Introduction
Hormone replacement therapy (HRT) was firstly introduced in 1897, when ovarian extract was reported to have successfully treated sever hot flushings. After Premarin (conjugated estrogens) was approved by Canada and U.S. in the early 1940s, HRT was gradually introduced for symptom relief. With women’s pursuit to “preservation of youth” and prevention of chronic disease, HRT got more and more popular since 1980s, when estrogens were documented to prevent osteoporosis, and the addition of progestins eliminated the risk of endometrial cancer. By the early 1990s, HRT was prescribed to over 20 million women in the U.S. But recently, with some negative results coming out from a large clinical trial called Women’s Health Initiative (WHI) Study, both clinicians and patients become more cautious to use HRT. Now, after balancing the risks and benefits of HRT, it’s pertinent to say that HRT is still playing a very important role in women’s health care, especially in peri- and postmenopause women, whose estrogen levels start to fall or have dropped significantly.
As we can see from the above figure, the average life expectancy was reported to be 80 years for women in well-developed countires, while the median age for menopause was 51, which means for a woman, over 1/3 of her life is in the menopausal period. During the menopausal stage, some women experience many sufferings, such as hot flushes, mood swing, night sweats, vulva pruritus, vaginal dryness, dyspareunia and dysuria. More importantly, some women start to experience coronary heart diseases and osteoporosis, or even fatal hip fracture. Proper medical intervention at this point of life offers women many years of benefit from preventive health care. Most of these menopausal symptoms can be relieved by HRT. That’s why besides creating good health behavior, HRT becomes a promising approach for women to seize.
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Based on the components of what used in HRT, it can be categorized as estrogen-progesterone therapy (EPT) and estrogen therapy (ET). Recently with the use of androgen, another estrogen, progesterone and androgen therapy (we call it as “EPAT”) has come out. The potential benefits of androgen treatment is improved sexual function, however, some unwanted effects, such like acne, alopecia, hirsutism, and a negative impact on the cholesterol-lipoprotein profile limit the use of EPAT.
The progestin administration in HRT is very important, which effectively protect endometrium against unchecked proliferation. ET is used only for some, but not all, hysterectomized women. For patients previously treated for endometrioid tumors of ovary, or endometriosis, or supracervical hysterectomy, unopposed estrogen increases the risk of disease recurrence, or the carcinogenesis of the residual endometrium. In such cases, EPT is a better choice for women need HRT. In EPT, there are two different regimens: sequential and continuous. In the sequential regimen, progestins are administered for about 2 weeks of every month, with the progestin withdrawal bleeding seen in 80-90% of women. This cyclic bleeding mimics menstruation, which not only makes some women feel natural and young, but also may help get rid of bad endometrial cells through menstruation. The later benefit may be more important from a biologic point of view. But for some women, monthly bleeding is not acceptable, they prefer the continuous combined method of treatment, which results in amenorrhea within 1 year of treatment in 80-90% of patients. The advantage or disadvantage of both regimens is still under clinical survey.
There are many routes of administration for HRT. Taken estrogen as an example, it can be given by oral, transdermal, vaginal or intranasal administration. As to progesterone, besides oral, the progestin intrauterine device is another method available. Which route to choose? It depends on women’s tolerance on the systemic or local side-effects of the treatment.
General Guidelines for HRT
In early 2002, the American College of Obstetricians and Gynecologists (ACOG) started a task force dedicating to evidence-based evaluation of the risks and benefits of HRT. The task force consisted of physicians from several specialties with expertise in the issues related to hormone therapy. Task Force participants then reviewed relevant full-text articles with emphasis on study design quality. Members focused on randomized controlled trials. If this type of research was lacking, then meta-analyses of observational, cohort, and case-control studies were considered. Case series and other reports were evaluated in the absence of other evidence. After two year’s hard work, ACOG published serial papers stating the benefit and risk of HRT, which are served as the current authority guidelines for HRT.
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How long does it take for HRT to be effective? It usually takes approximate 4 weeks for women to determine the effectiveness of HRT in alleviating vasomotor symptoms. Patients are encouraged to take HRT as long as they want the benefits. But usually, the lowest effective estrogen dose should be used for the shortest possible time to alleviate symptoms. And the regular physical examination and annual reassessment is required for women using HRT.
When should women start HRT? Are hormones more effective when initiated during, or very soon after menopause transition? It remains unclear and is an important area for future inquiry. In clinical practice, more physicians prefer to suggest women in perimenopause consider HRT. Actually, that is the right time for education.
Overall, before initiating HRT or when renewing annual HRT prescription, each patient and her physician should discuss all the known benefits and risks in detail, thus helps woman to make the best decision for her own health. And remember, for all postmenopausal women, lifestyle modification strategies including smoking cessation, healthy diet, physical activity, and weight reduction/maintenance should be pursued regardless the use of HRT.
Benefits and Risks
As the cartoon shown above, brain, heart, breast, uterus, liver and bone, etc. are all estrogen target tissues. Loss of estrogen will cause lots of problems in the function of these target tissues. HRT benefit women mostly through supplemental estrogen, however, excess estrogen in some tissues results in increasing risks.
Benefits
The short-term benefit of HRT is symptom control, while the long-term benefits include decreasing osteoporosis and fracture, and improved life quality.
ET or EPT is the effective treatment for hot flushes and night sweats. Intranasal and transdermal delivery of 17[beta]-estradiol have demonstrated comparable efficacy and safty.
Estrogen is effective for treatment of vaginal dryness and atrophic changes associated dyspareunia that impede sexual function. Topical and systemic estrogens appear equally efficacious. Androgen therapy has been shown in surgically menopausal women to improve desire, but the dose is relatively high (300 µg).
HRT may increase collagen content and skin thickness and reduce wrinkling in non—sun-exposed areas. But there is insufficient evidence to recommend estrogen to improve wound healing.
Local application of estrogens may reduce urinary tract infections, improve vaginal maturation index and even relief urinary incontinence. Even very low doses of estrogen, either orally or vaginally, are effective in relieving symptoms of atrophic vaginitis.
There is no evidence linking either natural or surgical menopause to psychologic distress. Women’s mood is largely affected by vasomotor symptoms and sleep disturbance, which can be improved by estrogen replacement.
So far, no strong evidence for beneficial effects of HRT on cognition or dementia can be found. National Institute of Aging has conducted a study called PREPARE (Preventing Postmenopausal Memory Loss and Alzheimer’s with Replacement Estrogens), more data is expected to come out soon.
HRT reduces the number of all osteoporotic fractures, and it may be an appropriate first choice of therapy for osteoporosis for women with menopausal symptoms. Estrogens are an effective antiresorptive agent and are equivalent to bisphosphonates for effect on bone density.
Risks
HRT increases at least a 2-fold greater risk of venous thromboembolism, and the risk of pulmonary embolism is also increased. The excess risk of pulmonary embolism for a woman, aged 50–59 years, treated 5 years with HT is 1.6/1,000 women; for women 60–69 years of age, the excess is 4/1,000 women. Venous thromboembolism is more likely to occur in the first year of therapy and especially in women with a history of cardiovascular disease.
HRT increases the risk of stroke in postmenopausal women.
Neither ET nor EPT has been shown a benefit for coronary heart disease (CHD).
And there is a concerning time trend for increased cardiovascular events within the first year after initiation of HRT that appears to diminish over time. Thus, HRT should not be started or continued for prevention of CHD.
- Pancreatitis and Cholecystitis
Pancreatitis is a rare but potentially fatal risk of estrogen therapy. HRT may also increase risks of gallstones and biliary tract surgery.
- Relationship with breast cancer and other cancer risk
1. Breast Cancer
The current use of HRT has a slightly increase risk of breast cancer. The absolute risk for breast cancer remains low (20 per 10,000 over 5 years), but the risk does increase. Most of the studies indicated a greater risk associated with EPT compared with ET. About 25% of women on EPT have an increase in their breast density, and the effect occurs within the first months of use, but no changes happen with increasing duration of use. The current epidemiologic data failed to show an increasing risk for women had a positive family history of breast cancer, but the use of HRT for these women still need to be prudent. On balance, multiple observational studies suggest an increased risk for developing breast cancer, but there are many that are well designed that do not.
2. Endometrial Cancer
Estrogen therapy alone can increase the risk of endometrial cancer, but the addition of progestins is protective. Continuous, combined EPT is reported not only to prevent the excess risk of endometrial cancer associated with unopposed estrogen, but also lower the risk of endometrial cancer with increasing duration of use. However, it is unwise to expect all women on EPT to never develop endometrial cancer. Appropriate monitoring of patients are still needed.
3. Ovarian Cancer
A weak association between HRT (after more than 10 years of use) and increased risks of ovarian cancer was found on a small retrospective study. But the majority of case-control studies find no increase of the risks of ovarian cancer with HRT. It remains an unsettled issue, needs further epidemiologic assessment.
4. Cervical Cancer
No adverse effects of HRT on the survival or recurrence of cervical cancer have been reported. But more extensive studies are needed.
5. Colorectal Cancer
EPT reduces the risk of colorectal cancer incidence and mortality, while ET didn’t record a difference in colorectal cancer. And EPT reduce the risk of new colonic cancers, but influence the already present cancers to reach a more advance stage. It is not encouraged to take HRT solely for colorectal cancer prevention.
Who Should Use HRT
Women who have middle or obvious menopausal syndrome should take HRT. And women have increased risks for fractures should consider using HRT to prevent bone loss after thoroughly discussing the risks and benefits.
Who Should NOT Use HRT
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Current or past breast cancer
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Women about to have major surgery
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Pregnancy
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Overweight
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Have a hypertriglyceridemia or a family history of hypertriglyceridemia
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Previous Venous thromboembolism
- A history of stroke or transient ischemic attach
For more information, please refer to our recent seminar “Hormone Replacement Do I need it?” [PDF].
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