Hormone replacement therapy—estrogens + progestogens

1692 Hormone replacement therapy—estrogens þ progestogens 38. Ewies AAA, Olah KSJ. Endometrial adenocarcinoma treated by hysterectomy and bilateral salpingo-oophorectomy at age 22-the dilemma of long-term HRT. J Obstet Gynaecol 2000;20:639–40. 39. Mattix H, Singh AK. Estrogen replacement therapy: implications for postmenopausal women with end-stage renal disease. Curr Opin Nephrol Hypertens 2000;9(3):207–14. 40. de Lignieres B. Hormone replacement therapy: clinical benefits and side-effects. Maturitas 1996;23(Suppl):S31–6. 41. Heikkinen JE, Vaheri RT, Ahomaki SM, Kainulainen PM, Viitanen AT, Timonen UM. Optimizing continuouscombined hormone replacement therapy for postmenopausal women: a comparison of six different treatment regimens. Am J Obstet Gynecol 2000;182(3):560–7. 42. Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000;95(5):726–31. 43. Bjarnason NH, Byrjalsen I, Hassager C, Haarbo J, Christiansen C. Low doses of estradiol in combination with gestodene to prevent early postmenopausal bone loss. Am J Obstet Gynecol 2000;183(3):550–60. 44. Hermenegildo C, Garcia-Martinez MC, Valldecabres C, Tarin JJ, Cano A. Transdermal estradiol reduces plasma myeloperoxidase levels without affecting the LDL resistance to oxidation or the LDL particle size. Menopause 2002;9(2):102–9. 45. Scarabin PY, Oger E, Plu-Bureau G, EStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362(9382):428–32. 46. Justice AJ, de Wit H. Acute effects of estradiol pretreatment on the response to d-amphetamine in women. Neuroendocrinology 2000;71(1):51–9.

Hormone replacement therapy— estrogens þ progestogens

Two alternatives to long-term estrogen therapy have been proposed, because of the fear of certain risks (particularly malignancy) that might result in postmenopausal women: 



combined estrogen þ progestogen regimens with a monthly interruption to allow for withdrawal bleeding long-term therapy with estrogens alone periodically interrupted by a cycle of combined treatment.

In those few countries in which hysterectomy is still endemic it has been argued that in the residual minority of women with an intact uterus combination therapy should be the normal form of HRT. Therapeutic benefits have also been claimed from using the combination. Unfortunately, some of the publications that have made claims for the therapeutic advantages of adding progestogens to estrogens in HRT have not provided exact comparative data, and the beneficial effects which are described are not clearly different from those claimed for estrogen alone. The dispute about the benefit to harm balance of the various competing forms of HRT for use in the climacteric or postmenopausally is becoming increasingly intense, with a sharp division of opinion between protagonists and critics of the individual patterns of treatment. The view was often defended by earlier workers that, at least for certain classes of users, some form of combined estrogen þ progestogen treatment is likely to be more appropriate and perhaps more physiological than estrogen replacement alone. Many variants have been used and none is likely to be ideal for all subjects. Some have argued that in the climacteric there are sound reasons for using estrogen with intermittent progestogen and that it is much underused, despite the fact that uterine bleeding and other adverse progestogenic effects are, with some combined formulations (but not all), major reasons for patient noncompliance and early withdrawal (1).

See also Estrogens and Progestogens

General Information For a complete account of the adverse effects of estrogens, readers should consult the following monographs as well as this one:      

Diethylstilbestrol Estrogens Hormonal contraceptives—emergency contraception Hormonal contraceptives—oral Hormone replacement therapy—estrogens Hormone replacement therapy—estrogens þ androgens.

For a complete account of the adverse effects of progestogens, readers should consult the following monographs as well as this one:      

Hormonal contraceptives—intracervical and intravaginal Hormonal contraceptives—oral Hormonal contraceptives—progestogen implants Hormonal contraceptives—progestogen injections Medroxyprogesterone Progestogens.

ª 2006 Elsevier B.V. All rights reserved.

Observational studies In 104 women with established postmenopausal osteoporosis, continuous estrogen þ progestogen therapy resulted in increases in bone mineral density of the femoral neck and a fall in systolic blood pressure; the most common adverse effects were mastalgia (44%) and vaginal bleeding (29%) (2). The combined use of estradiol and dydrogesterone reduce both diastolic and systolic blood pressures in postmenopausal women in whom the diastolic pressure had been raised (3). Evidence is also advanced from various quarters that adding a progestogen to adequate dosages of an estrogen promotes new bone formation, restores bone that has been lost and reduces the risk of carcinoma of the breast. When 16 diabetic and hypertensive postmenopausal women aged 47–57 years were treated cyclically with estradiol plus norgestrel, existing proteinuria and even creatinine clearance often improved (4). The effects were unrelated to conventional risk factors for vascular complications, such as raised blood pressure, plasma glucose, or serum cholesterol.

Hormone replacement therapy—estrogens þ progestogens General adverse effects Of 206 postmenopausal women who took the oral combination of estradiol valerate plus norethisterone (5) eight withdrew because of bleeding during year 1; during years 2 and 3 there were no withdrawals because of bleeding. By the end of year 3, 133 patients had completed the study. There were serious adverse effects in 24, but there was no definite relation to therapy. The numbers of adverse events reported each year by the patients who completed the study are shown in Table 1. The authors concluded that this combination was effective in the majority of patients and was well tolerated. Distinguishing adverse effects due to estrogens or progestogens When patients have adverse effects during combined hormone replacement therapy it is necessary to determine whether the progestogen or the estrogen is causing the problem. If heavy bleeding or breast tenderness is the primary complaint, the estrogen component is probably the problem and therefore the dose should be reduced. If the patient complains of irritability, depression, water retention, or headaches, the problems are probably due to the progestogen component and the latter should in that case be changed or the dose adjusted; since several different progestogens are in use (particularly norethindrone, norethindrone acetate, medroxyprogesterone acetate, and micronized progesterone) there is a degree of choice. Benefit to harm balance With increasing concern over the long-term safety of hormone replacement therapy, the benefit to harm balance has Table 1 The numbers of adverse events in 3 successive years in patients taking estradiol valerate þ norethisterone (5) Adverse event

Year 1 (n ¼ 164)

Year 2 (n ¼ 144)

Year 3 (n ¼ 133)

Cardiovascular Hypertension Palpitation Phlebitis

5 4 3

3 4 —

— 3 —

Respiratory Breathlessness

3

0

1

Metabolism Weight gain

10

5

2

Gastrointestinal Abdominal pain

2

2

—

Musculoskeletal Fractures Joint/bone pain

7 6

1 3

1 6

Reproductive system Menopausal symptoms Breast tenderness Breast lumps Bleeding/spotting Abnormal smear Ovarian cysts

4 63 2 91 — 1

1 4 4 60 2 1

5 3 2 24 — 4

Other adverse events

105

53

34

Total

306

143

85

to be continually reassessed, and conclusions as to its prophylactic or therapeutic value need to be adjusted as experience accumulates. Not all the promises held out for the benefits of this therapy have been confirmed. For example, while estrogens prevent peripheral bone loss they do not prevent vertebral fractures (6) and in a 2-year placebo-controlled, crossover study in 34 healthy postmenopausal women, treatment with transdermal estrogen alone (Menorest 50 micrograms/day) did not improve lipid profiles or any indices of arterial function (7). It is remarkable that, despite decades of accumulated observational evidence, the balance of benefits and harms for hormone use in healthy postmenopausal women remains uncertain (8). Quite apart from the constantly changing spectrum of the available data, one explanation for the confusion is the relatively high proportion of poor-quality clinical work, particularly studies that are designed to promote particular commercialized forms of treatment from among the many alternatives available. A study that cannot be faulted on that score is the Women’s Health Initiative, a randomized, controlled, primary prevention trial (planned to last for 8.5 years), in which 16 608 postmenopausal women aged 50–79 years with an intact uterus at baseline were recruited at 40 US clinical centers over the period 1993–98 (9). In one part of this study, 8506 participants received conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day; 8102 were given placebo. The primary desired outcome was reduction of coronary heart disease (non-fatal myocardial infarction and death), with invasive breast cancer as the primary anticipated adverse outcome. After a mean of 5.2 years, the data and safety monitoring board recommended stopping the trial of estrogen plus progestogen versus placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported harms exceeding benefits. The estimated hazard ratios (and 95% confidence intervals) were:       

ª 2006 Elsevier B.V. All rights reserved.

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coronary disease 1.29 (1.02, 1.63; n ¼ 286) breast cancer 1.26 (1.00, 1.59; n ¼ 290) stroke 1.41 (1.07, 1.85; n ¼ 212) pulmonary embolism 2.13 (1.39, 3.25; n ¼ 101) colorectal cancer 0.63 (0.43, 0.92; n ¼ 112) endometrial cancer 0.83 (0.47, 1.47; n ¼ 47) hip fracture 0.66 (0.45, 0.98; n ¼ 106) death due to other causes 0.92 (0.74, 1.14; n ¼ 331).

What the above amounts to is that the absolute excess risks per 10 000 woman-years attributable to the use of an estrogen plus a progestogen were seven more coronary heart disease events, eight more strokes, eight more pulmonary embolisms, and eight more invasive breast cancers, while the risk reductions per 10 000 woman-years were six fewer colorectal cancers and five fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 woman-years. The overall harms in this study thus clearly exceeded the benefits. All-cause mortality was not affected. Other published studies, many of which are of limited scope, do not run closely parallel to the above findings

1694 Hormone replacement therapy—estrogens þ progestogens from the Women’s Health Initiative, and the data on cardiovascular effects remain particularly confusing. However, Beral and colleagues have pointed out optimistically that ‘‘substantial new data should soon be available from randomized trials of estrogen-alone hormonal replacement therapy versus placebo,’’ although they added that ‘‘few additional trial data on combined hormone replacement therapy are expected for about a decade’’ (10). They also pointed out that existing randomized trials are too small to provide reliable evidence on some basic matters, including the relative risks of the various compounds in use.

Organs and Systems Cardiovascular Despite biologically plausible mechanisms whereby estrogens might be expected to confer cardioprotection in postmenopausal women, as well as observational data suggesting cardiovascular benefit, the literature continues to provide contradictory outcomes on this. Electrocardiographic work has suggested that not only the estrogen but also the progestogen component of HRT can have some impact on the electrophysiological properties of the heart (11), the clinical significance of which, if any, is not understood. The picture is further confused by evidence that a particular regimen may initially increase the risk, yet confer long-term benefit, as in the Heart and Estrogen/ progestin Replacement Study (HERS), while in other well-planned work, such as the recent Estrogen Replacement and Atherosclerosis trial (ERA), there was no benefit (12). There has been a randomized trial in 270 postmenopausal women to evaluate the effects on cardiovascular risk markers of two continuous combined estrogen þ progestogen replacement products (17-beta-estradiol 1 mg with or without norethindrone acetate 0.25 or 0.5 mg) compared with unopposed estrogen or placebo (13). LDL cholesterol was reduced to a similar extent in all those who took the active treatment (10–14% from baseline). Compared with unopposed 17-beta-estradiol, 17-beta-estradiol plus norethindrone acetate 0.5 mg enhanced the reductions in total cholesterol and apolipoprotein B concentrations. The combination of 17-beta-estradiol plus norethindrone blunted or reversed the increases in concentrations of high-density lipoprotein cholesterol, apolipoprotein A-I, and triglycerides produced by 17-beta-estradiol alone. The effects of 17-beta-estradiol plus norethindrone on hemostatic variables were similar to those of 17-beta-estradiol alone, except for factor VII activity, which was significantly reduced by 17-beta-estradiol plus norethindrone acetate 0.25 and 0.5 mg. The combination of 17-beta-estradiol plus norethindrone blunted reductions in C peptide and insulin concentrations produced by unopposed 17-beta-estradiol, but did not affect them compared with placebo. The authors concluded that 17-beta-estradiol plus norethindrone produced favorable changes in most cardiovascular risk markers and had a profile distinct from that of unopposed estrogen. The findings of the randomized HERS suggested that in women with clinically recognized heart disease, HRT ª 2006 Elsevier B.V. All rights reserved.

might be associated with early harm but late benefit in terms of coronary events. The findings of that study seem in the meantime to have been confirmed by some further US work. In one study the histories and subsequent course of 981 postmenopausal women who had survived a first myocardial infarct and had thereafter used estrogen or estrogen þ progestogen were examined (14). Relative to the risk in a parallel group of women not currently using hormones there was a suggestion of increased risk during the first 60 days after starting hormone therapy (RR ¼ 2.16; CI ¼ 0.94, 4.95) but of reduced risk with current hormone use for longer than 1 year (RR ¼ 0.76), although the confidence intervals were wide. However, in a second study, data on 1857 women from the Coumadin Aspirin Reinfarction Study were used to assess the incidence of cardiac deaths or unstable angina as related to the use of HRT. Of the population studied, 524 (28%) had used HRT at some point and 111 of the latter (21%) had started HRT after suffering a myocardial infarct (‘‘new users’’). Women who began HRT after their first myocardial infarct had a significantly higher subsequent incidence of unstable angina than women who had never used hormones (39 versus 20%); however, these new hormone users suffered death or recurrence of myocardial infarct at a much lower rate than never-users (4 versus 15%). These differences are striking. Prior/current users had no excess risk of the composite end-point after adjustment. Users of estrogen plus progestogen had a lower incidence of death, infarct, or unstable angina during follow-up than users of estrogen only (RR ¼ 0.56) (15). As Grady and Hulley have commented in an editorial, current data seem to make it clear that ‘‘postmenopausal hormone therapy should not be used for the purpose of preventing coronary disease unless future data from well-designed randomized trials document such benefit’’ (16). The thrombotic complications of combined HRT in a potentially high-risk group have been assessed in a randomized, multicenter study in the USA in 2763 women, average age 67 years (17). All had some degree of pre-existing coronary heart disease but no previous venous thromboembolism, and none had undergone hysterectomy. They took either conjugated equine estrogens 0.625 mg þ medroxyprogesterone acetate 2.5 mg or a placebo. During an average 4.1 years of follow-up, 34 women in the hormone therapy group and 13 in the placebo group had venous thromboembolism (relative risk ¼ 2.7, excess risk ¼ 3.9 per 1000 woman-years). The mean risk for venous thromboembolism was increased among women who had leg fractures (RR ¼ 18) or cancer (RR ¼ 4) and it was also raised several-fold for 3 months after inpatient surgery or non-surgical hospitalization. The risk was approximately halved by the use of aspirin or statins. Metabolism Hyperlipidemic postmenopausal women taking combined sequential estrogen þ progestogen replacement therapy have large fluctuations in lipid and lipoprotein

Hormone replacement therapy—estrogens þ progestogens concentrations. These fluctuations depend on the hormonal phase, that is estrogen alone or combined with progestogen. Progestogens blunt or even overwhelm the estrogenic effects on lipoproteins (18). Progestogen has also been claimed to produce more favorable concentrations of HDL cholesterol (19), but this is a questionable conclusion; most work seems to show that whereas estrogen alone increases HDL concentrations (for example by some 7%), combined treatment weakens this favorable effect and actually can reduce HDL concentrations by some 16%. Changes in lipids have been observed with both HRT and oral contraceptives and have sometimes been promoted as potentially advantageous, but it is not clear how significant such changes are, at least in biochemical terms. A review and pooled analysis of 248 prospective studies available up to the year 2000 has provided data on this issue in postmenopausal women (20). All estrogenonly regimens raised HDL cholesterol and lowered LDL and total cholesterol. Oral estrogens raised triglycerides. Transdermal 17-beta-estradiol lowered triglycerides. Progestogens had little effect on estrogen-induced reductions in LDL and total cholesterol. Estrogen-induced increases in HDL and triglycerides were opposed according to the type of progestogen in the following order (from least to greatest effect): dydrogesterone and medrogestone, progesterone, cyproterone acetate, medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and oral norethindrone acetate. Tibolone reduced HDL cholesterol and triglyceride concentrations. Raloxifene reduced LDL cholesterol concentrations. In 41 studies of 20 different formulations, HRT generally lowered lipoprotein (a). Thus, the route of estrogen administration and the type of progestogen used determine the effects of HRT on lipid and lipoprotein concentrations. In another study an estrogen þ progestogen combination produced no adverse effects on serum lipids or lipoproteins (21), but this again may depend very much on the exact combination and duration of treatment. Whatever the truth, the question arises whether the modifications in lipid effects resulting from the addition of progestogen will not interfere with the favorable impact of estrogen on coronary artery disease; there has been some earlier evidence that the combined therapy is rather less effective than plain estrogen in preventing cardiac disorders (SEDA-16, 459). Female sex hormones can also have effects on lipids when they are given transdermally, and this has been studied retrospectively in 159 women who used transdermal or oral replacement therapy (22). All used either transdermal estradiol 0.05 mg twice weekly or oral conjugated estrogen 0.625 mg/day, each combined with oral medroxyprogesterone acetate 2.5 mg/day. The mean increases in HDL cholesterol in the first year and second year averaged 10 and 31% with oral treatment, the corresponding figures for transdermal therapy being 14 and 34%. With oral therapy the mean reductions in total cholesterol in the first and second years were 2.9 and 15%, and with transdermal treatment 5.6 and 5.7%. With oral treatment, the mean falls in LDL cholesterol in the first and second years were 6.2 and 18% and with transdermal treatment 7.9 and 16% respectively. ª 2006 Elsevier B.V. All rights reserved.

1695

Transdermal treatment reduced triglyceride concentrations by 34%, whereas oral estrogen treatment increased them by 19% at the end of 2 years. Both treatments changed serum lipids favorably. Nevertheless, triglycerides were increased by oral estrogen but reduced by transdermal treatment at 2 years. It has been hypothetically suggested that the use of HRT could slow the progression of atherosclerosis by an effect on lipids. In a 1-year study of 321 women with increased thickness of the carotid intima media who were using either various forms of HRT or none at all, there was no slowing in the progression of subclinical atherosclerosis and no unfavorable effect on the process (23). HRT significantly reduced LDL cholesterol, fibrinogen, and FSH. Reproductive system Adding a progestogen to estrogen therapy means that regular withdrawal bleeding occurs, probably in some 97% of users up to the age of 60 years. This could explain why such combinations, although increasingly advocated, have not been used on a wider scale; few women relish the prospect of regular ‘‘menstrual’’ bleeding persisting for many years after the menopause, and it might introduce new and unforeseen risks, particularly to the aging uterus. However, on theoretical and practical grounds, such combinations have been developed and used for relatively short periods of treatment during the climacteric itself to regularize bleeding and to relieve menopausal symptoms. The pattern of short-term adverse effects of these products is very similar to that of the combined oral contraceptives. Some cases have underlined the need to use an estrogen in combination with a progestogen, rather than unopposed estrogen, when treating women who have undergone radical surgery (removal of both the ovaries and uterus) for endometriosis. If unopposed estrogen replacement is given, any residual area of endometriosis will rapidly expand (24). Continuous administration of an estrogen þ progestogen combination is effective in achieving amenorrhea with prolonged use (75% at 6 months). An adverse effect of such a regimen is a high incidence of unpredictable break-through bleeding, particularly during the initial months of treatment (25). Mammary tension and mastodynia are adverse effects related to the action of estrogens (26). In postmenopausal women estrogen þ progestogen replacement therapy can be associated with an increase in mammographic density and with the onset or worsening of mastodynia. Tibolone, a steroid with estrogenic, progestogenic, and some androgenic activity, does not seem to affect breasts of normal structure and can be considered a first-rate replacement therapy in women whose breasts are rather dense or who have benign mastopathy (26). Various companies and investigational groups continue to examine the relative efficacy and safety of different forms of combined postmenopausal treatment. In a randomized, placebo-controlled trial 579 women were treated for 26 cycles with sequential combinations of 17-beta-estradiol 1 mg plus dydrogesterone 5 or 10 mg or 17-beta-estradiol 2 mg with dydrogesterone 10 or 20 mg (27). The effects of these treatments in the 442 women who underwent biopsy were considered satisfactory in terms of

1696 Hormone replacement therapy—estrogens þ progestogens cycle control and endometrial response, but the 1 mg dose of 17-beta-estradiol was associated with more intermittent uterine bleeding than the 2 mg dose. Higher doses of dydrogesterone were associated with a higher incidence of cyclical bleeds and a later time of onset.

Long-Term Effects Tumorigenicity Breast cancer The complexity of the relation between hormonal replacement therapy and breast cancer has been stressed in previous volumes (SED-14, 1454) (SEDA-22, 465), and much depends on the type of replacement therapy given and the class of tumor studied. This latter point has been underscored by a US study that provided evidence that the use of combined hormonal replacement therapy increases the risk of lobular, but not ductal, breast carcinoma in middle-aged women (28). An American cohort study designed to determine whether increases in risk associated with an estrogen þ progestogen regimen are greater than those associated with estrogen alone has been carried out based on follow-up data for 1980–1995 from the National Breast Cancer Detection Demonstration Project (29). From 46 355 postmenopausal women, mean age at the start of follow-up was 58 years, 2082 cases of breast cancer were identified. Increases in risk with estrogen only and estrogen þ progestogen were restricted to use within the previous 4 years, the relative risks being 1.2 and 1.4 respectively. The relative risk increased by 0.01 with each year of estrogen use and by 0.08 with each year of estrogen þ progestogen use. Among women with a BMI of 24.4 kg/m2 or less, the mean increases in relative risk were 0.03 and 0.12 with each year of estrogen use and estrogen þ progestogen use respectively. These associations were evident for the majority of invasive tumors with ductal histology and regardless of the extent of invasive disease. The risk in heavier women did not increase with the use of estrogen only or estrogen þ progestogen. These data suggest that estrogen þ progestogen increases the risk of breast cancer beyond that associated with estrogen alone. Endometrial cancer Because sequential combined hormone replacement therapy with estrogen þ progestogen for 10–24 days per month can increase the risk of endometrial cancer in the long run, attention has been devoted to the possibility of giving the two types of hormone continuously. In one retrospective case-control study in the USA it was concluded that the risk of endometrial cancer among users of continuous combined treatment, relative to women who had never used hormone replacement therapy, was 0.6 (95% CI ¼ 0.3, 1.3); the risk relative to women who used intermittent combined therapy was 0.4 (CI ¼ 0.2, 1.1) (30). The authors’ conclusions were cautious, since most continuous combined hormonal therapy had been fairly short-term (under 72 months), but the figures suggested that women taking continuous combined hormone replacement therapy for several years were not at an ª 2006 Elsevier B.V. All rights reserved.

increased risk of endometrial cancer compared with women who had never taken hormone replacement therapy and might in fact be at reduced risk of endometrial cancer. In the meantime, others have concluded that the risk of endometrial cancer is present, but is less with combined therapy than with unopposed estrogen. However, the picture is not simple; the contradictions could be explained by the fact that risks appear to vary both by usage patterns and by patient characteristics, such as body weight and a history of diabetes (31).

Susceptibility Factors Genetic factors In a population-based, case-control study in 232 postmenopausal women who had had a non-fatal myocardial infarct during the previous 3 years, a stratified random sample of 723 postmenopausal women without a history of infarction acted as controls (32). Among hypertensive women, the presence of the prothrombin 20210 G!A variant was a significant risk factor for infarct (OR ¼ 4.32; 95% CI ¼ 1.52, 12) and in this group there was also a significant interaction between the use of HRT and the presence of the prothrombin variant in increasing the risk of infarction. Compared with non-users of HRT with the wild-type genotype, women who were current users and who had the prothrombin variant (n ¼ 8) had a nearly 11-fold increase in the risk of a non-fatal myocardial infarct. The interaction was absent among non-hypertensive women. No interaction with HRT was found for factor V Leiden in either hypertensive or non-hypertensive women. These findings suggest that screening for the prothrombin variant may allow a better assessment of the risks and benefits associated with HRT in individual postmenopausal women. Other features of the patient While the extent of vaginal bleeding when using estrogens plus progestogens varies somewhat with the exact formulation and dose, another determining factor is the pretreatment state of the endometrium: a thick endometrium at the start of treatment results in significantly more bleeding days than a thin endometrium (33). This might be a helpful predictor of the extent to which a particular woman will find this type of HRT acceptable.

Drug Administration Drug formulations The impact of a new formulation of low-dose micronized medroxyprogesterone plus 17-beta-estradiol on lipid profiles in menopausal women has been studied for 12 months. Total cholesterol concentrations fell 8.4%, low-density lipoprotein cholesterol fell 18%, and highdensity lipoprotein cholesterol increased 6.9%; total triglycerides increased 12%. The most frequently reported adverse events were menorrhagia, breast tenderness, cervical polyps or cysts, bloating, fatigue or lethargy,

Hormone replacement therapy—estrogens þ progestogens influenza or a flu-like syndrome, back pain, headaches, irritability, and depression (34). 2.

Drug dosage regimens In 438 postmenopausal women, randomly assigned to either constant 17-beta-estradiol (1 mg/day) plus inter mittent norgestimate 90 micrograms (3 days off, 3 days on) or a fixed combination of 17-beta-estradiol (2 mg/day) with norethisterone acetate (1 mg), the two regimens had similar bleeding profiles and provided comparable relief from vasomotor symptoms (1). However, breast discomfort and edema were experienced by twice as many subjects who used the fixed combination. The intermittent regimen was notably free of endometrial hyperplasia. Drug administration route In an open, non-comparative study, the efficacy of a low dose transdermal estrogen (Oesclim 25 transdermal patches, releasing 17-beta-estradiol 25 micrograms/day) was tested in 60 women with postmenopausal symptoms over 8 weeks (35). The dosage could be doubled if required and sequential treatment with an oral progestogen was also given for 12 days or more each month in all non-hysterectomized women. Of the 60 patients, 53 reacted satisfactorily to the basic dose and all the various treatments were said to be well tolerated. One could cite a dozen similar papers from the recent past in which the findings were so amorphous that they have not made a serious contribution to the evolution of knowledge. In two multicenter, double-blind, randomized, controlled trials of three once-a-week transdermal systems delivering continuous combined 17-beta-estradiol þ levonorgestrel (estrogen 45 micrograms/day þ progestogen 15, 30, or 40 micrograms/day) to treat vasomotor symptoms and prevent estrogen-induced endometrial hyperplasia in 1138 women, all were highly effective (36). Reactions at the site of application, vaginal hemorrhage, and breast pain were the most common adverse events, and the proportion of women with amenorrhea increased over time in all the treatment groups.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Drug–Drug Interactions Statins With growing interest in the use of statins in women, the question naturally arises whether hormonal replacement could have any effect on their efficacy or safety. Data from the HERS (conducted in women with cardiac disorders) seem to have shown that there is no interaction (37). Estrogen replacement itself resulted in a significant increase in the early risk of primary events in women who did not use statins but not in statin users. Adjustment for statin use after randomization showed no adverse effect of estrogen on the efficacy of statins, in terms of either cardiovascular events or mortality.

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1698 Human immunodeficiency virus (HIV) vaccine 16. Grady D, Hulley SB. Postmenopausal hormones and heart disease. J Am Coll Cardiol 2001;38(1):8–10. 17. Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000;132(9):689–96. 18. Weintraub MS, Grosskopf I, Charach G, Eckstein N, Ringel Y, Maharshak N, Rotmensch HH, Rubinstein A. Fluctuations of lipid and lipoprotein levels in hyperlipidemic postmenopausal women receiving hormone replacement therapy. Arch Intern Med 1998;158(16): 1803–6. 19. Gambrell RD Jr. Progestogens in estrogen-replacement therapy. Clin Obstet Gynecol 1995;38(4):890–901. 20. Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974– 2000. Fertil Steril 2001;75(5):898–915. 21. Jensen J, Christiansen C. Dose-response effects on serum lipids and lipoproteins following combined oestrogenprogestogen therapy in post-menopausal women. Maturitas 1987;9(3):259–66. 22. Erenus M, Karakoc B, Gurler A. Comparison of effects of continuous combined transdermal with oral estrogen and oral progestogen replacement therapies on serum lipoproteins and compliance. Climacteric 2001;4(3):228–34. 23. Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21(2):262–8. 24. Taylor M, Bowen-Simpkins P, Barrington J. Complications of unopposed oestrogen following radical surgery for endometriosis. J Obstet Gynaecol 1999;19(6):647–8. 25. Cameron ST, Critchley HOD. Continuous oestrogen and interrupted progestogen in HRT bleed-free regimens. Contemp Rev Obstet Gynaecol 1998;10:151–5. 26. Colacurci N, Mele D, De Franciscis P, Costa V, Fortunato N, De Seta L. Effects of tibolone on the breast. Eur J Obstet Gynecol Reprod Biol 1998;80(2):235–8. 27. Ferenczy A, Gelfand MM, van de Weijer PH, Rioux JE. Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17 beta-estradiol combined with sequential 5–20 mg dydrogesterone. Climacteric 2002;5(1):26–35. 28. Li CI, Weiss NS, Stanford JL, Daling JR. Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women. Cancer 2000;88(11):2570–7. 29. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283(4):485–91. 30. Hill DA, Weiss NS, Beresford SA, Voigt LF, Daling JR, Stanford JL, Self S. Continuous combined hormone replacement therapy and risk of endometrial cancer. Am J Obstet Gynecol 2000;183(6):1456–61. 31. Jain MG, Rohan TE, Howe GR. Hormone replacement therapy and endometrial cancer in Ontario, Canada. J Clin Epidemiol 2000;53(4):385–91. 32. Psaty BM, Smith NL, Lemaitre RN, Vos HL, Heckbert SR, LaCroix AZ, Rosendaal FR. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 2001;285(7):906–13. 33. Odmark IS, Jonsson B, Backstrom T. Bleeding patterns in postmenopausal women using continuous combination hormone replacement therapy with conjugated estrogen and

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Human immunodeficiency virus (HIV) vaccine See also Vaccines

General Information The difficult problems connected with clinical trials that have not been approved by independent authorities were highlighted in 1991 when Zagury published the first reports of immunization of humans using Vaccinia vaccine expressing HIV glycoprotein gp-160 (1,2). The first HIV vaccine approved for clinical trial status (1989) by the US Food and Drug Administration (FDA) was a recombinant gp-160 vaccine produced in a baculovirusinsect cell expression system by MicroGeneSys (3). Since then, various clinical trials using different HIV vaccines have been carried out. However, all HIV vaccines are still experimental. An overview of the current status of HIV vaccine development, with emphasis on efficacy and safety, has been provided by the AIDS Division of the National Institute of Allergy and Infectious Diseases (4).

References 1. Dorozynski A, Anderson A. Deaths in vaccine trials trigger French inquiry. Science 1991;252(5005):501–2. 2. Guillaume JC, Saiag P, Wechsler J, Lescs MC, Roujeau JC. Vaccinia from recombinant virus expressing HIV genes. Lancet 1991;337(8748):1034–5. 3. Midthun K, Garrison L, Gershman K. Cellular immunity in HIV-1 rgp 160 vaccines. In: Abstracts, V International Conference on AIDS, Montreal, 1989:544. 4. National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). HIV vaccines. http:// www.niaid.nih.gov/daids/vaccine/default.htm, 20/06/2005.