Pharmacology Update
Prometrium: Micronized "Natural" Progesterone
By William T. Elliott, MD, and James Chan, PharmD, PhD
The fda has approved micronized "natural" progesterone in an oral form. Developed by Schering-Plough, marketed by Solvay Pharmaceuticals of Marietta, GA, and released under the name Prometrium, this is the first progesterone that is chemically identical to progesterone produced by the ovaries. The drug is synthesized from yam sterol precursors harvested from wild Mexican yams and formulated in soft gelatin capsules with peanut oil, glycerine, and lecithin. Micronization increases the amount of drug in contact with the surface area of the gut, effectively increasing its absorption.
Natural progesterone has been available in Canada since 1995 and marketed in Europe as Ultrogestan, where it is reported to be the most popular progestogen.
Indications
Prometrium is approved for the treatment of secondary amenorrhea in premenopausal women.1
Potential Advantages
Micronized progesterone in Prometrium is chemically identical to progesterone of ovarian origin. Some women appear to prefer the "natural" progesterone to synthetic versions such as medroxyprogesterone acetate.
When used in hormone replacement therapy, progesterone had minimal effect in opposing the effect of estrogen-mediated increase in HDL cholesterol compared to medroxyprogesterone acetate.2
Potential Disadvantages
Prometrium is formulated with peanut oil and should not be used in patients allergic to peanuts.1 There is considerable intersubject variability in the absorption of micronized progesterone. A recent study reported that the maximum serum concentrations ranged from 15.72 ng/mL to 625.98 ng/mL after a single dose of 300 mg.7
Dosing Information
Prometrium is supplied as 100 mg capsules. For secondary amenorrhea, 400 mg is taken as a single dose in the evening for 10 days. Prometrium has not received FDA approval for use in hormone replacement therapy. Clinical studies indicate that 200 mg daily for 12 days/month is effective.2
Comments
Prometrium is FDA approved for the treatment of secondary amenorrhea, but it may be widely used for the prevention of endometrial hyperplasia in postmenopausal women on hormone replacement therapy. The addition of progestogens tends to attenuate the estrogen-mediated elevation of HDL cholesterol. The results from the three-year Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial suggest some potential advantages over medroxyprogesterone acetate on this effect.2 An increase in HDL cholesterol of 4.1 mg/dL was observed with cyclic progesterone (200 mg daily for 12 days) plus conjugated estrogen (0.625 mg) compared with a HDL increase of 1.6 mg/dL with cyclic medroxyprogesterone (10 mg for 12 days) plus conjugated estrogen. This compared favorably with the 5.6 mg/dL increase in HDL that was seen with unopposed conjugated estrogen (0.625 mg) alone. Data suggest that HDL cholesterol may be a negative risk factor for heart disease in women and may be more closely related to heart disease than LDL cholesterol.3 Progesterone, as with medroxyprogesterone acetate, has been shown to prevent endometrial hyperplasia.2,4 Progestogens, however, do not appear to alter the risk of breast cancer.5,6
Clinical Implications
Prometrium is the first FDA-approved oral progesterone. Due to its poor bioavailability, formulating an oral product has been problematic. By decreasing particle size (micronization), the bioavailability was improved sufficiently to provide adequate serum concentrations to achieve a biologic effect, although the absorption is still quite variable. Prior to Prometrium, pharmacies have been compounding oral forms from micronized progesterone using various recipes. Prometrium is manufactured to an FDA-approved standard. The preservation of most of the estrogen-mediated effects on HDL cholesterol makes Prometrium an attractive alternative to medroxyprogesterone. The cost for a 200 mg (2 ´ 100 mg capsules) dose of Prometrium is approximately $1.00.
References
1. Prometrium Product Information. Solvay Pharmaceuticals. May 1998.
2. The Writing Group for the PEPI Trial. JAMA 1995; 273:199-208.
3. Jacobs DR, et al. Am J Epidemiol 1990.
4. Moyer DL, et al. Fertil Steril 1993;59(5):992-997.
5. Colditz GA, et al. N Engl J Med 1995;332:1589-1593.
6. Pike MC, et al. J Natl Cancer Inst 1997;89:1110-1116.
7. McAuley JW, et al. Pharmacother 1996;16(3):453-457.
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