(LH) and follicle-stimulating hormone(FSH) (the gonadotropins) act on the ovaries and
testes. Gonadotropins induce the production of estrogens and progestins in the female,
which, in turn, produce appropriate changes in the reproductive tract. In the male, LH
and FSH regulate androgen formation. At the same time, the steroids have a feedback
regulatory effect on the hypothalamo-pituitary axis, setting up an exquisitely tuned reg-
ulatory loop. In addition, gonads produce the protein inhibin, which suppresses pro-
duction of follitropin (FSH) and gonadoliberinin the pituitary and hypothalamus,
respectively, and therefore, indirectly, steroid hormone production. There are many
opportunities to exercise direct or indirect drug control over a large number of metabolic
and reproductive phenomena in such a sensitive multicomponent feedback system.
Understanding the biochemistry, regulation, and molecular mechanism by which the
steroids act is therefore important in rational drug design and therapy.
5.6 STEROID HORMONES: CHOLESTEROL AS
A BIOSYNTHETIC PRECURSOR
Since cholesterol is the biosynthetic precursor of all the steroid hormones, a consider-
ation of cholesterol biochemistry is central to medicinal chemistry and rational drug
design as applied to steroids. Although cholesterol plays a role in a variety of processes,
its participation in gallstones and atherosclerosis are probably its two most important
aspects.
5.6.1 Cholesterol and Gall Bladder DiseaseCholesterol is metabolized in the liver to bile acids, which are necessary for digestion
since they act as natural detergents and solubilize dietary fats. The bile acids, once syn-
thesized in the liver, are stored in the gallbladder and then delivered via the common bile
duct to the duodenum to aid with digestion. All of the hydroxyl groups of the various
bile acids (a maximum of three OH groups) are axial, the A–B ring anellation is cis, and
the polarity of the side-chain is increased by conjugation with glycine or taurine.
Consequently, there are both hydrophilic and hydrophobic portions of the molecule,
which can thus act as a detergent and form inclusion compounds with fatty acids, pro-
moting their absorption through the intestinal wall. The excessive excretion of choles-
terol can lead to its crystallization and the formation of gallstonesthrough a process
calledcholelithiasis. Gallstones are more frequent in middle-aged women and present
with upper abdominal pain. Most stones are formed within the gall bladder and then
migrate into the common bile duct. The opening of the duct into the duodenum is only
2–3 mm in diameter and thus the duct becomes occluded, leading to pain. A possible
complication is the development of an infection in the blocked bile duct, leading to a
potentially life-threatening disorder called ascending cholangitis.
Cholesterol-containing gallstones can be dissolved slowly using long-term adminis-
tration of chenodeoxycholic acid (5.5, CDCA) or ursodeoxycholic acid (5.6, UDCA).
These two molecules are physiologically occurring stereoisomeric bile acids (7-OH
group, being αin CDCA and βin UCDA). UCDA is better tolerated and is effective at
doses of 8–10 mg daily; CDCA may cause liver toxicity and diarrhea, and requires a
dose of 15 mg/day. Provided that the gallstone is small (<15 mm), the stone may be
316 MEDICINAL CHEMISTRY