3alpha-Hydroxysteroid dehydrogenase type III deficiency: a novel mechanism for hirsutism.
BACKGROUND
Dihydrotestosterone (DHT), the primary active androgen in peripheral target tissues, is metabolized by 3alpha-hydroxysteroid dehydrogenase type III (3alpha-HSD), encoded by the AKR1C2 gene, forming 5alpha-androstane-3alpha,17beta-diol (3alpha-diol). 3alpha-HSD may play a role in the pathogenesis of hirsutism.


OBJECTIVE
Our objective was to evaluate the role of 3alpha-HSD in hirsutism by comparing 1) tissue levels of active androgens, 2) relative gene expression of AKR1C2, and 3) activity of 3alpha-HSD in genital skin from normal and hirsute women.


METHODS
Genital skin was obtained from normal and hirsute women. After homogenization, testosterone (T) and DHT levels were quantified by conventional RIA. From isolated RNA, relative expression of AKR1C2 was determined by real-time PCR. In addition, minced genital skin was incubated with [(3)H]DHT, and the product, [(3)H]3alpha-diol, was quantified by radio-HPLC.


METHODS
The study took place at an inner-city hospital.


METHODS
PATIENTS included women undergoing posterior colporrhaphy.


METHODS
We assessed 1) tissue levels of T, DHT, and 3alpha-diol; 2) relative expression of AKR1C2; and 3) conversion ratio of [(3)H]3alpha-diol to [(3)H]DHT.


RESULTS
In genital skin, tissue DHT and T concentrations in hirsute women were 1.90-fold and 1.84-fold higher than in normal women (P =0 .002 and 0.03), and relative expression of AKR1C2 mRNA was reduced approximately 7-fold (P = 0.04). Genital skin from hirsute women showed less metabolism of [(3)H]DHT to [(3)H]3alpha-diol (conversion ratio, 0.24 +/- 0.19 vs. 0.85 +/- 0.55, P = 0.01).


CONCLUSIONS
In genital skin of hirsute women, reduced AKR1C2 gene expression and 3alpha-HSD activity results in decreased DHT metabolism and elevated tissue levels of DHT. Diminished DHT metabolism may play an important role in the pathogenesis of hirsutism.
Steiner
Anne Z
AZ
Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. asteiner@med.unc.edu
Chang
Lilly
L
Ji
Qing
Q
Ookhtens
Murad
M
Stolz
Andrew
A
Paulson
Richard J
RJ
Stanczyk
Frank Z
FZ
D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000172:deficiency*; D000328:Adult; D013196:Dihydrotestosterone / Q000378:metabolism; D005260:Female; D006628:Hirsutism / Q000201:enzymology / Q000209:etiology*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis
D012333:RNA, Messenger; D013196:Dihydrotestosterone; D006913:Hydroxysteroid Dehydrogenases; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)