Oral Absorption of Progesterone

To the Editor:

Since many synthetic progestins are known to be luteolytic, Badawy SZA, Marshall L. Luteal phase inadequacy and infertility. Fam Pract News 1981; 6:17A-24A. and while progesterone itself exerts a positive feedback influence on steroidogenic tissue, Rothchild I. The regulation of the mammalian corpus luteum. Recent Prog Horm Res 1981; 37:183-298. it is clear that it would be useful to have an effec- tive way to administer proges- terone orally.

It is well known that fat-soluble substances are absorbed primarily by way of the lymphatic system, entering the general circulation directly rather than passing first through the liver. Simmonds WJ. Absorption of lipids. In: Jacobson ED, ed. Gastrointestinal Physiology. Baltimore: Butterworths, University Park Press, 1974, p 343. Progesterone is insoluble in water, but it is soluble in lipids. If the solution is stable, it seems clear that the progesterone will be preferentially absorbed by the lymphatic route.

I have investigated the oral use of progesterone in tocopherol, a nontoxic stable solvent, in cycling women with a luteal phase defi- ciency and in postmenopausal women.

In younger women, who are still producing large amounts of estro- gen, a therapeutic effective oral dose (50 to 200 mg daily during the luteal phase of their cycles) was found to prevent the symptoms associated with premenstrual de- crease in serum progesterone observed in previous cycles, but in some women the effective dose caused the blood levels to rise somewhat above the levels usually considered normal for the luteal phase.

Postmenopausal women, who have much lower average levels of estrogen and who produce little progesterone, show much more clearly the effects of administered progesterone. Seven women who had gone through “natural” meno- pause at least two years previously, and whose serum progesterone was either below the sensitivity limit of the competitive protein-binding technique or in the typically low postmenopausal range of meas- urement by radioimmunoassay, were given oral doses of 50 or 100 mg of progesterone in tocopherol.

The earliest any blood was drawn after an oral dose of progesterone was 20 minutes; in this case, the progesterone had risen from 0.2 ng/mL before to 0.7 ng/mL after a dose of 100 mg. When blood was drawn from four to eight hours after an oral dose of 50 to 100 mg, the blood levels were between 6 and 16 ng/mL. No attempt was made to assure that the progesterone was taken on an empty stomach; meals were eaten as usual while waiting for blood to be drawn. The progesterone was administered by the women’s physicians, and the measurement was done by commercial medical laboratories.

In two cases in which blood was drawn 24 hours after a single dose of 100 mg, the progesterone level was still in the normal luteal phase range.

Since the observations were made over a period of several years, with progesterone measurements made at several different laboratories by different techniques, the numbers are not strictly comparable. We recently got a clearer picture of the rate of absorption in a fasting person. A middle-aged man, with a fasting level of 0.2 took 100 mg. At the first hour, the progesterone level was already 7.0 ng/mL; the concentration rose each hour to a peak at the sixth hour of 14.0 ng/mL, and the last measurement, at the seventh hour, was 7.0 ng/mL. On average, men’s livers are quicker to remove substances from the blood, and the fact that no food was taken during the test very likely caused the rate of increase and the rate of decrease to be greater than in a nonfasting person.

In summary, when dissolved in tocopherol, progesterone is orally active. A single oral dose of 50 to 200 mg given to women with luteal phase insufficiency or to postmenopausal women brings their blood progesterone levels up to at least the normal luteal phase range and maintains it in that range for at least 12 hours.

Raymond Peat, PhD
Eugene, Oregon