A. Mifsud et al., Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries, J CLIN END, 85(9), 2000, pp. 3484-3488
Hyperandrogenism is currently thought to be central to the pathogenesis of
polycystic ovarian syndrome (PCOS), a common endocrine disorder in premenop
ausal women characterized by irregular menstruation and anovulatory inferti
lity. Although hyperandrogenism is characteristic, some women with PCOS hav
e normal serum androgen levels. All androgens act through the X-linked andr
ogen receptor (AR), the N-terminal domain of which contains a polyglutamine
tract encoded by a highly polymorphic CAG trinucleotide repeat tract. Rece
ntly, variations in this CAG microsatellite tract, while remaining within t
he normal polymorphic range (11-38 CAGs), have been inversely correlated wi
th receptor activity. Thus, short tracts are associated with high intrinsic
AR activity and increased severity and earlier age of onset of the androge
n-regulated tumor prostate cancer, whereas longer CAG tracts are associated
with low AR activity and oligospermic infertility. To investigate the role
of the CAG repeat tract in PCOS, we measured its length in 91 patients wit
h ultrasound diagnosis of polycystic ovaries, irregular menstrual cycles, a
nd anovulatory infertility and compared them to 112 control subjects of pro
ven fertility with regular menses. Fluorescent-labeled DNA fragments contai
ning the CAG repeat tract were amplified from leucocytic DNA, and their len
gths were compared with internal size markers on an automated DNA Sequencer
. There were no differences in the mean CAG length between patients and con
trols when both alleles were considered together or separately. Because the
re is a subset of PCOS patients whose serum androgens are normal, we compar
ed differences in CAG length between patients whose serum testosterone (T)
levels were below the normal laboratory mean, to those that were higher. Th
ere was a trend for a lower mean CAG biallelic length among anovulatory pat
ients with T less than 1.73 nmol/L compared with those whose T was more tha
n 1.73 nmol/L (22.47 +/- 0.36 vs. 23.25 +/- 0.29). This difference in CAG l
ength between patients with low and high T levels (20.38 +/- 0.51 vs. 21.98
+/- 0.29) was highly significant (P = 0.004) when only the shorter allele
of each individual was considered. Ethnic differences were also evident in
our data; Indian subjects had a significantly shorter AR-CAG length compare
d with Chinese, being 22.08 +/- 0.50 and 23.16 +/- 0.17, respectively. Our
data indicate an association between short CAG repeat length and the subset
of anovulatory patients with low serum androgens, suggesting that the path
ogenic mechanism of polycystic ovaries in these patients could be due to th
e increased intrinsic androgenic activity associated with short AR alleles.