Low dose ketoconazole attenuates serum androgen levels in patients with polycystic ovary syndrome and inhibits ovarian steroidogenesis in vitro.
OBJECTIVE
To investigate the effects of a low-dose ketoconazole on ovarian steroidogenesis and on serum androgen levels in polycystic ovary syndrome (PCOS).


METHODS
In vitro, human granulosa-luteal cells were incubated with ketoconazole and radiolabeled steroid substrates, to follow their metabolic fate by thin-layer chromatography analysis. In vivo, normally cycling women (n = 7) in their luteal phase were administered one tablet of 200 mg ketoconazole at 8 A.M. Serum steroid levels, sampled basally and at 12 P.M., 4 P.M., and 8 A.M. the next morning, were compared with untreated control group (n = 7) values. Polycystic ovary syndrome women (n = 11) were similarly administered ketoconazole 6 to 10 days after occurrence of spontaneous menses. Adrenal origin of hyperandrogenemia was excluded by stimulation with ACTH and a normal basal DHEAS. The steroid diurnal variation was determined in the same patients a day before treatment.


RESULTS
In vitro, ketoconazole selectively inhibited the key steroidogenic cytochromes, namely P450scc, P45017 alpha, and P450arom (IC50 = 0.5 to 1.0 microgram/mL). In vivo, in the luteal phase, ketoconazole transiently decreased serum values (mean +/- SE) of E2 (19.2% +/- 2.1%) and P (38.3% +/- 8.5%) within 4 to 8 hours. The same low-dose ketoconazole, administered to PCOS women, decreased serum values of androstenedione (17.6% +/- 4.7%), T (24.6% +/- 7.6%), and free T (30.7% +/- 7.7%). In contrast, 17 alpha-hydroxyprogesterone increased concomitantly (78.5% +/- 10.8%), suggesting a greater suppressibility of the P45017 alpha lyase activity. The E2 levels in PCOS patients were slightly elevated (29.1% +/- 5.6%), resulting in a 1.7- to 2.3-fold increase of the E2:T ratio.


CONCLUSIONS
These findings suggest that a low-dose ketoconazole may facilitate a decreased intraovarian T:E2 ratio, which may prove favorable for follicular maturation in PCOS.
Gal
M
M
Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel.
Orly
J
J
Barr
I
I
Algur
N
N
Boldes
R
R
Diamant
Y Z
YZ
D015067:17-Hydroxysteroid Dehydrogenases / Q000097:blood / Q000378:metabolism*; D019326:17-alpha-Hydroxyprogesterone; D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000328:Adult; D000728:Androgens / Q000097:blood*; D001141:Aromatase / Q000097:blood / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000097:blood / Q000378:metabolism; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006908:Hydroxyprogesterones / Q000097:blood / Q000378:metabolism; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000008:administration & dosage / Q000627:therapeutic use*; D008183:Luteal Phase / Q000502:physiology; D010053:Ovary / Q000166:cytology / Q000378:metabolism*; D011085:Polycystic Ovary Syndrome / Q000097:blood* / Q000188:drug therapy*; D011374:Progesterone / Q000097:blood / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000097:blood / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism
D000728:Androgens; D006908:Hydroxyprogesterones; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D007654:Ketoconazole