Research Pipeline: HRT

THE RESEARCH PIPELINE
Clinical trials in women's health

Hormone replacement therapy

About 75% of all women experience some menopausal symptoms, the result of the loss of the hormone estrogen and its beneficial effects. While these symptoms can vary in intensity among different women, the brain, bones, heart, blood vessels, vagina, and skin can all be affected. Hormone replacement therapy (HRT), the mainstay of treatment for many of these women, has been a topic of research and debate for many years. CenterWatch and the National Institutes of Health's ClinicalTrials.gov Web site have identified several new drugs and important new research projects on the subject.

New products in the pipeline

Solvay Pharmaceutical's product, Estrogel, a topical gel steroid (17-beta estradiol), is being evaluated in Phase III clinical trials for estrogen replacement therapy. Indications include systemic treatment of vasomotor symptoms.

Another estrogen replacement therapy, Estrasorb, is a 17-beta estradiol topical lotion being produced by Novavax; it's currently in Phase III clinical trials. Results of Phase II trials demonstrated Estrasorb successfully delivered therapeutic doses of estradiol transdermally without skin irritation and fluctuations in blood hormone levels.

Solvay Pharmaceuticals is also in Phase III clinical trials for its Combi-Patch of estrogen and progestin while Wyeth-Ayerst is in Phase II trials for its combined progesterone/estrogen product, Trimegestone with Premarin.

New research on benefits and adverse effects

Several government-sponsored trials are now looking at the potential benefits of HRT in treating or preventing heart disease. One randomized, double-blind Phase III study supported by the National Heart, Lung, and Blood Institute (NHLBI) is currently recruiting patients to determine if estrogen or estrogen plus progesterone can help postmenopausal women with unstable angina.

A second trial will examine whether HRT affects insulin sensitivity—which probably plays an important role in coronary artery disease (CAD). This Phase II study, sponsored by the National Center for Research Resources, will compare unopposed estrogen or combination estrogen and progesterone with placebo in early menopausal women. Among the endpoints being studied are (1) insulin sensitivity and glucose oxidation as determined by euglycemic clamp, and (2) the effects of insulin sensitivity on muscle biopsy cultures, with the primary endpoints being glucose uptake and glycogen accumulation and synthesis.

Another research group sponsored by NHLBI will try to determine if postmenopausal HRT given to women after coronary bypass surgery will cut the risk of graft occlusion and delay the development of graft atherosclerosis, while the goal of a fourth trial is to evaluate the effects of HRT on artery wall inflammation and stiffening.

The latter investigation will evaluate the role of estrogen therapy in influencing serum markers of blood vessel wall inflammation. The hormone is known to increase levels of C-reactive protein, interleukin-6, and matrix metalloproteinase 9 (MMP-9), a substance secreted near atherosclerotic plaques by macrophages and cytokine-activated smooth muscle cells. Researchers theorize that increased MMP-9 could be harmful to women with existing CAD because it digests the fibrous caps of vulnerable plaques, thus increasing the risk of a thrombus. On the other hand, in healthy women, MMP-9 may actually remove the excess matrix proteins that stiffen the arterial wall. If that's the case, the improved arterial compliance would reduce the threat of cardiovascular disease.

A separate study, sponsored by the NIH's Warren G. Magnuson Clinical Center, is recruiting patients to try to determine the biochemical mechanisms responsible for the two- to fourfold increased risk of venous thromboembolism among women using HRT. The protocol will evaluate women who carry two genetic risk factors for thrombosis: factor V-Leiden and hyperhomocys-tinemia. In the words of the investigators: "We want to explore the feasibility of using a battery of laboratory parameters to assess the effect of HRT on coagulation and fibrinolysis in women with these traits."

At least two clinical studies will also look at the effects of HRT on systemic lupus erythematosus. The SELENA-HRT trial is recruiting postmenopausal women with SLE from clinics and private practices. A second trial will study the effects of OCs and HRT in SLE. In the HRT arm of the study, which will include women 50 and over who are postmenopausal, subjects will receive either oral estradiol and medroxyprogesterone or placebo on days 1 through 12 of each month. Treatment will continue for 13 courses and all patients will be followed for 1 year.

In the area of mental health, one double-blind, placebo-controlled, crossover trial will be evaluating the effects of estrogen and testosterone among older women and men, respectively, on cognition and mood. Women who have not had a hysterectomy will be given Prempro (estrogen and progesterone) and those who have had the surgery will take Premarin (estrogen only).

A second trial will explore the hypothesis that the progesterone in HRT may cause irritability, depressed mood, and anxiety. Sponsored by the National Institute of Mental Health, it will compare medroxyprogesterone (Provera) with placebo.

In ongoing research to determine the safety of HRT, a new study sponsored by the International Breast Cancer Study Group will look at the effects of HRT on the risk of breast cancer recurrence among women with previously treated stage 0 to II breast cancer. This is an open label, randomized study in which patients will be assigned to one of two arms: In arm one, women with an intact uterus whose last period occurred within 2 years will receive estradiol alone on days 1 through 12 and estradiol/norethindrone on days 13 through 22, then estradiol alone on days 22 through 28. Women whose last period was more than 2 years ago receive continuous daily oral estradiol/norethindrone, while those who have had a hysterectomy receive only continuous estradiol.

Subjects in the other arm of the trial, however, receive one or more nonhormonal treatments, including clonidine, beta blockers, physical exercise, and acupuncture.

Finally, in a Phase III investigation supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, low-dose HRT is being combined with the bisphosphonate alendronate to determine if the two together have a greater effect on bone density than either given alone. The trial will take 31Ž2 years and patients will also be given calcium and vitamin D supplements.

Although there is ongoing research to evaluate the combination of higher-dose HRT and alendronate, the new study, which is still recruiting patients, will be the first to test the effects of 0.3 mg/day of conjugated equine estrogen along with 2.5 mg/day of medroxyprogesterone, in combination with 10 mg/day of alendronate. The study will divide women into three groups of estrogen-deficient postmenopausal women over age 60.

In group one, women will receive low-dose HRT; in group two, they will get the bisphosphonate; and in group three, they will get both. All three groups will also receive the nutritional supplements.

A bird's-eye view of emerging drugs

Phase I trials

Menorest, a matrix HRT patch by Rhône-Poulenc Rorer Pharmaceuticals

Phase II trials

Testosterone, administered in the MTX transdermal patch, by Watson Pharmaceuticals

Trimegestone and ethinyl estradiol by Wyeth-Ayerst

Phase III trials

Trimegestone, estradiol, combination therapy to treat vasomotor symptoms, by Wyeth-Ayerst

Combi-Patch, estrogen/progestin, a dual hormone transdermal matrix patch to treat moderate-to-severe vasomotor symptoms, by Solvay Pharmaceuticals

Estrogel, 17-beta estradiol, a topical gel steroid for systemic treatment of vasomotor symptoms, by Solvay Pharmaceuticals

Source: CenterWatch, 22 Thompson Place, 36T1, Boston, MA 02210-1212; (617) 856-5900; www.centerwatch.com.; e-mail: cntrwatch@aol.com, and www.clinicaltrials.gov.

Paul Cerrato, ed. Paul Cerrato. Research Pipeline: HRT.

Contemporary Ob/Gyn

2000;10:118-120.