Page 737 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 723

are synthesized by the luteinized granulosa and theca cells of Synthetic Estrogens
the corpus luteum, and the pathways of biosynthesis are slightly
different. A variety of chemical alterations have been applied to the natural
During pregnancy, a large amount of estrogen is synthesized estrogens. The most important effect of these alterations has been
by the fetoplacental unit—consisting of the fetal adrenal zone, to increase their oral effectiveness. Some structures are shown in
secreting androgen precursor, and the placenta, which aromatizes Figure 40–3. Those with therapeutic use are listed in Table 40–1.
it into estrogen. The estriol synthesized by the fetoplacental unit is In addition to the steroidal estrogens, a variety of nonsteroidal
released into the maternal circulation and excreted into the urine. compounds with estrogenic activity have been synthesized and
Repeated assay of maternal urinary estriol excretion has been used used clinically. These include dienestrol, diethylstilbestrol, benzes-
in the assessment of fetal well-being. trol, hexestrol, methestrol, methallenestril, and chlorotrianisene.
One of the most prolific natural sources of estrogenic sub-
stances is the stallion, which liberates more of these hormones than Pharmacokinetics
the pregnant mare or pregnant woman. The equine estrogens— When released into the circulation, estradiol binds strongly to an
equilenin and equilin—and their congeners are unsaturated in α globulin (sex hormone–binding globulin [SHBG]) and with
2
the B as well as the A ring and are excreted in large quantities in lower affinity to albumin. Bound estrogen is relatively unavailable
urine, from which they can be recovered and used for medicinal for diffusion into cells, and it is the free fraction that is physiologi-
purposes. cally active. Estradiol is converted by the liver and other tissues
In normal women, estradiol is produced at a rate that varies to estrone and estriol (Figure 40–2) and their 2-hydroxylated
during the menstrual cycle, resulting in plasma levels as low as derivatives and conjugated metabolites (which are too insoluble
50 pg/mL in the early follicular phase to as high as 350–850 pg/mL in lipid to cross the cell membrane readily) and excreted in the
at the time of the preovulatory peak (Figure 40–1). bile. Estrone and estriol have low affinity for the estrogen receptor.

Steroidal,
natural
OH O OH
H C H 3 C H 3 C
3
OH

HO HO HO
Estradiol Estrone Estriol
Steroidal,
synthetic
OH OH OH
H 3 C 20 21 H C H 3 C
3
C CH C CH C CH

HO H C O O
3
Ethinyl estradiol Mestranol Quinestrol

Nonsteroidal,
synthetic
CH 3 Cl
CH 2 H C O C C O CH 3 C H CH 3
2 5
3
HO C C HO CH C COOH
CH 2 H C O CH 3
3
CH 3 O CH 3
Diethylstilbestrol Chlorotrianisene Methallenestril

FIGURE 40–3 Compounds with estrogenic activity.