Inhibition of progesterone secretion with trilostane for mid-trimester termination of pregnancy: randomized controlled trials.
BACKGROUND
Progesterone is central to the maintenance of pregnancy, and is thus the ideal target for fertility regulation. Two mechanisms by which progesterone can be targeted are: receptor blockade and reduction of progesterone production through enzyme inhibition. Mifepristone, a receptor blocker, is usually given as 'pretreatment' prior to prostaglandin administration in mid-trimester termination of pregnancy (TOP). Unfortunately, there are difficulties accessing mifepristone in developing countries, and TOP is therefore performed using prostaglandins alone, which results in unacceptably long induction-to-abortion intervals. Trilostane is a 3beta-hydroxysteroid dehydrogenase inhibitor which reduces progesterone production. In these mid-trimester studies it is evaluated as a method of pretreatment prior to misoprostol administration.


METHODS
Three consecutive randomized controlled trials comparing different trilostane regimens for pretreatment were performed. In study 1, trilostane was compared with placebo; in study 2, two doses of trilostane were compared (1080 mg and 720 mg); in study 3, the effect of adding danazol to trilostane as combination therapy was evaluated. The primary outcome in all the studies was the induction-to-abortion interval. Serum progesterone, estradiol and cortisol were measured serially during treatment.


RESULTS
In study 1, 48 women were randomized. The median induction-to-abortion interval was 9 h in the trilostane group and 18.5 h in the placebo group (P < 0.0001). Progesterone and estradiol production was significantly reduced in the women receiving trilostane, with maintenance of diurnal cortisol variation. Twenty-eight women were randomized in study 2, which demonstrated that there was no significant difference in the induction-to-abortion interval using 1080 mg and 720 mg trilostane when compared with the higher doses used in study 1. Study 3, in which 40 women were included, failed to show any additional benefit using combination therapy with danazol and trilostane.


CONCLUSIONS
Trilostane is an effective pretreatment agent in mid-trimester TOP.
le Roux
P A
PA
Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, University of Cape Town/Groote Schuur Hospital, Cape Town, South Africa. pleroux@uctgsh1.uct.ac.za
Tregoning
S K
SK
Zinn
P M
PM
van der Spuy
Z M
ZM
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000020:Abortifacient Agents, Nonsteroidal / Q000008:administration & dosage; D000021:Abortifacient Agents, Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D000028:Abortion, Induced / Q000379:methods*; D000328:Adult; D003613:Danazol / Q000008:administration & dosage; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008875:Middle Aged; D016595:Misoprostol / Q000008:administration & dosage; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011374:Progesterone / Q000097:blood / Q000378:metabolism*; D013997:Time Factors
D000020:Abortifacient Agents, Nonsteroidal; D000021:Abortifacient Agents, Steroidal; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D016595:Misoprostol; D011374:Progesterone; D004958:Estradiol; D015096:3-Hydroxysteroid Dehydrogenases; C009954:trilostane; D003613:Danazol; D006854:Hydrocortisone