Cyproterone

A variety of well-respected observational and randomized clinical trials have shown that hormone therapy (HT) effectively treats and prevents menopausal symptoms and osteoporosis. (1-4) Controversial issues concerning additional potential risks and benefits of HT have received much attention in the medical literature and the lay press, particularly as a result of the reports from the Women's Health Initiative (WHI). (5)

THE WHI: WHAT DOES IT MEAN TO YOUR PATIENTS?

The findings from the WHI are, in many ways, consistent with earlier observational studies, which reported increased risks of venous thromboembolic (VTE) events, breast cancer, and stroke with HT use and decreased risks for hip fracture and colon cancer. The Will and earlier observational trials do differ in 2 important respects: the WHI showed increased risk of coronary heart disease (CHD) among hormone users in the first year of use and increased risk for dementia. Conversely, a large cohort study published in 2003 reported that dementia was diminished with estrogen administration. (6)

Are the WHI findings relevant to clinical practice? Clinicians should note that the WHI findings, while important, may not correlate to the patient population using HT for the relief of menopausal symptoms. The Will was designed to validate the use of HT in preventing CHD, as had been suggested by observational studies. Hence, the primary endpoint was CHD (defined as acute myocardial infarction [MI], silent MI determined from serial electrocardiograms, or CHD death). Hip fracture was the secondary outcome, and invasive breast cancer a primary adverse outcome. Other cardiovascular disease (CVD), fractures, and cancers were also evaluated.

The study population was limited to women aged 50 to 79 years who were, thus, significantly older than the normal population of women who use HT to alleviate hot flushes, sleep disturbances, sexual dysfunction, urinary symptoms, and vaginal atrophy. Indeed, study participants were not experiencing menopausal symptoms. This group was selected specifically to meet the study design: to assess the impact of HT on CVD in an at-risk population. The use of a symptomatic cohort would have precluded successful randomization and blinding of the study groups. Accordingly, the protocol of the Will hormone studies precluded the inclusion of symptomatic menopausal women. Therefore, the WHI outcome data may not necessarily be relevant to the care and management of symptomatic menopausal women.

The study had significant limitations in assessing risks and benefits: The impact of HT on quality of life was not assessed, although most women take HT specifically for relief of menopausal symptoms.

Still, in the aftermath of the WHI, physicians are often asked to discuss with patients the key health issues--regarding both risks and benefits--associated with HT. The key results, and their implications for physicians in practice, are described below.

Osteoporosis. After menopause, low estrogen levels lead to an imbalance in bone metabolism; the rate of bone resorption increases, and bone mineral density (BMD) and bone strength decrease. Spinal or hip fractures often occur in the absence of trauma. While calcium and vitamin D supplements and exercise may retard bone resorption, they have not been shown to significantly reduce osteoporosis or fractures.

In numerous studies, bisphosphonates and raloxifene have demonstrated fracture prevention in women with evidence of osteoporosis. However, only bisphosphonates have been shown to prevent hip fracture in women with preexisting osteoporosis. No data show that these agents reduce fracture in women who do not yet have osteoporosis.

The HT arm of the Will showed a significant reduction in hip fracture in a population not previously diagnosed with osteoporosis. At the end of year 3, BMD had increased by 3.7% in the HT group and 0.14% in the placebo group (P<.001). At the end of 5.6 years, 8.6% (n = 733) of patients receiving HT experienced a fracture, compared with 11% (n = 896) in the placebo group. Cumulatively, HT reduced the risk of fracture by 33% in a population already at risk for fracture (44% of the WHI subjects were older than 65 years). While these findings are compelling, they do not justify using HT in a population not experiencing menopausal symptoms.

Breast cancer. The WHI findings were consistent with observational data from earlier studies. At 5.6 years, there were 245 reported cases of breast cancer in the HT group and 185 in the placebo group (P<.001). Breast cancer characteristics seen in the 2 groups were different: In the lit group, invasive breast cancers were larger, more likely to be node positive, and at a more advanced stage than were tumors diagnosed in the placebo group.

In contrast, observational data showed a greater likelihood of localized disease in estrogen-users with cancer. In these reports, the risk of breast cancer diagnosis was shown to increase with duration of HT use in current users. This effect was reduced after HT cessation and returned to baseline in about 5 years. (7-12) Of interest, the estrogen-alone arm of the WHI has not shown the same effect on breast cancer risk as was seen in the combination-HT arm.

Cardiovascular disease. In the WHI, oral HT was associated with a 24% higher rate of nonfatal MI and death from CHD. This was caused primarily by a 28% higher rate of nonfatal MI during year 1 in HT users compared with placebo; the small increases in years 2 through 5 were not statistically significant. The rate of CHD death did not increase significantly. Use of HT did not affect the rate of revascularization procedures, acute coronary syndromes, or congestive heart failure. It did, however, show a trend for reduced rates of confirmed angina and hospitalizations for angina (Figure 1). (13)

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Additionally, the WHI demonstrated that risk for CHD was significantly greater among women who were more than 20 years postmenopause. WHI estrogen-only arm. Fortunately, the recently released results of the estrogen-only arm (discontinued in February 2004) revealed no increase in CHD compared with placebo. The investigators noted that estrogen alone did not appear to increase or decrease the incidence of heart disease. Administration of estrogen, however, was associated with an increased risk of stroke similar to that observed in the estrogen/progestin study arm (discontinued in 2002). No increase in breast cancer was seen. A decrease in fracture was also observed. (14)

CARDIOVASCULAR DISEASE RISK FACTORS, MENOPAUSE, AND HT

In assessing risk of CVD in menopausal women, many factors come into play. Traditional risk factors for CHD include older age, dyslipidemia, family history of premature CHD, diabetes, hypertension, obesity, and a sedentary lifestyle. However, recent experimental and clinical evidence suggests that other independent factors may increase CHD risk, among them C-reactive protein (CRP) and other inflammatory markers, various lipid fractions, thrombogenic and hemostatic factors, homocysteine, and insulin resistance. (15)

Menopause is associated with deleterious lipid changes. In a study of 542 healthy premenopausal and postmenopausal women, post

menopausal women had significantly higher levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), and a significantly lower level of high-density lipoprotein cholesterol (HDL-C). These differences were independent of age, body-mass index, or other potentially confounding factors. (16) In this light, the route of administration of HT, as well as the dosage and the type of progestin used, may be of significance.

The Nurses' Health Study, which enrolled 70,533 postmenopausal women and was conducted from 1976 to 1996, showed that the relative risk for stroke was associated with dosage of HT, ranging from a high of 1.63 (95% confidence interval [CI], 1.18-2.26) for conjugated equine estrogen (CEE) dosages equal to or higher than 1.25 mg, and declining to 0.54 (95% CI, 0.28-1.06) for 0.3 mg of CEE. (17)

The lipid effects associated with HT were evaluated in a meta-analysis of prospective studies published between 1974 and 2000. (18) A total of 248 studies yielded information on the effects of 42 different HT regimens. The author noted that oral and transdermal regimens--consisting of either estrogen-only or estrogen/progestin formulations--each reduced total LDL-C and raised HDL-C

Oral HT increased TG levels--estrogen alone more so than estrogen/progestin. The elevations in TG associated with oral administration were lessened by the addition of a progestin. Estrogen-induced lipid changes were opposed according to type of progestogen, with dydrogesterone and medrogestone having the least effect, followed by progesterone, cyproterone acetate, medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and oral norethindrone acetate.

Transdermal formulations lowered TG levels whether or not a progestin was administered. Tibolone decreased HDL-C and TG levels. Raloxifine reduced LDL-C levels.

A recent study enrolled 845 healthy postmenopausal women with or without menopausal symptoms. Participants were randomized to receive either transdermal estradiol (E2), 0.045 mg/d plus levonorgestrel 0.015 mg/d, or transdermal unopposed E2, 0.045 mg/d. Transdermal patches were applied once weekly for 13 28-day cycles. Mean baseline lipid levels were recorded. At the end of the study (Figure 2), transdermal administration of combined therapy (E2, 0.045 mg/d alone with levonorgestrel, 0.015 mg/d) was associated with significant reductions in total cholesterol, LDL-C, and TG levels, and minor reductions in HDL levels. Unopposed E2 resulted in smaller reductions in total cholesterol and LDL-C, with small and insignificant increases in HDL and TG levels. Both regimens controlled the vasomotor symptoms well. (19)

[FIGURE 2 OMITTED]

Additionally, oral and transdermal HT have shown different effects on coagulation factors, although limited investigations conducted to date make it difficult to draw useful conclusions for clinicians. (18) New findings regarding CRP are described in detail in "After Menopause: Novel Marker Helps to Identify Women at Risk for Heart Disease," by Sandra J. Lewis, MD, on page S18.

VTE, HT, AND ROUTE OF ADMINISTRATION

In the WHI, the risk for VTE in women who received oral HT was 2.1 times higher than that seen in the placebo group. Pulmonary embolism accounted for one third of serious adverse events in healthy women using supplemental estrogen. (20)

A recent case-control study evaluated the VTE risk for women using oral vs transdermal estrogen in 155 postmenopausal women who had a documented first episode of idiopathic VTE and in 381 controls (Figure 3). After adjustment for confounding factors, the women using oral estrogen had 3.5 times the risk of VTE, 3.8 times the risk for pulmonary embolism, and 3.2 times the risk for deep-vein thrombosis when compared with controls. Transdermal users had no increased risk in any category. (21) This finding suggests that it may be possible to greatly improve the risk-benefit profile of HT by selecting a nonoral route of administration.

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CONCLUSION

When treating women for menopausal symptoms, clinicians should put the findings of the WHI into perspective. The patient's overall risk profile and the severity of menopausal symptoms should be evaluated. The beneficial effects of HT on bone health and risk reduction for colorectal cancer should not be casually dismissed. Additionally, the selection of a nonoral or low-dose product may provide an efficacious treatment with a lower risk profile.

The basic question is: Why is HT being prescribed? For several years, most physicians prescribed HT to prevent heart disease and treat vasomotor symptoms or osteoporosis. The WHI has shown that HT should not be prescribed to prevent heart disease. Hormone therapy represents an appropriate treatment of osteoporosis after other medications with potentially less serious outcomes have failed. Studies have not shown that pharmocologic treatment of women with osteopenia or family history of osteoporosis is indicated.

If HT is of potential value to the patient for the relief of menopausal symptoms or for the prevention or treatment of osteoporosis, the potential impact of routes of administration should be considered. Further study may answer the question regarding potential effects of transdermal vs oral administration. It is possible that future investigations will show that HT applied transdermally does not produce the cardiovascular events that were shown in the WHI.

REFERENCES

(1.) Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol. 1998;92:982-988.

(2.) Notelovitz M, Cassel D, Hille D, et al. Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause. Am J Obstet Gynecol. 2000;182:7-12.

(3.) Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329:73-76.

(4.) The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;276:1389-1396.

(5.) Writing Group for the WHI Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health initiative randomized controlled trial. JAMA. 2002; 288:321-333.

(6.) Zandi PP, Carlson MC, Plassman BL, et al; Cache County Memory Study Investigators. Hormone replacement and incidence of Alzheimer's disease in older women: the Cache County Study. JAMA. 2002;288:2122-2129.

(7.) Armstrong BK. Oestrogen therapy after the menopause--boon or bane? Med J Aust. 1988;148:213-214.

(8.) Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med. 1991; 151:57-72.

(9.) Steinberg KK, Thacker SB, Smith SI, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA. 1991;265:1985-1990.

(10.) Colditz GA, Egan KM, Stamfer MJ. Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol. 1993;168:1473-1480.

(11.) Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-1037.

(12.) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997; 350:1047-1059.

(13.) Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.

(14.) WHI study finds no heart disease benefit, increased stroke risk with estrogen alone. NIH News. April 13, 2004. Available at: http://www.nhlbi.nih.gov/news/press/04-03-02.htm. Accessed May 10, 2004.

(15.) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106:3143-3421.

(16.) Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis. 1993;98:83-90.

(17.) Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941.

(18.) 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;75:898-915.

(19.) Shulman LP, Yankov V, Uhl K. Safety and efficacy of a continuous once-a-week 17beta-estradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials. Menopause. 2002;9:195-207.

(20.) Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet. 2002;360:942-944.

(21.) 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;362:428-432.

PRACTICE RECOMMENDATIONS

Despite concerns about the risks of HT, relief of menopausal symptoms is an important goal. Clearly, HT remains an important option to improve the quality of life for menopausal women.

Administration should be at the Lowest possible dosage and for the shortest duration required to provide symptom relief.

Route of HT administration also should be considered. Nonoral formulations typically administer lower doses than do oral products and provide dosing over extended periods of time, avoiding the peak-to-trough fluctuations associated with daily oral administration.

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