June 2003, Vol. 9, No. 2

Reproductive Health
Hormone Choice May Reduce Risks of Menopause Therapy

The type of progestin hormone used in menopausal hormone therapy may have a large influence on the safety and potential side effects of that therapy, says Régine Sitruk-Ware, Population Council executive director for product research and development. “The results of a recent study have made many women and doctors skeptical of hormone therapy in general,” says Sitruk-Ware. “But this study was based on a single hormone therapy. Other therapies, particularly ones using different progestin hormones, may have fewer side effects than the one studied.” Sitruk-Ware recently outlined the properties of various progestins and progesterone, paying particular attention to potential risks and benefits. Some progestins are synthetic versions of the natural hormone progesterone, while others are derived from testosterone, a male hormone. 

Progestogens in hormone therapy 
Women usually use hormone therapy after menopause to alleviate symptoms, such as hot flashes, and health risks, such as heart disease, that result from a reduction of estrogen in their bodies. However, it is unsafe for women with intact uteruses to take estrogen alone. This causes cells in the endometrium to proliferate and greatly increases women’s risk of endometrial cancer. Thus, for these women, it is necessary to use a therapy that combines estrogen with progesterone or a progestin. This combination reduces the risk of endometrial cancer from hormone therapy. Some people have argued, however, that progestins carry risks of their own that can offset the benefits of estrogen. 

In July 2002, the U.S. National Institutes of Health announced the early end of a large study, part of the Women’s Health Initiative, on the effects of estrogen plus progestin hormone therapy in healthy menopausal women. The study was halted because the overall health risks, particularly the risks of cardiovascular disease and invasive breast cancer, exceeded the benefits of the treatment. As a result of this study, the U.S. Food and Drug Administration requested that all manufacturers of menopausal hormone therapies change their labeling. These therapies now warn of an increased risk for heart disease, heart attack, stroke, and breast cancer. Sitruk-Ware contends, however, that “it would be inappropriate to extend the results of this trial to hormone therapy in general, because the effects of such therapies relate specifically to the type of hormones used in each drug.” 

The treatment employed in the Women’s Health Initiative study, for example, used a progestin known as medroxyprogesterone acetate (MPA). Sitruk-Ware points out that, unlike natural progesterone, MPA may reverse some of the heart-protective effects of the estrogen in the drug and increase the risk of cardiovascular disease. 

Unintended side effects 
Human and animal studies have shown that different progestins have different influences on blood sugar and insulin levels, cholesterol levels, and the dilation of blood vessels. All of these factors play a role in cardiovascular disease. Some progestogens negatively affect these bodily functions and some have no effect. 

The influence of hormones in the body, whether beneficial or detrimental, is determined by the hormones’ interactions with cellular structures known as receptors. Hormones act in cells by binding to receptors. Progesterone and the progestins trigger specific responses within cells when they bind to progesterone receptors. Additionally, some progestins have the ability to bind to other receptors. This binding can trigger cellular responses that are different from the intended effects that result when hormones bind to the progesterone receptor. MPA's ability to offset some beneficial actions of estrogen on cholesterol and on blood vessels may be caused in part by the hormone's binding to structures known as androgen receptors. Natural progesterone and a few other progestins do not bind to androgen receptors and thus do not produce these side effects.

The chemical structure of the hormone determines what receptors it will bind to, says Sitruk-Ware. "Very small structural changes may induce considerable differences in the effects of progestogens," she explains. 

Breast cancer 
The effect of progesterone and the progestins on breast cancer is less clear. The use of estrogen in hormone therapy has been known for years to slightly increase the risk of breast cancer. Clinical trials, however, have produced conflicting results on whether progestins further increase this risk, or have no effect. The conclusions of the Women's Health Initiative study on breast cancer were generalized to all women using hormone replacement therapy, says Sitruk-Ware. The breast cancer risk found in the study appeared only in women who had previously used hormone therapy for several years and thus were at a higher risk before the study began. 

"Further studies are needed to compare the effects of a wide range of estrogen/progestin hormone therapy formulations used in clinical practice around the world, so that beneficial and deleterious effects can be quantified," concludes Sitruk-Ware.

Source
Sitruk-Ware, Régine. 2002. “Progestogens in hormonal replacement therapy: New molecules, risks, and benefits,” Menopause 9(1): 6–15.

See Also

• Hormone Therapy