Page 743 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 729

CH 3
21 CH 3 CH 3 C O
20 C O C O OH
18 OH
17
11 13
19
O
O O CH 3
Progesterone Hydroxyprogesterone Medroxyprogesterone

C C CH 3
OH CH
C CH 3 C CH
OH CH 2 CH 2 OH

O
CH 3 O
Dimethisterone Norethindrone Desogestrel

FIGURE 40–4 Progesterone and some progestational agents in clinical use.

Physiologic Effects known, but an alteration of the temperature-regulating centers in
the hypothalamus has been suggested. Progesterone also alters the
A. Mechanism
function of the respiratory centers. The ventilatory response to CO 2
The mechanism of action of progesterone—described in more is increased by progesterone but synthetic progestins with an ethinyl
detail above—is similar to that of other steroid hormones. group do not have respiratory effects. This leads to a measurable
Progestins enter the cell and bind to progesterone receptors that reduction in arterial and alveolar Pco during pregnancy and in the
2
are distributed in the nucleus and the cytoplasm. The ligand- luteal phase of the menstrual cycle. Progesterone and related steroids
receptor complex binds to a progesterone response element also have depressant and hypnotic effects on the brain.
(PRE) to activate gene transcription. The response element for Progesterone is responsible for the alveolobular development
progesterone appears to be similar to the corticosteroid response of the secretory apparatus in the breast. It also participates in the
element, and the specificity of the response depends upon which preovulatory LH surge and causes the maturation and secretory
receptor is present in the cell as well as upon other cell-specific changes in the endometrium that are seen following ovulation
receptor coregulators and interacting transcription factors. The (Figure 40–1).
progesterone-receptor complex forms a dimer before binding to Progesterone decreases the plasma levels of many amino acids
DNA. Like the estrogen receptor, it can form heterodimers as well and leads to increased urinary nitrogen excretion. It induces
as homodimers between two isoforms, A and B. These isoforms changes in the structure and function of smooth endoplasmic
are produced by alternative splicing of the same gene. reticulum in experimental animals.
Other effects of progesterone and its analogs are noted below
B. Effects of Progesterone in the section, Hormonal Contraception.
Progesterone has little effect on protein metabolism. It stimulates
lipoprotein lipase activity and seems to favor fat deposition. The C. Synthetic Progestins
effects on carbohydrate metabolism are more marked. Proges- The 21-carbon progesterone analogs antagonize aldosterone-
terone increases basal insulin levels and the insulin response to induced sodium retention (see above). The remaining compounds
glucose. There is usually no manifest change in carbohydrate (“19-nortestosterone” third-generation agents) produce a decidual
tolerance. In the liver, progesterone promotes glycogen storage, change in the endometrial stroma, do not support pregnancy
possibly by facilitating the effect of insulin. Progesterone also in test animals, are more effective gonadotropin inhibitors, and
promotes ketogenesis. may have minimal estrogenic and androgenic or anabolic activ-
Progesterone can compete with aldosterone for the mineralo- ity (Table 40–2; Figure 40–4). They are sometimes referred to
+
corticoid receptor of the renal tubule, causing a decrease in Na as “impeded androgens.” Progestins without androgenic activity
reabsorption. This leads to an increased secretion of aldosterone include desogestrel, norgestimate, and gestodene. The first two
by the adrenal cortex (eg, in pregnancy). Progesterone increases of these compounds are dispensed in combination with ethinyl
body temperature in humans. The mechanism of this effect is not estradiol for oral contraception (Table 40–3) in the United States.