In addition to their characteristic hydroxylase activities, some steroidogenic CYP enzymes also catalyse lyase reactions. Specifically, the CYP11A (cytochrome P450 cholesterol side chain cleavage) and CYP17 (cytochrome P450 17α-hydroxylase/C17,20-lyase) enzymes can each catalyse cleavage of the C․C bond weakened by the hydroxylation reactions. CYP11A acts in the IMM to catalyse the rate-limiting reaction in steroid synthesis: the conversion of cholesterol to pregnenolone. This crucial CYP enzyme hydroxylates two adjacent carbons (C20 and C22) in the D-ring side chain of cholesterol, facilitating cleavage between C20 and C22 to leave the Δ 5 21 carbon steroid, pregnenolone ( Miller 2008 ). Similarly, CYP17 introduces a hydroxyl group at position C17 of either pregnenolone or progesterone, as a result of which the weakened C17–C20 bond breaks to generate either DHEA or androstenedione, respectively ( Miller 2008 ) (see Figure ). Other members of the CYP enzyme family simply catalyse introduction of oxygen to generate hydroxyl groups at specific carbon positions (see Table ). The hydroxylations catalysed by CYP21 (21-hydroxylase) and CYP11B1 (11β-hydroxylase) are pivotal in the formation of corticosteroids by the adrenal cortex ( Miller 2008 ). The hydroxyl group generated at position C18 by CYP11B2 (aldosterone synthase) undergoes rapid oxidation to form an aldehyde group ( Curnow et al 1991 ), hence giving rise to the name ‘aldosterone’ (see Figure ). Finally, CYP19 (aromatase) is the most complex member of the steroidogenic CYP enzyme family, catalysing a series of reactions that convert C19 androgens (androstenedione and testosterone) to their C18 oestrogen metabolites (oestrone and oestradiol, respectively). In this reaction sequence, the C19 methyl group is lost and the ketone at position C3 is reduced to a hydroxyl group ( Miller 2008 ). This liberates electrons which are invested in the A-ring of the steroid to generate the aromatic phenol ring, the hallmark of oestrogens (see Figure ) and a prerequisite for activation of the oestrogen receptor.
Depending on the number and character of their functional groups, steroid molecules may show diverse reactivities. Moreover, the reactivity of a functional group varies according to its location within the molecule (for example, esters are formed readily by 3-OH groups but only with difficulty by the 11β-OH group). An important property of steroids is polarity —., their solubility in oxygen-containing solvents (., water and alcohols ) rather than hydrocarbon solvents (., hexane and benzene ). Hydroxyl, ketonic, or ionizable (capable of dissociating to form electrically charged particles) groups in a steroid molecule increase its polarity to an extent that is strongly influenced by the spatial arrangement of the atoms within the molecule.
Progestogens The discovery that ethinyl substitution leads to oral potency led to the preparation of ethisterone, an orally active derivative of testosterone. In 1951, it was found that removal of the carbon-19 from ethisterone to form norethindrone did not destroy the oral activity and, most importantly, changed the major hormonal effect from that of an androgen to that of a progestogen. Accordingly, the progestational derivatives of testosterone were designated 19-nortestosterones. The androgenic properties of these compounds, however, were not completely eliminated, and minimal anabolic and androgenic activity remains. Examples of this class of progestogens include norethindrone, norethynodrel, ethynodiol diacetate, and some other related compounds not used in the United States. The second group of 19-nor compounds are gonanes, which have an 18-ethyl instead of an 18-methyl group. They include racemic norgestrel, levonorgestrel, and three newer compounds: gestodene, desogestrel (a pro-drug that must be converted to 3-ketodesogestrel to be biologically active) and norgestimate, which is the 17-acetyl-3-oxime derivative of norgestrel, into which it is rapidly metabolized.