Micronized progesterone: A new option for women's health care

Nurse Practitioner, May 1999 by Wetzel, Wendy

ABSTRACT

Although progestational agents have been widely used for gynecologic conditions, treatment options have usually been limited to synthetic agents with adverse effects and sparse patient acceptance. Recent Food and Drug Administration approval of oral micronized progesterone (MP) has introduced therapy with a safe, effective, well-tolerated drug. This article reviews therapeutic Indications for MP as illustrated in five case studies. Issues of patient compliance, individualized treatment plans, and patient partnership to obtain the most beneficial outcomes are discussed.

Hormone interventions have become increasingly prominent features of women's health care. Improved estrogenic compounds have appeared on the market, but progestogen's availability has been limited.

Progesterone, discovered in 1934, has long been recognized as a fundamental female hormone with potential treatment uses. However, therapeutic options have been limited to a few synthetic agents. These progestins have been effective in endometrial protection and menstrual regulation, but often cause unwanted adverse effects that reduce patient satisfaction and compliance.1,2

In May 1998, the Food and Drug Administration (FDA) approved micronized progesterone (MP, Prometrium), provided in an oral gel cap, for use in secondary amenorrhea. The progesterone used in this product is derived from the yam plant and is chemically identical to the human hormone, thus offering distinct advantages over synthetic progestins. Approval for hormone replacement therapy (HRT) was granted in December 1998. Meanwhile, clinicians are likely to begin to prescribe human-- identical progesterone for all conditions that call for progestational support.

Synthetic Versus Natural Progesterone

The ovary creates progesterone in response to ovulation and the formation of the corpus luteum. Besides supporting pregnancy, progesterone plays a key role in other phases of female physiology, including regulating the menstrual cycle and protecting the endometrium against hyperplasia.3-5

A hormone defined as natural is indigenous to the species, produced by the endocrine system, and free from chemical variation. In common parlance, the term natural refers to components from nonsynthetic sources, primarily botanical ones, that are identical in structure to their human counterparts. The term human-identical hormone (HIH) was coined to overcome the intrinsic difficulties of identifying what is natural. An HIH is not human in origin but is identical in structure and function to human hormones without being chemically altered.6

Pure progesterone cannot be taken orally because it is rendered ineffective by normal gastric secretions and the first-pass liver effect. Various chemical alterations to enhance the bioavailability of the oral form have been attempted; however, the resulting compounds exhibit slightly different biologic actions from those of native progesterone. Although these products are effective, they cause numerous and often bothersome adverse effects, including dysphoria, bloating, weight gain, depression, and headaches.1,4,5,7,8

Medroxyprogesterone acetate (MPA; Cycrin, Provera) and norethindrone acetate (found in many oral contraceptives and in Aygestin) have been used extensively to treat dysfunctional uterine bleeding, oligomenorrhea, secondary amenorrhea, polycystic ovarian syndrome, and endometrial hyperplasia. The two drugs are often components of HRT as well.

Although these agents' clinical value has been well documented, they tend to be poorly tolerated. Many patients discontinue use without consulting their health care providers. MPA has been identified as a vasoconstrictor and has been found to cause or exacerbate angina in susceptible individuals. MPA can offset the increased high-density lipoprotein cholesterol levels achieved with estrogen replacement. These findings may indicate that MPA negates the cardiovascular protection offered by estrogen therapy. Investigators have suggested that MPA demonstrates an adverse alteration to clotting function, raises blood pressure, and may be teratogenic or, in large doses, carcinogenic.5,9-12

Although research and clinical practice support the use of synthetic progestins in HRT, FDA approval of MPA for this indication did not occur until August 1998. MPA may, under this indication, be used only when taken in a cyclic regimen to reduce endometrial hyperplasia with a specific dose of conjugated equine estrogen.1-3,8,9,11,13

Micronization of progesterone for oral use increases the surface area contact between the steroid molecule and the mucosa.14 Suspending progesterone in a longchain fatty acid leads to adequate absorption through the gastric mucosa, as measured by serum levels. Proponents assert that because of the human-analogous structure of MP, the drug is generally well-tolerated, does not produce the same unacceptable adverse effect profile as synthetic compounds, and provides similar therapeutic benefits.4,14-6

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial documented that MP provides adequate protection from endometrial hyperplasia without reversing estrogen's positive impact on the lipid profile." MP does not appear to affect carbohydrate metabolism, liver function, or clotting mechanisms. Some authors suggest that progesterone assists with thyroid function, prevents fibrocystic breast changes and fluid retention, and may serve as an antidepressant.4,5,8,12,17