Metabolism Of Progesterone

Progesterone has a half-life of only about 5 minutes when taken orally, because of rapid metabolism. Progesterone can be transformed to many other steroid hormones (Fig. 25.5) and, in that sense, has numerous metabolic products. The principal excretory product of progesterone metabolism, however, is 5j8-pregnane-3a,20a-diol and its conjugates (Fig. 25.18). The steps that are involved in the formation of

5/3-reductase

3a-HSD

20a-HSD

5/3-reductase

3a-HSD

20a-HSD

5/3-Pregnane-3a,20S-diol (5/3-Pregnane-3a,20a-diol)

Figure 25.18 • Progesterone metabolism (timing of the reduction steps can vary). (HSD, hydroxysteroid dehydrogenase.)

this metabolite are reduction of the C4-5 double bond, reduction of the C3 ketone providing the 3a-ol, and reduction of the C20 ketone. The reduction at C5 must precede the reduction of the C3 ketone, but the timing of the C20 can vary, depending on the tissue.77,78 Structural features that can block reduction at C5 or C20 have greatly increased the half-lives of progesterone derivatives.

BIOLOGICAL ACTIVITIES OF THE PROGESTINS12

Like the estrogens, progesterone has various pharmacological actions, with the main target tissues being the uterus, the breast, and the brain. Progesterone decreases the frequency of the hypothalamic pulse generator and increases the amplitude of LH pulses released from the pituitary. The actions of progesterone in the uterus include development of the secretory endometrium. When release of progesterone from the corpus luteum at the end of the menstrual cycle declines, menstruation begins. Progesterone also acts to thicken cervical secretions, decreasing cervical penetration by sperm. Progesterone is critical for the maintenance of pregnancy by suppressing menstruation and decreasing uterine contractility. Progesterone has important actions in the breasts during pregnancy, acting in conjunction with estrogens to prepare for lactation.

A thermogenic action is also associated with progesterone. During the menstrual cycle, progesterone mediates a slight temperature increase near midcycle and maintains the increased temperature until the onset of menstruation. The exact mechanism for this temperature increase is not known. Progesterone and its metabolites have additional central effects, which are being actively explored (see "Neurosteroids" section at the end of the chapter).79

STRUCTURAL CLASSES—PROGESTINS

Progestins are compounds with biological activities similar to those of progesterone. They include three structural classes: (a) progesterone and derivatives, (b) testosterone and 19-nortestosterone derivatives, and (c) miscellaneous synthetic progestins (Fig. 25.19). Progesterone itself has low oral bioavailability because of poor absorption and almost complete metabolism in one passage through the liver. A recently available oral formulation is micronized progesterone in gelatin capsules. The micronized drug is much more readily absorbed, allowing oral delivery of progesterone, even though the dose must be much higher than a parenteral dose to compensate for extensive liver metabolism. Adding 17 a-acyl groups slows metabolism of the 20-one, whereas a 6-methyl group enhances activity and reduces metabolism. Medroxyprogesterone acetate (MPA) is a particularly potent example (Table 25.2).

The structural requirements of the PR have been studied in detail.27,28 The progesterone 4-en-3-one ring A is a key to binding but only when it is in a conformation quite different from that of testosterone or the GCs. Reviews of this work contain stereo drawings that show the required conformations in three dimensions.27,28 Structural features modifying the steroid D ring are also important for optimal interactions with the PR.

Two important discoveries led to the development of the nortestosterone derivatives. One was the discovery that 19-norprogesterone still maintained significant progestational activity. The second was that 17a-alkynyl testosterone

TABLE 25.2 Comparative Progestational Activity of Selected Progestins

Relative Oral Activity

TABLE 25.2 Comparative Progestational Activity of Selected Progestins

Relative Oral Activity

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