Natural Progesterone: What Role in Women's Healthcare?, Part 1

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

BIOSYNTHESIS AND BIOCHEMISTRY

Progesterone is manufactured in the corpus luteum of the human ovary through the conversion of pregnenolone to progesterone. The theca internal cells of the corpus luteum have all the enzymes necessary to convert cholesterol to estradiol, whereas the granulosa cells—which acquire a rich blood supply after ovulation and follicular rupture—convert pregnenolone to progesterone. Thus, a physiologic increase in progesterone occurs during the luteal phase of the menstrual cycle, probably stimulated by the luteinizing hormone (LH) surge at this time. It is thought that LH stimulates the uptake of acetate into the cholesterol molecule, which forms pregnenolone (Figure 3).

Progesterone is also synthesized by the placenta, mainly by hydroxylation of the low-density lipoprotein fraction of cholesterol to pregnenolone, then to progesterone.¹⁶ It is also found in the adrenals and even the uterus in many mammals, including humans. A substantial portion of progesterone is stored in adipose tissue.¹⁷

Plasma concentrations of progesterone in women vary with the menstrual cycle, with levels during the follicular phase being low, generally under 2 ng/mL. During the luteal phase, levels rise to 2 to 20 ng/mL in a surging pattern after ovulation (Figure 4). In the first trimester of pregnancy, blood levels are about 10 to 40 ng/mL, and they rise to 100 to 200 ng/mL near term. Progesterone levels also vary throughout the day;a decline in plasma levels of as much as 15% occurs 1 hour after a meal and in the early morning hours.¹⁶

Progesterone is a key precursor to the biosynthesis of cortisol and the C-18 and C-19 steroids, such as androstanedione, estrone, and estradiol ¹⁷ (Figure 3). When progesterone circulates in blood, 90% is bound to an albumin fraction, but a specific binding protein has not been identified. Only 3% circulates unbound. Very little progesterone is present in erythrocytes.

Two thirds of circulating progesterone is metabolized by liver conjugation; there is substantial biliary excretion and reabsorption of its metabolites.¹⁷ Progesterone is excreted primarily by the kidney. Pregnanediol is one of the major specific urinary metabolites of progesterone; its measurement can be used as an index of endogenous progesterone secretion.¹⁵

Progesterone formation appears to be regulated by both the stimulatory and inhibitory effects of other steroids and neurochemicals. Stimulatory modulators include ß-adrenergic signals, human chorionic gonadotropin, dehydroepiandrosterone (DHEA), and estrogens. Progesterone has been measured in the adrenal vein of postmenopausal women after corticotropin (ACTH) stimulation. Inhibitory signals come from DHEA-sulfate and androgens.¹⁶

PHYSIOLOGIC ACTIVITY

Progesterone serves many vital functions in the human organism. The hormone interacts both synergistically and antagonistically with estrogens; however, the ratios of the 2 hormones vary widely in different target organs. It is somewhat difficult, therefore, to indicate exactly what effect the various sex steroids have on tissues and organs, since they work together in an intricate relationship.

Reproductive system:  It is generally known that progesterone promotes mucus formation in the vagina, participates in mammary gland development,¹⁷ and counteracts the breast epithelial cell proliferation stimulated by estrogen.¹⁸ One of its primary functions, of course, is to maintain the uterine lining to support the implantation of a fertilized ovum, as its name implies. Progesterone receptors in the uterus also decrease myometrial sensitivity to oxytocin stimulation. (The antiprogesterone drug, RU-486, negates this uterine quiescent effect in order to induce uterine contractions.¹⁶) Although the data are not entirely clear, it appears that progesterone may also have an effect on transport time of the ovum in the fallopian tube, and it may make the ovum more susceptible to sperm penetration. ¹⁷ High levels of progesterone, as are seen in pregnancy, also contribute to suppression of ovulation.

In menstruating women, progesterone is necessary to effect secretory transformation of the endometrium and to produce appropriate withdrawal bleeding.¹⁹

Other Systems: In addition to its effects on the reproductive system, progesterone appears to influence other aspects of human physiology. Exogenous administration of progesterone raises body temperature by about 0.3^oC (0.5^oF) in both men and women. This response seems to disappear after prolonged exposure to progesterone (such as in late pregnancy, when body temperature actually drops). Progesterone administered to rats appears to increase body weight, and it induces a catabolic and natriuretic effect in humans.¹⁷ Possibly because of its natriuretic effect, progesterone has some ability to lower blood pressure. Additionally, it has recently been used to stimulate respiratory drive in patients with the pickwickian syndrome.^17,20

In rats, progesterone appears to influence the differentiation and maturation of central nervous system functions that determine future sexual behavior, and it has a favorable effect on insulin utilization and blood sugar levels.¹⁷ Some studies have found specific progesterone receptors in many areas of the brain, especially (in animals) the hypothalamus. High doses of progesterone can act as an anesthetic agent in humans, and they can lower the seizure threshold.¹¹

Few studies have been performed in humans on the possible effects of progesterone on the thyroid, adrenals, and skeletal system. However, some early work has sparked interest and is discussed further below.

TOXICITY

Rudel and Kincl,²¹ in their review of the international literature, noted that "Nowhere . . . is the oral toxicity of progesterone reported." They therefore undertook a study with rats, administering various doses of progesterone both orally (via gavage) and by subcutaneous injection for 26 weeks. Their only finding was an increase in the body and liver weights of female rats receiving parenteral progesterone.²¹

Not infrequently, women complain of drowsiness, headache, dizziness, or nausea just after ingesting an oral dose of micronized progesterone ^11,22 or transmucosal lozenges. Intravenous administration induces sleep at doses of 250 to 500 mg. ¹¹ Synthetic progestins, on the other hand, often cause androgenic side effects (acne, body and facial hair), depression, and weight gain.

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