1. Principles of Pharmacology The Pathophysiologic Basis of Drug Therapy

2. Pharmacology of Reproduction
Chapter 29
Pharmacology of Reproduction

3. Synthesis of Progestins, Androgens, and Estrogens
Figure 29-1
Progestins, androgens, and estrogens are steroid hormones derived from cholesterol. The major progestins include progesterone and 17α-hydroxyprogesterone. The androgens include dehydroepiandrosterone (DHEA), androstenedione, and testosterone. Estrogens include estrone and estradiol. Estrogens are aromatized forms of their conjugate androgens: androstenedione is aromatized to estrone, and testosterone is aromatized to estradiol. Estradiol and estrone are both metabolized to estriol, a weak estrogen (not shown). Some of the precursor–product relationships among the hormones are omitted for clarity (see Fig. 28-2). HSD, hydroxysteroid dehydrogenase.

4. Intracellular Conversion of Testosterone to Dihydrotestosterone
Figure 29-2
Testosterone circulates in the plasma bound to sex hormone-binding globulin (SHBG) and albumin (not shown). Free testosterone diffuses through the plasma membrane of cells into the cytosol. In target tissues, the enzyme 5α-reductase converts testosterone to dihydrotestosterone, which has increased androgenic activity relative to testosterone. Dihydrotestosterone binds with high affinity to the androgen receptor, forming a complex that is transported into the nucleus. Homodimers of dihydrotestosterone and androgen receptor initiate transcription of androgen-dependent genes. Finasteride and dutasteride, drugs used in the treatment of benign prostatic hyperplasia and male pattern hair loss, inhibit the enzyme 5α-reductase.

5. The Hypothalamic-Pituitary–Reproduction Axis
Figure 29-3
The hypothalamus secretes gonadotropin-releasing hormone (GnRH) into the hypothalamic–pituitary portal system in a pulsatile pattern. GnRH stimulates gonadotroph cells in the anterior pituitary gland to synthesize and release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These two hormones, referred to as gonadotropins, promote ovarian and testicular synthesis of estrogen and testosterone, respectively. Estrogen and testosterone inhibit release of GnRH, LH, and FSH. Depending on the time in the menstrual cycle, the concentration of estrogen in the plasma, and the rate at which estrogen concentration increases in the plasma, estrogen can also stimulate pituitary gonadotropin release (e.g., at ovulation). Both the ovaries and testes secrete inhibin, which selectively inhibits FSH secretion, and activin, which selectively promotes FSH secretion.

6. Two-Cell Systems for Gonadal Hormone Action
Figure 29-4
In the male, the binding of luteinizing hormone (LH) to the LH receptor (LH-R) activates testosterone synthesis in Leydig cells. Testosterone then diffuses into nearby Sertoli cells, where the binding of follicle-stimulating hormone (FSH) to its receptor (FSH-R) increases levels of androgen binding protein (ABP). ABP stabilizes the high concentrations of testosterone that, together with other FSH-induced proteins synthesized in Sertoli cells, promote spermatogenesis in the nearby germinal epithelium (not shown). In the female, LH acts in an analogous manner to promote androgen (androstenedione) synthesis in thecal cells. Androgen then diffuses into nearby granulosa cells, where aromatase converts androstenedione to estrone, which is then reduced to the biologically active estrogen, estradiol. FSH increases aromatase activity in granulosa cells, promoting the conversion of androgen to estrogen. Note that dihydrotestosterone is not a substrate for aromatase.

7. The Menstrual Cycle Figure 29-5
The menstrual cycle is divided into the follicular phase and the luteal phase. Ovulation defines the transition between these two phases. During the follicular phase, gonadotroph cells of the anterior pituitary gland secrete LH and FSH in response to pulsatile GnRH stimulation. Circulating LH and FSH promote growth and maturation of ovarian follicles. Developing follicles secrete increasing amounts of estrogen. At first, the estrogen has an inhibitory effect on gonadotropin release. Just before the midpoint in the menstrual cycle, however, estrogen exerts a brief positive feedback effect on LH and FSH release. This is followed by follicular rupture and release of an egg into the fallopian tube. During the second half of the cycle, the corpus luteum secretes both estrogen and progesterone. Progesterone induces a change in the endometrium from a proliferative to a secretory type. If fertilization and implantation of a blastocyst do not occur within 14 days after ovulation, the corpus luteum involutes, secretion of estrogen and progesterone declines, menses occurs, and a new cycle begins.

8. Pharmacologic Modulation of Gonadal Hormone Action
Figure 29-6
Pharmacologic modulation of gonadal hormone action can be divided into inhibitors of hormone synthesis and hormone receptor antagonists. Continuous administration of GnRH suppresses LH and FSH release from the anterior pituitary gland, thus preventing gonadal hormone synthesis. GnRH receptor antagonists (cetrorelix, ganirelix) are also used for this purpose. Finasteride and dutasteride inhibit the enzyme 5α-reductase, thus preventing conversion of testosterone to the more active dihydrotestosterone. Aromatase inhibitors (exemestane, formestane, anastrozole, letrozole) inhibit production of estrogens from androgens. A number of hormone receptor antagonists and modulators prevent the action of endogenous estrogens (some SERMs), androgens (flutamide, spironolactone), and progesterone (mifepristone).

9. A Model for the Tissue Specificity of Action of SERMs
Figure 29-7
Selective estrogen receptor modulators (SERMs) exhibit tissue-specific estrogen receptor antagonist or partial agonist activity. This tissue specificity of action seems to be explained by the following observations: (1) transcriptional coactivators and/or corepressors are expressed in a tissue-specific manner; (2) a SERM–estrogen receptor (ER) complex can associate with some coactivators or corepressors, but not others; and (3) genes can be activated or inhibited by different combinations of SERM–ER and coactivators or corepressors. In the example shown, assume that bone cells express coactivators (cofactors) X and Y, whereas breast cells express only coactivator Y. The estrogen–ER complex can associate with X and Y, whereas the SERM–ER complex can associate with only X. A. In bone cells, estrogen binding to ER and recruitment of coactivators X and Y induce expression of genes 1, 2, and 3. The SERM–ER complex cannot bind coactivator Y, and the SERM–ER-cofactor X complex induces expression of only gene 1. In bone, then, estrogen is a full agonist, whereas the SERM is a partial agonist. B. In breast cells, estrogen binding to ER and recruitment of coactivator Y induce expression of gene 2, but the SERM is unable to promote expression of any gene. In breast, then, the SERM acts as an antagonist. For simplicity, this model shows only coactivators, although corepressors are also involved in SERM action.

10. Structural Comparison of Estrogen (Natural Ligand) and Raloxifene (SERM) Bound to the Estrogen Receptor
Figure 29-8
The ligand-binding domain of the human estrogen receptor-alpha is displayed in ribbon format from the yellow-brown N-terminus to the dark blue C-terminus. The natural ligand 17β-estradiol (estrogen) and the selective estrogen receptor modulator (SERM) raloxifene are displayed in space-filling format. A. In the estrogen-bound structure, the position of the orange helix (H12) defines the agonist conformation of the receptor that recruits coactivators and thereby regulates transcription of estrogen-regulated genes (see Fig. 29-7). B. In the raloxifene-bound structure, the bulky side chain of raloxifene disrupts the agonist conformation of the receptor (note that helix H12 is substantially displaced); in this conformation, the receptor is capable of recruiting some coactivators but not others (see Fig. 29-7).

11. Structure of Synthetic Estrogens
Figure 29-9
Ethinyl estradiol and mestranol are used in combination estrogen–progestin contraceptives.

12. Structure of Synthetic Progestins
Figure 29-10
Medroxyprogesterone acetate is commonly combined with estrogen for hormone therapy in postmenopausal women. Megestrol acetate is often used as therapy for endometrial cancer. Norethindrone was the first progestin to be synthesized in quantities sufficient to mass produce combination estrogen–progestin contraceptives. Norethindrone acetate is commonly used in contraceptives; it is metabolized to the parent compound, norethindrone.

13. Structure of Progestins Commonly Used in Oral Contraceptives
Figure 29-11
Levonorgestrel is the most androgenic of the commonly used progestins. Gestodene, norgestimate, and desogestrel are less androgenic than levonorgestrel.