Health Initiative (WHI) in 2002. However, the arm of the WHI receiving combined Estrogen and Progesterone therapy was closed prematurely by its Data Monitoring Committee (DMC) due to perceived health risks, although the trial arm was stopped only 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.

Risks and benefits

Proprietary mixtures of progestins and conjugated equine estrogens are a commonly prescribed form of HRT. As the most common and longest-prescribed type of estrogen used in HRT, most studies of HRT involve CEE. More recently developed forms of drug delivery include suppositories, subdermal implants, skin patches and gels. They have more local effect, lower doses, fewer side effects and constant rather than cyclical serum hormone levels.[13]

The data published by the WHI suggested supplemental estrogen increased risk of venous emboli and breast cancer but were protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed.[14] These results were later confirmed in trials from the United Kingdom, but not in more recent studies from France and China.

Effect on venous and arterial coagulation

Clot in the greater saphenous vein; oral HRT is associated with increased risk of venous clot due to increased hepatic synthesis of Vitamin K dependent clotting factors.

Comparisons between orally administered pill and transdermal patch suggests that when estrogens are taken orally the risks of thrombophlebitis and pulmonary embolism are increased, an effect which is not seen with topical administration. Transdermal and transvaginal administration are not subject to first pass metabolism, and so lack the anabolic effects that oral therapy has on hepatic synthesis of Vitamin K dependent clotting factors.[15] This effect refers only to patches for post menopausal hormone replacement, which contain 17 beta estradiol, not those used in oral contraceptive therapy, which contain ethinyl estradiol. The later is associated with an increased incidence of venous clot.[16] The WHI also showed an increased incidence arterial disease, namely stroke, in patients who began HRT after the age of 65, although this effect was not significantly present in those who began therapy during their fifth decade.

Cardiovascular effects

At the time of menopause, there are predictable effects on the lipid profile. Specifically, HDL decreases, while LDL, triglycerides and lipoprotein a increase. Supplemental estrogen improves the lipid profile by reversing each of these effects. Beyond this, it improves cardiac contractility, coronary artery blood flow, metabolism of carbohydrates, and decreases platelet aggregation and plaque formation.

The impact of hormone replacement on cardiovascular morbidity is a subject of much controversy in the medical literature. The reduced risk of cardiovascular diseases associated with hormone replacement therapy (HRT), reported in observational studies, has not been subsequently confirmed in randomized clinical trials. The increased risk of cardiovascular disease in the WHI was not statistically significant, and only found in the oldest women, and those who started HRT late after menopause began.[17] The increase in risks of coronary heart disease in the treatment arm of the study varied according to age and years since onset of menopause. Women aged 50 to 59 using HRT showed a trend towards lower risk of coronary heart disease,[18] as did women who were within five years of the onset of menopause.[19]

The adverse cardiovascular outcomes may only apply to oral dosing with the progestin and equine estrogens in oral systemic therapy, while topical estradiol and estriol may not produce the same risks, due to the absence of anabolic effects of hepatic vitamin K dependent clotting factors.[16]

Another recent randomized controlled trial found HRT may reduces development of heart disease and reduce the incidence of heart attack in women between 50 and 59, although not in women past the age of 60. The mechanism may have something to do with the contradictory effects of increasing propensity for clotting, versus positive effect on the lipid profile. Follow-up studies are being performed which are intended to confirm these findings. The increased risk of breast cancer remains.[20]

Endometrial effects

Endometrial tumor on histology. Most commonly, the tumor is in situ with minimal morbidity; patients still have lower all-cause mortality than those not on HRT.

While combined estrogen-progesterone supplementation has been linked to an increased incidence of endometrial cancer, the specific subtype is usually stage I, or in situ, and has extremely low morbidity and mortality, and studies in American women have shown the tumor to not have propensity for growth into the myometrium or parametrial soft tissues. When seen in the context of all cause mortality, women who take estrogen and develop endometrial cancer have high survival rates than women who do not take hormonal therapy at all, which was due to the preventive effect of HRT on hip fractures.

Unopposed estrogen (the supplementation of endogenous estrogens without a progestogen) can also result in endometrial hyperplasia, a precursor to endometrial cancer. The extensive use of high-dose estrogens for birth control in the 1970s is thought to have resulted in a significant increase in the incidence of this type of cancer.[21]

Musculoskeletal effects

HRT is effective at reversing the effects of aging on muscle [22] and promoting reverse cholesterol transport (RCT) via the induction of cholesterol ABC transporters.[23]

Neurologic effects

According to a 2007 presentation at an American Academy of Neurology meeting,[24] hormone therapy taken soon after menopause may help protect against dementia, but it raises the risk of mental decline in women who do not take hormone replacement until they are older. Dementia risk was 1% in women who started HRT early, and 1.7% in women who didn't, (i.e. women who didn't take hormone replacement seem to have had—on average—a 70% higher relative risk of dementia than women who began HRT around the time of the beginning of menopause). This suggests that there may be a "critical period" during which time taking HRT may have benefits, but if HRT is initiated after that period, it will not have such benefits and may cause harm. This is consistent with research that hormone therapy improves executive and attention processes in postmenopausal women.[25] It is also supported by research upon monkeys that were given ovariectomies to imitate the effect of menopause and then estrogen therapies. This showed replacement treated compared to nontreated monkeys had long term improved prefrontal cortex executive abilities on the Wisconsin Card Sorting Test.[26]

Breast tissue effects

The WHI found breast cancer increased in post-menopausal women taking combined estrogen-progesterone therapy, but not in post-hysterectomy patients on estrogen therapy alone.

The relative risk (RR) of breast cancer varies from 1.24 in the WHI study to 1.66 in the Million Women Study, with results differing according to interval between menopause and hormone therapy and methods of hormone replacement.[27] The WHI preliminary results in 2004 found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer[18] and a 2006 update concluded that use of estrogen-only HRT for 7 years does not increase the risk of breast cancer in postmenopausal women who have had a hysterectomy.[28] The results of the WHI estrogen-alone trial suggest that the progestin used in the WHI estrogen-plus-progestin trial increased the risk for breast cancer above that associated with estrogen alone.[29]

A recent randomized controlled trial recently showed that increased breast cancer risk applied only to those women who take progesterone analogues, but not to those taking bio-identical progesterone itself, nor to hysterectomized women who take unopposed estrogen.[30]

Some reports have not found an association of progesterone therapy and breast cancer. The absence of effect in these studies has been suggested to be due to selective prescription to overweight women, or to the very low progesterone serum levels after oral administration leading to a strong tumor inactivation rate.[31]

Prevention of hip fractures

File:Femoral neck fracture, right hip.jpg
Hip fractures were decreased in patients on HRT, causing a significant reduction in all cause mortality.

Estrogen prevents the activity of osteoclasts, and improves bone mineral density. Hip fracture is a leading cause of morbidity and mortality in older females, and usually does not occur in the setting of osteoporosis. Estrogen is the only medical therapy that has been shown to prevent hip fractures in women that are not osteoporotic, with efficacy superior to bisphosphonates or calcium and vitamin D supplementation.

Premature stoppage of Women's Health Initiative

Clinical medical practice changed with two parallel WHI studies of postmenopausal HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. The WHI studies were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy, postmenopausal women.

The WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined conjugated equine estrogen and progestin exceeded their benefits. The estrogen-alone trial, performed on women who were post hysterectomy, due to the proliferative effect of the hormone on endometrial tissue, did not show such problems and was continued. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in estrogen only arm, risks of stroke and pulmonary embolism were increased, predominantly in patients who began HRT over the age of 60.[32]

The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.[33] It 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 progestin medroxyprogesterone acetate and conjugated equine estrogen.

The study 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." [1] The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with PremPro, the specific proprietary combination of conjugated equine estrogen and progestin studied.

After the increased clotting found in the first WHI results was reported in 2002, the number of Prempro prescriptions filled reduced by almost half. An unknown number of women started taking alternatives to Prempro, such as bioidentical hormones.[34] A sharp drop in breast cancer rates was observed following these changes, and held steady in subsequent years.[35]

Women's Health Initiative limitations and criticisms

The WHI trial was limited by low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens.[36] The double blinding limited validity of study results due to its effects on patient exclusion criteria. Patients who were experiencing symptoms of menopause were excluded from the study. As a result, while the average age of menopause is at age 51, study participants were on average 62 years of age. Demographically, the vast majority were Caucasian, and tended to be slightly overweight and former smokers.

Bioidentical hormone replacement therapy

Main article: Bioidentical hormone replacement therapy

Bioidentical hormone replacement therapy refers to the use of hormones that are chemically identical to those produced in a woman's body, though they are also associated with the practices of pharmaceutical compounding and saliva testing to determine, and adjust a woman's hormone levels. The latter two practices are not widely accepted in clinical medicine. Compounding has not demonstrated any benefits and presents risks of uncertain dosing, potency and possible contamination. In addition, saliva testing is of limited utility due to natural fluctuations in hormone levels, and lack of consensus for ideal dosage in humans.[37]

Proponents also claim that BHRT can offer advantages beyond those typical of traditional HRT, though there is no evidence to support these claims. The United States Food and Drug Administration states that BHRT is expected to present the same risks and benefits of non-bioidentical HRT, but that traditional products have been researched to quantify these risks and benefits, and are produced by manufacturers with stringent purity and potency standards.[38]

Contraindications

Absolute contraindications

Relative contraindications

Side effects

Administration and formulations

HRT is available in various forms. It generally provides low dosages of one or more estrogens, and often also provides either progesterone or a chemical analogue, called a progestin. Testosterone may also be included. In women who have had a hysterectomy, an estrogen is usually given without any progesterone, a therapy referred to as "unopposed estrogen therapy". HRT may be delivered to the body via patches, tablets, creams, troches, IUDs, vaginal rings, gels or, more rarely, by injection. For example, vaginally administered estrogens include those given by intravaginal tablets, creams and rings, and can have more effect on atrophic vaginitis with fewer systemic effects than estrogens delivered by other means.[40]

Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progesterone or progestins taken for about two weeks every month or two; a method called "cyclic HRT" or "sequentially combined HRT" (abbreviated scHRT). An alternate method, a constant dosage with both types of hormones taken daily, is called "continuous combined HRT" or ccHRT, and is a more recent innovation. Sometimes an androgen, generally testosterone, is added to treat diminished libido. It may also treat reduced energy and help reduce osteoporosis after menopause.

HRT is often given as a short-term relief (often one or two years, usually less than five) from menopausal symptoms (hot flushes, irregular menstruation, fat redistribution, etc.). Younger women with premature ovarian failure or surgical menopause may use hormone replacement therapy for many years, until the age that natural menopause would be expected to occur.

Formulations of estradiol include:

In addition, there are many formulations of estradiol combined with one of various progestins, such as norethisterone (in Activelle), levonorgestrel, medroxyprogesterone, dienogest or drospirenone.

See also

References

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  37. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15167316, please use {{cite journal}} with |pmid=15167316 instead.
  38. ^ "FDA Takes Action Against Compounded Menopause Hormone Therapy Drugs". FDA. 2008-01-09. Retrieved 2009-02-17.
  39. ^ Suchowersky O, Muthipeedika J (2005). "A case of late-onset chorea". Nat Clin Pract Neurol. 1 (2): 113–6. doi:10.1038/ncpneuro0052. PMID 16932507. {{cite journal}}: Unknown parameter |month= ignored (help)
  40. ^ Estrogen (Vaginal Route) from Mayo Clinic / Thomson Healthcare Inc. Portions of this document last updated: Nov. 1, 2011

External links

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