Natural Progesterone: What Role in Women's Healthcare?, Part 2

by Jane Murray, M.D. (September 1998)

ADMINISTRATION

Progesterone can be administered through a variety of routes, including oral, transdermal, injection, vaginal, rectal, sublingual/buccal, and intrauterine (Table 1).

ORAL

Because oral progesterone is rapidly metabolized by first-pass effects in the liver, oral administration is essentially ineffective. But because of its potential efficacy for a variety of disorders, synthetic versions were developed during the 40 years after the hormone's discovery in 1934. Micronized progesterone for oral administration became available in the 1980s, first by a French pharmaceutical company and later by an American firm.²³ The American manufacturer produces capsules of 100 mg of progesterone particles (with a mean diameter of 10 µm) suspended partly in oil and partly in solution. Studies have shown that when progesterone is given orally in this fashion, plasma levels peak at about 2 hours and decline to pretreatment levels at about 8 hours.²⁴

Physiologically, micronized progesterone (at a dose of 200 mg/d) has been demonstrated to cause endometrial atrophy in women who were receiving postmenopausal estrogen replacement therapy (ERT) for 21 days monthly, with the other hormone added for 10 days.²⁴ This is a most reassuring finding because estrogen-mediated endometrial cancer is a worrisome side effect of ERT.There is wide consensus that concomitant cyclic or continuous progestin therapy is needed for women with an intact uterus who are receiving ERT.^25.26 The finding that micronized progesterone can produce this beneficial effect is necessary if we are to consider its use in postmenopausal HRT.

Micronized progesterone has other effects as well. For example, a wealth of evidence demonstrates that it is markedly better at elevating high-density lipoprotein levels than are any of the progestins commonly used for HRT.^8,24In the Postmenopausal Estrogen/Progestin Interventions trial,⁸ high-density lipoprotein levels increased 3.5 times more in the group using micronized progesterone than in those receiving medroxyprogesterone acetate. Micronized progesterone appears to achieve this effect without producing any adverse effects on hemostasis, blood pressure, or levels of other lipids, ²⁴ probably because it has virtually no androgenic side effects.

TRANSDERMAL

Drug delivery through the skin is a rapidly growing area in pharmaceutical development. Transdermal delivery of steroids has been seen as a real breakthrough, given that patients may experience unacceptable side effects from oral medications. Estradiol, progesterone, and testosterone are good candidates for transdermal delivery because a relatively continuous release of each drug is desirable.

Progesterone can penetrate the skin but is rapidly metabolized by the 5-a-reductase enzyme, which converts it to 5-a-dihydroprogesterone, thereby lowering plasma progesterone levels. However, when the hormone is applied to the breast directly, high progesterone concentrations can be measured in mammary tissue.¹⁸ The implications of this for the treatment of benign breast diseases are discussed below.

Transdermal patches of progesterone are not commercially available, but many progesterone cream preparations are available over the counter (marketed as cosmetics). Higher concentrations can be formulated by compounding pharmacies. Transdermal creams can contain quite variable amounts of progesterone and are not well standardized, as they are not supervised by the FDA. The most potent preparations available without a prescription contain 450 mg progesterone per ounce of cream. Compounding pharmacies can formulate concentrations of up to 900 mg/oz.

Obviously, standardized dosing is difficult in this nonregulated environment. The dosage typically recommended is 1/4 to 1/2 teaspoon of the cream applied to the skin twice daily, but the amount of drug delivered to the patient will vary depending on the cream used.

INJECTION

Plasma levels of progesterone are most reliable and consistent when the hormone is given as an intramuscular injection of progesterone in oil.²⁹ It is rapidly absorbed, and a 100-mg injection produces plasma concentrations of 40 to 50 ng/mL in 2 to 8 hours.¹¹ Plasma progesterone levels remain elevated for up to 72 hours. (These data for the injection of natural progesterone in oil are in marked contrast to the long-acting physiologic effects of the injectable synthetic progestins that are used for contraception.) Although reliable, injectable progesterone is not practical for daily or frequent use.

VAGINAL

Some women find this administration route to be acceptable and convenient; others do not. Progesterone suppositories have been used for years as treatment for some types of infertility and in the management of habitual abortion." It was also recommended by clinics specializing in the treatment of PMS during the 1970s and 1980s.¹² (Current use of progesterone for this indication is discussed below.)

Vaginal suppositories of 100 mg progesterone produce a rapid increase in plasma progesterone levels, which peak within 4 hours between 9.5 and 19.0 ng/mL. Over the next 8 hours, there is a gradual fall in plasma a levels.²⁹

It is often difficult to place the suppositories high enough in the vagina; furthermore, they can liquefy at body temperature, resulting in vaginal discharge and vulvar residue. Also, suppositories have been shown to produce high plasma levels of progesterone when first used but declining levels with continued administration.³⁰ Some patients experience irritation, pruritus, vaginal discharge, monilial infections, or other bothersome side effects with vaginal preparations.¹¹

One method developed to overcome the problems with suppositories, and that results in relatively reliable plasma levels, is a nonliquefying vaginal cream containing micronized progesterone.³¹ More recently, a sustained-release vaginal gel has been developed; this product contains 45 or 90 mg progesterone in 1.1 g of gel with a polycarbophil base.³² Several studies of vaginal gels have shown that they prevent estrogen-induced endometrial stimulation, even with relatively low plasma progesterone levels,^32,33 indicating a direct uterine effect of vaginal administration at doses resulting in lower plasma levels than intramuscular or other systemic routes of administration.

RECTAL

In order to avoid the vaginal symptoms some women experience, rectal preparations have been advocated by some clinicians. Rectal suppositories containing 100 mg progesterone in a variety of bases produce variable results on plasma hormone levels (range, 15.0 to 51.9 ng/mL) .²⁹

SUBLINGUAL/BUCCAL

A sublingual dose of 10-mg progesterone suspension produces a peak plasma level of 5 ng/mL one hour after application; return to baseline occurs 24 hours after administration. Transmucosal lozenges or troches may be compounded with natural hormones in a cyclodextrin base, which allows for easy solubility in water and does not enter or damage oral tissues .³⁴ Usual doses of transmucosal troches are in the range of 50 to 200 mg twice daily to alleviate symptoms of PMS, and 100 to 200 mg twice daily for at least 10 days each month to counteract endometrial hyperplasia in menopausal women on ERT.

INTRAUTERINE

At this time, the only commercially available intrauterine device contains levonorgestrel, a synthetic progestin, which releases 20µg of levonorgestrel per 24 hours for 5 years. Plasma levels of levonorgestrel achieved with this method are about 200 pg/mL .³¹ It has been compared favorably with other forms of progesterone administration (vaginal gel and oral micronized progesterone) for postmenopausal HRT^35,36 because it does not appear to cause as much vaginal bleeding as other methods do.³⁶

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