Are all oral continuous combined hormone replacement therapies (CCHT) equally effective in preventing disease states-such as cardiovascular disease and osteoporosis-associated with prolonged estrogen deprivation? Attempting to answer that question during an industry sponsored symposium, which was supported by Pharmacia Corporation in conjunction with the XVI FIGO World Congress of Gynecology and Obstetrics, leading women's health researchers said recent clinical trial evidence suggests the answer is no.

According to program chair Dr. Morris Notelovitz, Clinical Professor of Internal Medicine, Executive Health Center, University of Florida College of Medicine, Gainesville, some estrogen/progestin combination therapies appear to be less effective in some patients than alternative preparations.

"At present," he explained, "three oral regimens are available in the United States-0.625 mg conjugated equine estrogens plus 2.5 or five milligrams of medroxyprogesterone acetate (Premphase®, Prempro™), 35 µg of ethinyl estradiol plus one milligram of norethindrone acetate (Necon®), or one milligram of 17-beta estradiol plus 0.5 mg of norethindrone acetate (Activella™)." "Even though the pharmacologic basis of these products is the same," he added, "the pharmcokinetics of their absorption and metabolism differ, thus influencing their potential efficacy."

Menopause is a universal experience among women, Dr. Notelovitz explained, but the clinical presentations vary from patient to patient in terms of symptoms experienced and the relative risks for cardiovascular disease and osteoporosis. Researchers now know, he added, that this variability is due to the distribution of alpha and beta estrogen receptors throughout a woman's body. The distribution of these receptors differs significantly among women, as does the production of estrogen by aromatization in related organs-such as breast tissue, coronary arteries, and the brain. A third contributor is sex hormone binding globulin (SHBG), which can affect the bioavailability of "free" circulating estrogen and testosterone, impacting a woman's physical response to menopause.

Consequently, CCHT therapy should proceed on a highly individual basis, he said. With estrogen, for example, clinicians need to understand how the hormone is absorbed, whether the administration method chosen can achieve a steady state, and, most importantly, whether estrogen bioavailability is sufficient for the woman being treated. Estrogen bioavailability is determined, to a large extent, by receptor distribution and SHBG levels.

While progestin is given to counteract estrogenic stimulation of the endometrium, clinicians should also be aware that some forms of the hormone-notably, medroxyprogesterone acetate-can down-regulate estrogen receptors in other target tissues, attenuating the known cardioprotective benefits of administered estrogen-particularly, normalization of lipid profiles and improved glucose/carbohydrate metabolic processes that serve to enhance insulin sensitivity.

"Basically, the balance of what is prescribed is the key," he added, "and like the progestins, studies have shown not all estrogens are the same. Even the route of administration can influence SHBG activity and, therefore, estrogen bioavailability." Recent trial evidence, he said, has equated conjugated equine estrogens with much more SHBG activity compared to micronized estradiol when given in equivalent doses [.625 mg and one milligram], while less SHBG activity was seen with transdermal administration."

Interestingly, Dr. Notelovitz said measuring follicle stimulating hormone (FSH) levels is gaining currency in clinical practice settings as a surrogate means of determining whether estrogen bioavailability is adequate. "With 17-beta estradiol at one milligram, for instance," he explained, "the FSH value should decline, but remain within allowable limits, telling you the patient is responding to therapy, but is not being overdosed, which would be indicated if the FSH results were very low."

Although down-regulation of progestin receptors is impractical to measure clinically, the effect can be estimated by varying the pharmacokinetic profile of the progestin used. Research shows a distinct differentiation between preparations containing norethindrone acetate, which has an eight to ten hour half-life, he explained, and those containing medroxyprogesterone acetate, which have a 30-hour half-life.

Affirming that women usually start hormonal therapy primarily for symptomatic control of vasomotor symptoms, Dr. Notelovitz said one way to assess results in this crucial area is to define responders as women who achieve a 90-100 percent reduction in hot flashes. "At that level, the placebo effect is minimalized," he added, "which we noted during evaluation trials of Activella™."

"Further, when we compared patients receiving one milligram of 17-beta estradiol alone to those who received the combination product, an immediate enhancement in efficacy was seen [from 44 percent to 74 percent] by adding norethindrone acetate," Dr. Notelovitz said, "with symptom relief that continued as long as patients stayed with the therapy."

This therapy has also proved beneficial in terms of preventing cardiovascular (CV) disease, Dr. Notelovitz explained. How it does this is complicated, he added, and raises some controversy as to the mechanisms involved.

Although numerous studies show all CCHT preparations decrease low-density lipoprotein (LDL) cholesterol, it is also known that the progestins used in these preparations will attenuate the beneficial effects of estrogen on high-density lipoprotein (HDL) cholesterol and triglycerides.

"However, this varies considerably according to the type of estrogen and progestin used," he added. "Norethindrone acetate, for instance, has been used for 20 years and has invariably decreased HDL levels, but this has not been associated with increased CV disease, so we need to ascertain how low is low from a safety standpoint."

In short, Dr. Notelovitz suspects the depressed HDL levels seen with CCHT may be a clinical "red herring" in terms of increased risk for heart disease, particularly in light of on-going research that has identified a previously unknown HDL "scavenger-receptor" in the liver, which appears to help transport cholesterol from peripheral tissues to the liver for metabolism. In animal studies, he added, this has been associated with decreases in atherosclerosis and plasma HDL. Further, research has increasingly focused on the importance of triglycerides and competing lipid fractions in the pathogenesis of CV disease. "Here again, the type of CCHT used is important," he said, "because the degree of triglyceride stimulation will vary considerably depending on whether conjugated equine estrogens/medroxyprogesterone acetate or 17-beta estradiol/norethindrone acetate combination is administered."

Elevated triglycerides are now known to be associated with insulin resistance and increases in plasminogen activator inhibitor (PAI-1), he explained. Further, insulin resistance and increases in PAI-1 have become important risk factors for the identification of patients at high risk for coronary artery disease (CAD). At the same time, other studies have shown that estrogen by itself improves insulin resistance, but the effect is attenuated when medroxyprogesterone acetate is added, he said. Conversely, other data show that 17-beta estradiol/norethindrone acetate results in increased insulin sensitivity compared to placebo by reducing both PAI-1 and lipid fractions, which was identified in the recent Heart and Estrogen/progestin Replacement Study (HERS) investigation as an independent risk factor for heart disease. Further, animal studies have indicated that this form of CCHT enhances the protective effects of estrogen against atherogenic plaque, he added, whereas the benefit was largely negated with the addition of medroxyprogesterone acetate to estrogen. Similarly, other animal studies indicate the addition of medroxyyprogesterone acetate will induce vasoconstriction, diminishing the dilatory effects of estrogen on vascular tone, he confirmed.

"In conclusion," said Dr. Notelovitz, "all progestins should be incorporated into the life of a naturally menopausal woman to protect the endometrium against cancer and to prevent unwanted vaginal bleeding-a key issue for long term adherence-but we need to choose a progestin that limits the negative systemic effects this hormone can have on the benefits provided by estrogen."

Following up on Dr. Notelovitz's examination of the scientific rationale for the use of 17-beta estradiol/norethindrone acetate in the management of menopause and the prevention of CV disease, Dr. Pierre Delmas, Professor of Medicine and Rheumatology, University Claude Bernard; Director, French National Institute for Medical Research on the Pathophysiology of Osteoporosis, Hospital Edouard Herriot, Lyon, France, reviewed findings from French and US studies that investigated the efficacy of this preparation in preventing bone loss and osteoporosis.

Dr. Delmas said that based on research conducted by himself and fellow reseachers to date, hormone replacement therapy (HRT) remains a first-line prevention therapy-not only because it can actually improve lipoprotein profiles, but also because it has an independent beneficial impact on bone. "By comparison, various studies show medroxyprogesterone acetate and micronized progesterone have no additional effect on bone mass density (BMD) as compared to estrogen alone," he added, "no matter whether conjugated equine estrogens or 17-beta estradiol are involved."

"In fact, studies have shown NETA [norethindrone acetate] has an effect by itself on BMD and bone markers in early postmenopausal women," he said, "that is in addition to results seen with 17-beta estradiol alone, other forms of estrogen replacement, and alternative treatments like alendronate sodium (Fosamax®)."

Turning to studies of low dose 17-beta estradiol/norethindrone acetate, Dr. Delmas confirmed that the preparation can be used to reduce the burden of osteoporosis on fracture risk, provided the therapy encourages tolerance and long-term adherence. With that caveat, he presented results from two studies conducted in France and in the US. The French study involved late postmenopausal women (58 years of age or older) with BMD standard deviation scores between +2.0 and -2.0. The US study was performed in younger women (mean age = 53), one to five years after menopause, with similar bone loss deviations. Both studies were double-blind, randomized, multi-center trials.

In the French study, Dr. Delmas and colleagues treated 135 postmenopausal women with 0.25 mg or 0.50 mg of 17-beta estradiol with one milligram of norethindrone acetate or placebo, and all participants received calcium supplements (500 mg/d).

Focusing on the data for the placebo and 0.50 mg norethindrone acetate cohorts, this dose later proved to be the most appropriate for protection of the endometrium, Dr. Delmas confirmed.

After two years, comparison of other skeletal sites (distal radius and total skeletal BMD) showed more than a four percent difference between the two groups as measured by dual-energy X-ray absorptiometry (DEXA). Over three years, BMD increases at the spine were greater than six percent compared to the placebo group, representing a substantial and significant gain in women close to 60 years of age. Results were corroborated by the US study, which involved 327 postmenopausal women (mean age = 53) in their first to fifth postmenopausal year, Dr. Delmas said.

"Again, patients were randomized to 17-beta estradiol/norethindrone acetate or placebo over two years, and the increase in BMD was much more pronounced than when 17-beta estradiol was given alone," he said, "underlining the fact norethindrone acetate has an additive BMD effect, in addition to that provided by 17-beta estradiol."

"In conclusion," said Dr. Delmas, "this new preparation-which is associated with very little vaginal bleeding, with better tolerance because the estrogen dose is reduced, and with preferable effects on the cardiovascular profile-should be very helpful for the management of postmenopausal women, especially in the context of long term therapy to reduce the burden of osteoporosis."