Natural Progesterone: What Role in Women's Healthcare? Part 3

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

THERAPEUTIC USES FOR NATURAL PROGESTERONE

Progestational agents are currently used in a variety of clinical settings:

• Contraceptive pills and devices.
• Treatment of dysfunctional uterine bleeding, endometriosis, and PMS.
• Management of threatened habitual abortion and certain types of infertility.
• Postpartum lactation suppression.
• Postmenopausal HRT.
• Treatment of hypoventilation (in selected situations).
• Management of some types of breast, endometrial, and renal carcinomas.

I will not review all these indications here. Instead, I will focus on the question, "In which clinical situations is natural progesterone useful, or perhaps even preferable to a synthetic progestin?"

MENOPAUSAL HRT

As discussed above, there appears to be ample evidence that daily doses of 200 to 300 mg of micronized progesterone are as effective as standard progestins in protecting the endometrium from the stimulatory effects of estrogen.^10,37 Furthermore, it appears that micronized progesterone is devoid of the androgenic effects on the lipid profile seen with MPA and other synthetic progestational agents; for that reason, it may be preferable in HRT protocols for perimenopausal and postmenopausal women.^8,10,37 Synthetic progestins also have a tendency to increase plasma glucose and decrease plasma insulin levels, whereas natural progesterone does not have these effects.³⁸

One limiting factor to more widespread use of micronized progesterone for HRT is its availability in the US medical marketplace. Most metropolitan areas have at least one compounding pharmacy that will make micronized progesterone capsules or transmucosal lozenges upon a physician's prescription. (Transmucosal lozenges may have certain advantages over the oral drug in terms of bioavailability and elimination of first-pass liver effects.) In addition, there are mail-order compounding pharmacies that will fill prescriptions for micronized progesterone and other progesterone compounds that may not be available in most retail and chain pharmacies. Based on endometrial proliferation studies, the following combination methods appear to be safe and effective:

• Silicon vaginal ring (containing 2 mg micronized 17-fl-estradiol) along with a 100-mg progesterone vaginal suppository inserted daily for 7 days each month.³⁵

• Estradiol (via a patch or in an oral micronized form) with either oral micronized progesterone (100 mg 2 or 3 times daily) or vaginal progesterone (25 to 50 mg/d) for 10 days each month.¹⁹

OSTEOPOROSIS

A fascinating area of research that does not seem to have reached the broad medical literature is progesterone's role as a bone-trophic hormone. On its own—without the influence of estrogen—progesterone could have a significant effect on the prevention and treatment of osteoporosis .^9,39,40 Popular medical thought widely holds that it is estrogen that is needed to protect perimenopausal and postmenopausal women from the ravages of osteoporosis. In fact, medical consensus suggests that osteoporosis in women is a disease of estrogen deficiency.^41,42

However, before the onset of menopause, luteal levels of progesterone decline, whereas levels of estrogen, LH, follicle-stimulating hormone, and other reproductive hormones remain intact.⁴³ We know that bone loss begins in women well before menopause, while ovulation is still occurring and estrogen levels are essentially normal. These facts raise the question: Is it really estrogen loss that is responsible for bone loss, or is progesterone involved, perhaps even more so than estrogen?

The works of Lee^4,39,40 and of Prior⁹ in the 1980s and 1990s have brought up for discussion, at the very least, the potential of natural progesterone (not progestins) as key to the prevention and treatment of osteoporosis. Lee³⁹ studied 100 postmenopausal women with height loss and followed 63 of them with dual photon absorptiometry for 3 years. The patients were treated with transdermal progesterone cream, exercise, and dietary interventions, but no exogenous estrogen. Lee reported significant increases in bone density (averaging 15.4%) and showed that those with the lowest density at baseline experienced the greatest improvement during the 3 years.

There are a variety of ways by which progesterone can affect bone metabolism. For example, the hormone appears to stimulate new bone formation.³⁷ Urinary calcium excretion decreases during progesterone administration.

Progesterone also partially antagonizes dexamethasone-induced osteoblast growth inhibition, indicating that it binds to the glucocorticoid receptor in osteoblasts, and thus it may be especially useful in corticosteroid-induced osteoporosis.⁹ In addition, progesterone appears to increase levels of insulin-like growth factor-1, which promotes bone formation.³¹

In premenopausal women. the mean length of the luteal phase (when endogenous progesterone levels are normally highest) correlates positively with the percentage annual change in vertebral mineral density. In other words, women with shorter luteal phases had more severe osteopenia than did those with longer luteal phases.⁹

When natural progesterone is used for osteoporosis prevention and/or treatment, a recommended regimen is twice-daily administration of 1/4 to 1/2 teaspoon of a progesterone cream that contains 20 mg progesterone per 1/4 teaspoon.^2,39 The cream can be applied anywhere on the body. Usually, the "fleshy parts" (breasts, abdomen, thighs, upper arms) are recommended sites. At this time, there is no standardized dosage or delivery system that has been proved in repeated clinical trials to be effective for preventing or treating osteoporosis. Although there are no studies to refute the assertion that progesterone has estrogen-independent effects on bone metabolism, more study on its effectiveness is certainly indicated.

PREMENSTRUAL SYNDROME

Use of natural progesterone for PMS was popularized in the 1960s after publication of Dalton's groundbreaking work, The Premenstrual Syndrome, in 1964.⁴⁴ In a subsequent book, this author specifically outlined the use of progesterone for PMS,¹² and she later produced further research to support natural progesterone's role in the treatment of PMS.⁴⁵ Dalton stated that "Progesterone is the treatment of choice for patients with severe symptoms which have resisted other forms of treatment, and for those who are at the end of their tether when first reporting for treatment."¹² She also described PMS as an imbalance in the estrogen-progesterone axis; a relative deficiency of progesterone was held responsible for most of the symptoms women experience. Conversely, she stated that an imbalance in the direction of a relative estrogen deficiency gives rise to dysmenorrhea in many women.

In 1984, progesterone was the most widely recommended treatment for PMS by US and Canadian physicians¹¹; however, clinical trials of progesterone for PMS have provided conflicting results.^46-48 Some of these studies had methodologic flaws; others had a high placebo response rate. In all of them, the necessary reliance on subjective means to measure treatment success¹¹ complicates our ability to evaluate results. The only controlled trial that suggested progesterone's superiority over placebo was performed on a relatively small sample of women and used oral micronized progesterone (100 mg in the morning and 200 mg at night for 10 days during the luteal phase in 2 consecutive cycles).⁴⁹ Recently, the psychiatric world has undertaken numerous studies of psychoactive agents for the management of premenstrual dysphoric disorder (also referred to as late luteal phase dysphoric disorder). In a review of studies designed to look at dysphorias specifically, Gold et al⁵⁰ painted a pessimistic picture of progesterone's effectiveness.

Despite the numerous studies that have been undertaken and the strongly held views of many clinicians and patients that progesterone significantly improves PMS symptoms, there is no convincing evidence yet to provide a strong basis for this treatment approach, nor are there any long-term studies of its safety. Also, the FDA has not approved the use of natural progesterone in the management of PMS. On the other hand, the use of natural progesterone is relatively benign, and it may be of use for some patients suffering from PMS. Whitaker² recommends progesterone cream (20 mg per 1/4 teaspoon) applied transdermally as follows:

• 1/4 teaspoon twice daily on days 13 through 23 of the menstrual cycle.
• 1/2 teaspoon twice daily on days 24 through 1

AFFECTIVE DISORDERS

There has also been some interest in the use of sex steroids in the management of various affective disorders. One study showed decreased pregnenolone levels in cerebrospinal fluid of depressed patients, although progesterone levels remained normal.⁵¹Although this observation is of interest, there is too little research available to date to comment on the use of natural hormones to treat affective disorders. The 1998 Physicians' Desk Reference indicates that medroxyprogesterone acetate should be used cautiously in patients with a history of depression; if the depression recurs or worsens, the progestin should be stopped.⁵²

MENSTRUAL-RELATED ALLERGY SYMPTOMS

Only a small number of studies have addressed the use of progesterone desensitization for the treatment of menstrual-related allergy symptoms, such as asthma, allergic rhinitis, headache, urticaria, and vertigo. One study, published in 1974, showed promising results; it used progressively more dilute concentrations of an aqueous progesterone suspension (injected intradermally) to desensitize patients to progesterone and alleviate overt allergy symptoms.⁵³ This technique sounds much like a homeopathic approach and it is not well explained, but nonetheless is a potential area for further research.

A second study, published in 1982, attempted a similar experiment using progressively dilute aqueous progesterone injections to alleviate symptoms felt to be progesterone-related: dysmenorrhea and PMS.⁵⁴ It reported rapid clearing of symptoms. Another study published in 1988 evaluated the effect of intramuscular progesterone on peak flow and the need for corticosteroids in 3 patients with severe premenstrual asthma exacerbations. All 3 had marked improvements with progesterone therapy.⁵⁵

Although these studies are interesting, it appears that little further work has been done in regard to the connection between allergy-immunology and the endocrine system—clearly a field ripe for more research.

BREAST DISEASE

There has been some work published examining the potential relief of mastodynia (breast pain and tenderness) during the premenstrual period using direct application of progesterone cream on the breast tissue.^12,26,56 In addition nodularity disappeared in 10% of breasts. Mastodynia is likely an effect of estrogen on breast tissue; estrogen's ability to cause edema can be counteracted by progesterone.

Chang et al¹⁸ noted that progesterone gel applied topically to breast tissue significantly decreased the number of cycling epithelial cells. No studies have compared topical to oral or other routes of progesterone delivery.

With regard to the potential effect of progesterone on breast cancer, an interesting 1981 study⁵⁷ indicated that breast cancer incidence was more than 5 times higher in women with premenopausal progesterone deficiency than in age-matched infertile patients without progesterone deficiency. However, it is not yet known whether progesterone administration can lower the breast cancer risk.