Menopause II: Types of HRT and Physiological Consequences
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Components of Common Hormone Therapies
17-beta estradiol (E2), the primary circulating estrogen during reproductive years, was first isolated in 1935 from sow ovaries (Stumpf, 1992). E2 is difficult to use as a postmenopausal therapy as much of the compound is deactivated in the gastrointestinal tract unless the hormone is micronized, and even then most E2 is converted to the less potent estrone (E1).
In the United States, conjugated equine estrogens (CEE), or oral Premarin, is the most widely used form of estrogen replacement therapy (ERT). Conjugated equine estrogens are extracted from the urine of pregnant mares (Stumpf, 1992). CEE is a mixture of many different compounds, some of which are not naturally present in the human: estrone sulfate (50%), equilin sulfates (40%), and at least ten other estrogenic compounds. E2 is not a major component of Premarin, although an oral dose of 0.625 mg/day is sufficient to produce normal E1 and E2 levels in most women. CEE is often used in conjunction with a progestin. Natural progesterone faces the same problems of absorption as E2 (Stumpf, 1992), consequently the most common progestin in the United States is the synthetic medroxyprogesterone acetate (MPA), which is produced by addition of a methyl group to the 6 position, and one acetoxy group to the 17α position of progesterone. MPA is also administered orally and is absorbed quickly, with levels peaking in serum in a few hours.
During oral administration sex steroids experience the “first pass” effect of exposure to the liver, where they undergo metabolic conversions, conjugation to water-soluble sulfates, and prepararation for excretion. Thus, oral administration of hormones can reduce bioavailability of estrogens as they become inactivated by conjugation (Lobo, 1987). This first pass also stimulates production of hepatic proteins and lipoprotein packaging that could have positive consequences for the circulatory system. Progesterones are subject to the same first-pass effect, where they can negate any benefit on lipid profiles exerted by estrogen.
Other forms of estrogen + progesterone combinations (hormone replacement therapy, or HRT) are available, and a number of routes and regimens are also available. Transdermal patches, vaginal creams, or intramuscular injections are common routes of administration that bypass the first-pass effects of the liver in an attempt to deliver estrogens directly into the bloodstream (Stumpf, 1992). Treatment regimens may include any combination of cyclic or continuous estrogen and/or progesterone, tailored to the needs of the individual.
Consequences of Ovarian Hormone Loss and ERT or HRT
Symptoms Associated with Menopause: Hot flashes, the increase in perception of heat within or on the body, often accompanied by perspiration, skin flushing, and insomnia, are a common complaint of women undergoing menopause. Estimates of hot flash prevalence are between 50 and 85% of women, and incidence of hot flashes decreases with the postmenopausal interval. Other symptoms such as vaginal dryness and changes to vaginal epithelium, epidermal changes, and a variety of urinary dysfunctions are common (Greendale and Sowers, 1997). Psychological symptoms may also occur, such as increased anxiety and depression (Rogers, 1956a). Early studies pointed to the benefits of using hormonal replacement to treat these physiological and psychological symptoms (reviewed in Rogers, 1956b). In the 1960s, hormone replacement became the subject of numerous studies that attempted to discern whether they could be used effectively to treat chronic conditions relating to menopause, and whether prolonged use of hormones had consequences of their own.
Osteoporosis: Albright et al (1941) suggested estrogen replacement therapy as a treatment for postmenopausal osteoporosis. Measures of bone density became available in the 1960s, prompting an increase in attention to these issues and confirming that decreases in bone density follow the loss of circulating estrogens that occurs with menopause, and which can lead to osteoporosis. Bone mineral density declines at a rate of roughly 1% per year during perimenopause (Greendale and Sowers, 1997), and this loss is accelerated to 2-3% in radius and 5% in spine immediately following menopause (Cann et al., 1980). ERT was found to reduce the risk of hip and wrist fractures by 60%, and doses of Premarin as low as 0.625 mg inhibit postmenopausal bone loss (Lindsay et al., 1976), both with and without a progestin (The Writing Group for PEPI, 1996).
Cancers: Endometrial cancer rates increased in association with estrogen replacement therapy from 1953-1973, with the first reports appearing in 1975 (Smith et al., 1975; Ziel and Finkle, 1975), prompting a shift to therapies that included a progestin to offset endometrial hyperplasia. Combined hormone replacement therapy is not associated with endometrial cancer, making this therapy more appropriate for women who still had a uterus. In the 1980s, the first studies reported that combining ERT with a cyclic or continuous progestin could prevent endometrial cancer in women (Thom et al., 1979; Whitehead et al., 1981; Gambrell et al., 1983). An increased risk of breast cancer was identified from observational studies of ERT (Steinberg et al., 1991; Grady et al., 1992), and a later meta-analysis of 51 studies also suggested the same (Beral et al., 1997). Unfortunately, human and animal studies in the 1930s and 1940s had suggested associations between hyperestrogenism and mammary cancer (reviewed in Rogers, 1956b), but these potential links were not adequately addressed for decades.
Coronary Heart Disease: The first studies demonstrating that ERT could reduce the risk of coronary heart disease (CHD) were released in the 1980s (Bain et al., 1981; Ross et al., 1981; Sullivan et al., 1988). It was also shown that ovariectomy led to a doubling of the risk of CHD, which could be prevented with ERT (Colditz et al., 1987). Other studies demonstrated favorable outcomes of ERT and HRT on CHD and serum lipid profiles (Bush et al., 1987; Rijpkema et al., 1990; Stampfer and Colditz, 1991; Grady et al., 1992), with as much as a 40-50% decrease in CHD, and studies in primates also suggested a protective effect of ERT on coronary artery atherosclerosis in ovariectomized (OVX) monkeys, although addition of a progestin had no effect (Adams et al., 1990). However, in studies of women with prior CHD, HRT seemed to increase risk of a CHD event (Hulley et al., 1998; Grady et al., 2002). Moreover, HRT did not reduce progression of atherosclerosis in another study (Herrington et al., 2000).
A Response to the Controversies: The Women’s Health Initiative
The Women’s Health Initiative (WHI) began as a pair of randomized clinical trials designed in 1991-1992 to assess the relative risks and benefits of HRT and ERT on major outcomes associated with menopause, primarily CHD, and hopefully shed light on prior conflicting reports. The studies enrolled 161,809 postmenopausal women between the ages of 50 and 79 from 40 clinical centers around the United States and was divided into two arms: The HRT arm targeted the effects of most common regimen, a daily oral dose of 0.625 mg CEE + 2.5 mg MPA (Prempro, Wyeth-Ayerst, Philadelphia, PA) in healthy women who still had a uterus, and the ERT arm examined 0.625 mg CEE daily on major outcomes in women who had undergone hysterectomy. The major outcomes assessed were CHD (primary outcome) and invasive breast cancer (the primary negative outcome), stroke, pulmonary embolism, endometrial and colorectal cancer, and hip fracture.
The HRT arm was stopped after 5.2 of a planned 8.5 years, due to the relative risks exceeding benefits. All-causes mortality was not affected, but there was a 26% increased risk of breast cancer, a surprising 29% significant increased risk of CHD, and a 41% increase in stroke rates with a twofold increase in venous thromboembolism for the HRT group. Colorectal cancer risk was reduced 37% and fractures reduced by 24% in the HRT group, but these benefits were not enough to confer an overall benefit and justify continuation of the trial (WHI Writing Group for the Women’s Health Initiave Investigators, 2002). The ERT arm was also terminated early due to an increased risk of stroke (39%) in the CEE group. There was a decreased risk of hip fracture in the CEE group compared to controls (30 to 39%), a possible reduction in breast cancer (23%), but no overall effect on CHD. As the overall risk was not different between CEE and placebo, the trial was terminated (WHI Writing Group for the Women’s Health Initiative Investigators, 2004).
Ovarian Hormones and Alzheimer’s Disease--The WHI Memory Study: Postmenopausal women have a higher risk of developing Alzheimer’s Disease (AD) than men, and it has been suggested that ERT can reduce this risk. A number of studies support this notion; case-controlled, cross-sectional, and prospective studies have reported that women taking ERT have a lower risk of dementia than do postmenopausal women not taking estrogen (Kawas et al., 1997; Henderson et al., 1994; Waring et al., 1999; Steffens et al., 1999; Baldereschi et al., 1998; Tang et al., 1996; Cauley et al., 1990; Matthews et al., 1999). Recent meta-analyses suggest the risk reduction for AD is 29-34% (Yaffe et al., 1998; Nelson et al., 2002) for women receiving ERT. A recent prospective study reported that HRT also decreased risk of the disease, with increasing duration of HRT conferring an increased benefit (Zandi et al., 2002). ERT might also have positive effects on cognition in women diagnosed with AD, as early studies found improvements on memory (Honjo et al., 1989), attention and orientation (Fillit et al., 1986), and subsequent studies seemed to bolster these findings (Henderson et al., 1994; Okhura et al., 1994; Okhura et al., 1995). However, some observational studies of ERT did not find a cognitive benefit or decreased risk of AD (Cauley et al., 1990; Barrett-Connor and Kritz-Silverstein, 1993; Brenner et al., 1994; Matthews et al., 1999), and neither have some prospective clinical trials (Henderson et al., 2000; Mulnard et al., 2000; Wang et al., 2000).
With these issues in mind, the WHI Memory Study (WHIMS) was conducted. This ancillary study to the WHI found that the risk of probable dementia in patients receiving Prempro was actually increased in postmenopausal women age 65 or older (Shumaker et al., 2003). Additionally, CEE increased the risk of developing mild cognitive impairment combined with AD (Shumaker et al., 2004), and CEE or CEE + MPA decreased performance on a cognitive profile (Espeland et al., 2004). The results from WHIMS differ markedly from prior reports which often consisted of mixed hormone regimens and doses, suggesting that specifically, the CEE + MPA combination may be detrimental.
Implications for WHI and WHIMS: While the WHI and WHIMS studies provide us with valuable information about the risks and benefits of ERT and HRT, the results must be interpreted with caution. Firstly, the studies assessed only very select forms of ERT and HRT, so their results should not be generalized to all forms of hormone replacement. Secondly, these studies were initiated in women who had been postmenopausal for a number of years, which suggests that they might have missed the “window of opportunity” where they could have received the most benefit from treatment. Additionally, many of the women in the study also displayed risk factors for the major outcomes of the study, which could have put them at increased risk for the negative consequences for the use of HRT. While there was no increased mortality, the lack of overall benefit of ERT/HRT justified early termination of the trials, as it was unlikely that prolonged exposure to hormone therapy would benefit the subjects.
While the WHIMS study found negative consequences for women taking ERT or HRT on a number of measures, including an overall cognitive profile, this study did not assess the effects of hormone therapy on specific cognitive domains. Indeed, a recent review of the literature suggests that symptomatic younger women who complain of more specific cognitive impairments associated with menopause may benefit from hormone therapy, while incurring little to no risk from the treatment (Maki, 2005).
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