Periodical Women's Health Update: Natural Progesterone; Clinical Indications in Women's Health

Tagged:  

For the purposes of this article, hormones manufactured from plant compounds (usually diosgenin or beta-sitosterol) and resulting in a hormone chemically identical to the progesterone of ovarian origin, are referred to as "natural progesterone." The development of synthetic progesterone derivatives occurred because of poor absorption and rapid hepatic metabolism of orally administrated natural progesterone. Most of the synthetic progesterone derivatives are C-17 derivatives of progesterone (medroxyprogesterone acetate=MPA), or C-19 nortestosterone derivatives (norgestrel). The disadvantage of the synthetic compounds (progestins) is that they do not precisely replicate the biologic activities of the parent hormone. The progestins may adversely affect lipoprotein metabolism and cardiovascular health, and are poorly tolerated by as many as 40% of women who use them.

Natural progesterone can be delivered via diverse routes of administration. They include oral, transdermal, sublingual, vaginal, intramuscular injection and intrauterine. The two most popular are oral capsules and transdermal cream or gel.

Oral delivery of natural progesterone has been improved using a micronized form of the hormone which now offers an efficient oral delivery. Micronization of progesterone increases the available surface area of the drug and enhances the intestinal absorption of progesterone. Suspending the micronized natural progesterone in oil has been shown to further enhance the intestinal absorption.( 1) Oral micronized natural progesterone is available from compounding pharmacies, in Europe as Utrogestan; Besins-Iscovesco and recently approved in the US as Prometrium; Solvay Pharmaceuticals, Inc.

Natural progesterone creams are a diverse lot. Some creams in the over-the-counter setting contain less than 2 mg of progesterone per 1 oz of cream, others 2-15 mg of progesterone per 1 oz. of cream and some 400 mg or slightly more progesterone per I oz of cream: 1/4 tsp of the 400 mg per oz product delivers 20 mg. Natural progesterone can also be compounded to the practitioner's specifications in either a cream or gel. This enables the practitioner to be more select in the dose she/he prescribes for their patient. Numerous compounding pharmacies in local communities and across the country are eager to teach practitioners about how to utilize transdermal progesterone prescriptions.

Note that some natural progesterone creams sold over-the-counter are just wild yam extracts and contain no natural progesterone. Vigilance, studious inspection and sometimes an investigative reporter's mentality will be required to decipher labels, product literature and company personnel salesmanship.

Progesterone Physiology

Progesterone is a 21-carbon hormone formed from steroid precursors in the ovary, testes, adrenal gland, placenta and glial cells in the central nervous system.( 2, 3) It is present in highest concentrations in the ovarian corpus luteum. Progesterone receptors are found in the uterus, central nervous system, mammary gland and pituitary gland. The synthesis of progesterone is stimulated by LH, which primarily acts to regulate the conversion of cholesterol to pregnenolone, a progesterone precursor. When progesterone is administered orally, it first undergoes metabolism in the gut, then the intestinal wall, and the liver to form its hydroxylated metabolites and their sulfate and glucuronide derivatives.( 4, 5)

The LH stimulation of progesterone formation and release during the luteal phase is the key opposing event in the estrogen stimulated endometrial proliferation and the development of a secretory endometrium. This all occurs in anticipation of a fertilized egg. When progesterone release halts, menstruation is triggered. In a pregnant woman, progesterone is secreted by the placenta and is necessary to maintain the pregnancy. Progesterone also plays a role in the glandular development of the breasts and exerts effects on urinary sodium excretion.

Bioavailability of Oral and Transdermal Progesterone

The absorption of progesterone varies among individuals, whether they are using oral or transdermal progesterone. Much criticism has been dealt to transdermal progesterone, asserting that it will not adequately raise serum levels. A recent study demonstrated that progesterone cream applied once a day for 2 weeks (60 mg/day) raised serum progesterone concentrations with a mean ranging from 1.6 to 3.3 ng/mL.( 6) After 2 weeks of dosing, progesterone concentrations were sustained for at least 8 hours. Serum progesterone levels from 5 to 30 ng/mL are generally considered representative of luteal phase progesterone levels. This new research about transdermal progesterone's ability to raise serum levels is an exciting step in the history of natural progesterone. The next logical area of research will be to ascertain whether or not this delivery method, and these concentrations of progesterone, will provide adequate endometrial protection to estrogen replacement therapy. Just as the PEP I trial created a great leap forward for OMP, proving that 200 mg of progesterone ally for 12 days per month provides adequate endometrial protection when given with .625 conjugated equine estrogens, transdermal progesterone, in adequate dosages, may soon be shown to further the use and indications for these creams.

The mean plasma levels with oral progesterone doses >100 mg are at least as high as luteal phase levels. When oral micronized progesterone (OMP) is administered orally at doses of 100-300 mg, the maximum concentration is achieved within 2-3 hours. The mean half-lifes for 100-mg, 200-mg, and 300-mg doses of OMP are similar (18.3,16.8, and 16.2, respectively. Significantly elevated levels of progesterone can be maintained for approximately 12 hours and do not return to baseline until at least 24 hours afar oral administration.

The ingestion of food significantly enhances the absorption and bioavailability of oral progesterone but does not modify the rate of progesterone absorption. When the OMP is packaged with oil (usually peanut oil), this improves the absorption over the powdered form.

Clinical Indications for Natural Progesterone

Secondary Amenorrhea

The effectiveness of OMP in the induction of withdrawal bleeding in women with secondary amenorrhea has been evaluated at doses of 200 mg or 300 mg or 400mg for 10 days. Shangold et al. studied 60 patients in their randomized, double-blind study.( 7) Withdrawal bleeding was induced in 90% of the women who took the 300-mg dose, 58% of those who took the 200-mg dose, and only 29% of those who received placebo. Withdrawal bleeding generally occurs within 7 days of the last dose. The rate of secretory transformation was evaluated in a multicenter, randomized, double-blind clinical study in estrogen-primed postmenopausal women. OMP administered for 10 days at 400 mg/day induced complete secretory changes in the endometrium in 45% of women compared to 0% in the placebo group.( 8)

It is unknown whether or not transdermal progesterone is effective in treating secondary amenorrhea. It should not be considered adequate for a progesterone challenge test, but anecdotal reports include successful initiation of menses after using progesterone cream 1/4 tsp twice daily (40 mg total daily dose) for 2 weeks.

Premenopausal Abnormal Bleeding

The effects of oral synthetic progestin, norethisterone (NET; 15mg/day), or OMP (300 mg/day) for 10 days (days 15-24 of each cycle) on endometrial hyperplasia, hormone levels and lipid levels have been evaluated. A total of 80 women with anovulation and 11% with an incomplete progestational effect were included in this abnormal bleeding study. Most cases of hyperplasia or proliferative endometrium were resolved aider the third treatment cycle using both NET and OMP. After they had discontinued their treatment for 3 months, some of the patients had a recurrence of their bleeding disorder. Plasma levels of progesterone after OMP corresponded with physiolgic luteal phase values. More patients being treated with OMP had a continuation of bleeding disorders. NET, but not OMP, lowered serum levels of estradiol, FSH, LH, sex hormone-binding globulin, HDL, and triglycerides.

Fertility and Pregnancy

One cause of female infertility is luteal phase dysfunction in which there is insufficient progesterone secretion to prepare the endometrium for implantation. Progesterone supplementation has been therapeutic for this condition. Progesterone suppositories, progesterone cream (Crinone), IM injections and OMP are possible avenues for administering the progesterone. The effects of 200 mg three times daily of OMP was evaluated in women with luteal phase defects.( 10) All seven patients had a significant peak in their progesterone levels 2 hours after dosing and all seven had endometrial biopsies that revealed normal in-phase endometrium. Four of the women experienced drowsiness as an adverse effect. Additional research compared the effects of 90 mg of vaginal progesterone and 300 mg or OMP for women undergoing IVF procedures.( 11) Pregnancy rates and spontaneous abortion rates were not significantly different between the two groups.

The effects of vaginal and oral micronized progesterone on luteal phase support and successful pregnancy was studied in 299 women.( 12) Total number of pregnancies and continuing pregnancy rates were significantly higher in patients who received OMP compared with vaginal micronized progesterone. Again, transdermal progesterone has not been studied for luteal phase defects causing fertility or spontaneous abortion rates to my knowledge.

Premature Labor

Progesterone can be used to treat uterine activity and premature labor. Investigators in 1985 reported that 400 mg of OMP successfully decreased uterine activity in 88% of the patients versus 42% of the patients who received placebo.( 13) Beta agonist drugs can be costly and risky in the treatment of premature labor and OMP could allow for a reduced risk profile.

Progesterone cream has been used successfully for treating dysmenorrhea, but lacks sufficient research in both this area and in the treatment of premature labor.

Hormone Replacement Therapy

Hormone replacement therapy (HRT) in peri and postmenopausal women has many benefits, including symptom relief, and prevention of osteoporosis. It may also decrease the incidence of coronary artery disease. The most common regimens for HRT are continuous estrogen with continuous progestins, or continuous or at least 21 days per month of estrogen with the cyclic addition of progestin for 10-15 days of the cycle. Opposing estrogen with the addition of a progestin is necessary to reduce the incidence of endometrial hyperplasia. However, the synthetic progestins tend to counteract the beneficial effects of estrogen on lipoproteins, thereby attenuating the potential benefits of HRT in the area of cardiovascular disease. An optimal HRT regimen, when indicated at all, would be the use of an estrogen and a progesterone or progestin that provided endometrial protection while at the same time being an optimal combination for the heart.

The most significant study to date comparing estrogen/progestin regimens with estrogen/progesterone regimens has been the PEPI trial.( 14) A large sample of postmenopausal women were evaluated for up to 3 years while receiving placebo or one of four hormone regimens: conjugated equine estrogen (CEE) .625mg daily; CEE .625 daily plus MPA 2.5 mg daily; CEE .625 mg daily, plus MPA 10 mg days 1-12; or CEE .625 mg daily, plus OMP 200 mg on days 1-12.

Compared with the placebo group, the patients in each of the HRT groups had significant favorable changes in HDL and LDL. The patients who received CEE plus MPA had significantly lower levels of HDL than the patients who received either CEE alone or CEE plus OMP. Other findings of the PEPI trial: 1) No significant differences in systolic blood pressure and insulin levels amongst the different treatment regimens; 2) A higher incidence of atypical endometrial hyperplasia (34%) among the patients in the estrogen alone group than in the other treatment groups; 3) OMP equal to MPA in providing endometrial protection and prevention of endometrial hyperplasia; 4) No significant differences in bone density between the estrogen, estrogen plus MPA and estrogen plus OMP.

The results of the PEPI Trial demonstrate that HRT with a regimen of estrogen and OMP provides a greater preservation of the positive lipid effects of estrogen than the effects of estrogen plus MPA. The results also demonstrate that 200 mg/day of OMP for 12 days of the cycle in conjunction with estrogen provides the same opposing effect to estrogen endometrial stimulation as does MPA.

As discussed earlier, progesterone creams have not yet been studied on the endometrium itself. When using an oral estrogen in a woman with a uterus, it is only appropriate to use OMP, 200 mg/day for 12 days (or 100mg continuous) or MPA, 10 mg/day for 12 days (or 2.5mg continuous). Practitioners who use progesterone cream with estrogen replacement should presume that they are giving unopposed estrogen, and providing no endometrial protection.

There have been other studies to determine the effect of progestins on coronary heart disease risks. Studies in rhesus monkeys have yielded evidence that estrogen plus MPA causes coronary artery vasospasm, but estrogen plus OMP does not.( 16) These findings suggest that HRT with estrogen and OMP could have a cardioprotective effect by reducing coronary vascular reactivity.

A transdermal progesterone cream was studied for its ability to control vasomotor symptoms (hot flashes) and to evaluate its ability to prevent bone loss: 102 healthy women within 5 years of menopause were randomly assigned to receive either transdermal progesterone cream or a placebo. Subjects were instructed to apply a quarter teaspoon of cream (1/4 tsp contained 20 mg progesterone or placebo) to the skin daily. The formulator of the cream was Transitions for Health in Portland, Oregon, the makers of "Progest." Each also received a multivitamin and 1200 mg of calcium. Measurements included medical history, physical examination, bone mineral density testing of the hip and spine (DEXA), thyroid (TSH), hormone (FSH), lipids profile (cholesterol, etc), and regular chemistry profile. The women kept weekly symptom diaries and were seen every 4 months for one year. Bone density and chemistry profile were repeated at the end of one year.

Prior to the initiation of the study, 30 of the 43 (69%) in the treatment group and 28 of the 47 (55%) had hot flashes. Twenty-five of 30 (83%) women in the treatment group experienced improvement or resolution of their hot flashes and five of 26 (19%) placebo subjects showed improvement or resolution. The number of women who showed a gain in bone mineral density did not differ between the treatment group and the placebo group.

It was very exciting to see this study published in the journal Obstetrics and Gynecology, perhaps the most prestigious journal in women's health. Hot flashes are the most bothersome complaint of menopause, and not a very well understood physiological event. Hot flashes can often be treated with herbal preparations such as black cohosh, as well as vitamin E and biofiavonoids. The mainstay of conventional treatment for hot flashes and all menopausal symptoms is estrogen. This study gives alternative practitioners vindication for our expanded list of options, including the prescribing of natural progesterone creams to menopausal women for the relief of their hot flashes.

Many alternative practitioners and consumers will be surprised and disappointed to see that progesterone cream did not slow bone loss or prevent bone loss or improve bone loss. There has been a populist movement that treats progesterone cream as almost the messiah of hormone options and the savior of women who may be led into temptation towards estrogen replacement therapy. This study should help to set the record straight: neither natural progesterone in cream or in oral form has been proven to prevent or slow or reverse postmenopausal bone loss. The theory has been based on two studies showing that oral medroxyprogesterone (synthetic progestin) showed a benefit on bone mineral density. Others have not seen similar positive effects on bone mineral density with progestins. The findings of John Lee, MD who observed an increase in bone mineral density in 63 of 100 postmenopausal women treated with 20 mg of progesterone cream, has also helped to create the mythic stature of progest erone cream. Although Dr. Lee's findings are intriguing, it is important to realize that the majority of the women were on at least .3mg of estrogen replacement therapy, calcium, vitamin D, exercise regimens and dietary changes. His observations are not grounds for the conclusion that progesterone cream prevents or reverses osteoporosis, although his work and postulates should be respected, taken seriously and fairly evaluated. Until then, this recent study, as well as other studies on natural progesterone, leave us with the conclusion that natural progesterone cream at 20mg per day does not slow bone loss or improve bone density.

Premenstrual Syndrome

Dr. Raymond Green and Dr. Katharina Dalton advanced a theory in the 1950s that PMS was caused by unopposed estrogen during the luteal phase of the menstrual cycle. Dr. Dalton's original work with progesterone therapy is the historical root on which the use of natural progesterone is based today. Research scientists and therefore the majority of the conventional medical community ultimately did not embrace Dr. Dalton's conclusions about the efficacy of progesterone therapy and PMS.

Dr. Dalton reports that she has used natural progesterone via injections (25-100mg daily), vaginal and rectal suppositories (400-1,600mg daily), and subcutaneous pellets (500-1,600mg every 3- 12 months) with results as good as complete relief of PMS symptoms in 83% of women.( 17) There have been several studies that demonstrate a lack of efficacy of rectal and vaginal suppositories in the treatment of PMS. Sampson and Freeman found these forms of progesterone to be no better than placebo.( 18, 19) Although the suppository method of delivering natural progesterone for PMS has not held up to scientific scrutiny, oral micronized natural progesterone has. A study by Dennersten and colleagues in 1985 found an overall beneficial effect using 300mg/day for 10 days of each menstrual cycle starting 3 days after ovulation.( 20) After only one month of treatment, those receiving progesterone could be clearly distinguished from those receiving placebo on measures of stress, anxiety and concen tration. Most all other symptoms also continued to improve with each menstrual cycle. A 1993 study also reported successful use of progesterone in doses of 300 mg OMP daily or 3cc rectal solution twice daily.( 21)

For severe PMS symptoms that have not responded to nutritional, botanical, and lifestyle changes, I have consistently excellent results using progesterone creams (400 mg per oz). Clinical trials have not been done regarding the treatment of PMS with progesterone creams, but such positive clinical experience cannot be ignored. I recommend applying 1/4 tsp twice daily starting at mid-cycle and stopping the day before the menses is due.

Although abnormal blood levels of progesterone in the luteal phase of women with PMS cannot be consistently documented compared to women without PMS, progesterone treatments seem to be a viable option in treating women with PMS.

Summary

Many different natural progesterone products are widely available. Practitioners need tn stay aware of differences in these products, delivery methods, formulations and dosages, effects on target tissues, and proven clinical indications specific to each formulation. As more research becomes available on the actions and therapeutic uses for natural progesterone, both in the oral micronized form and in the transdermal form, we can give women sound, safe advice and offer them real solutions and options.
References

(1.) Hargrove J, Maxson W, Wentz A. Absorption of oral progesterone is influenced by vehicle and particle size. Am J Obstet Gynecol 1989;161:948-51.

(2.) Aufrero M, Benson H. Progesterone: an overview and recent advances. J Pharm Sci 1976;65:783-800.

(3.) Mauvais-Jarvis P. Progesterone and progestins: a general overview. In: Bardin D, Milgrom E, Mauvais-Jarvis, eds. Progesterone and progestins. New York: Raven Press, 1983;1-16.

(4.) Adlercreutz H, Martin F. Bihary excretion and intestinal metabolism of progesterone and estrogens in man. J Steroid Biochern 1980;13:231-44.

(5.) Whitehead M, Townsend P, Gill D, Collins W, Campbell S. Absorption and metabolism of oral progesterone. Br Med J 1980;280:825-827.

(6.) Burry K, Patten P, Hermsmeyer K. Percutaneons absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Crynecol 1999;180:1504-1511.

(7.) Shangold M, Tomai T, Cook J, Jacobs S, Zinaman M, Chin S, et al. Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea. Fertil Steril 1991;56:1040-7.

(8.) Solvay Pharmaceuticals. Prometrium, micronized progesterone, USP. education materials 1999

(9.) Saarikoski S, Yliskoski M, Penttila I. Sequential use of norethisterone and natural progesterone in premenopausal bleeding disorders. Maturitas 1990;12:89-97.

(10.) Frishman G, Klock S, Luciano A, Nulsen J. Efficacy of oral micronized progesterone in the treatment of luteal phase defects. J Reprod Med 1995;40:521-4.

(11.) Pouly J, Bassil S, Frydman R, Hedon B, Nicollet B, Prada Y, et al. Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone. Hum Reprod 1996;11:2085-2089.

(12.) Wang H, Soong Y. Transvaginal progesterone supplementation increases serum insulin-like growth factor-binding protein-1 levels. Gynecol Endocrinol 1996;10:349-355.

(13.) Erny R, Pigne A, Prouvost C, Gamerre M, Malet C, Serment H, et al. The effects of oral administration of progesterone for premature labor. Am J Obstet Crynecol 1986;154:525-529.

(14.) The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208.

(15.) The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density. JAMA 1996;276:1389-1396.

(16.) Minshall R, Stanczyk F, Miyagawa K, Uchica B, Axthelm M, Novy M, et al. Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys. J Clin Endocrinol Metab 1998;83:649-659.

(17.) Keye W Jr. Medical treatment of premenstrual syndrome. Can J Psychiatry 1985;30:483-487.

(18.) Sampson G. Premenstrual syndrome: a double-blind controlled trial of progesterone and placebo. Br J Psychiatry 1979;135:209.

(19.) Freeman E, Rickels K, Sonheimer S, Polansky M. Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA 1990;264:349-353.

(20.) Dennerstein L, et al. Progesterone and the premenstrual syndrome: a double blind crossover trial. Br Med J 1985;290:1617-1621.

(21.) Martorano J, Ahlgrimm M, Myers D. Differentiating botween natural progesterone and synthetic progestegens: clinical implications for premenstrual syndrome management. Compr Ther 1993;19(3):96-98.

Townsend Letter for Doctors & Patients.

~~~~~~~~

By Tori Hudson

Share this with your friends