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Original Articles: Hormones and Reproductive Health |
Department of Pharmacology (L.W., M.H., M.J., E.E.), Institute of Heart and Lung Disease (F.B., R.R., G.H., P.B.), and Institute of Clinical Neuroscience, Section of Psychiatry (M.L.), Goteborg University, SE 405 30 Goteborg, Sweden
Address all correspondence and requests for reprints to: Dr. Lars Westberg, Department of Pharmacology, Goteborg University, P.O. Box 431, DE 405 30 Goteborg, Sweden. E-mail: lars.westberg{at}pharm.gu.se
Abstract
To elucidate the possible role of genetic variation in androgen
receptor (AR), estrogen receptor 
(ER), and ERß on serum
androgen levels in premenopausal women, the CAG repeat polymorphism of
the AR gene, the TA repeat polymorphism of the ER gene, and the CA
repeat polymorphism of the ERß gene were studied in a
population-based cohort of 270 women. Total testosterone, free
testosterone, dehydroepiandrosterone sulfate, androstenedione,
17-hydroxyprogesterone, 3-androstanediol glucuronide,
17ß-estradiol, LH, FSH, and sex steroid hormone-binding globulin
(SHBG) were measured in serum samples obtained in the follicular phase
of the menstrual cycle. Women with relatively few CAG repeats in the AR
gene, resulting in higher transcriptional activity of the receptor,
displayed higher levels of serum androgens, but lower levels of LH,
than women with longer CAG repeat sequences. The CA repeat of the ERß
gene also was associated with androgen and SHBG levels; women with
relatively short repeat regions hence displayed higher hormone levels
and lower SHBG levels than those with many CA repeats. In contrast, the
TA repeat of the ER gene was not associated with the levels of any
of the hormones measured. Our results suggest that the serum levels of
androgens in premenopausal women may be influenced by variants of the
AR gene and the ERß gene, respectively.
THE PHYSIOLOGICAL and pathophysiological roles of androgens in women are gaining increasing attention. Recent studies thus suggest an important role of testosterone in conditions such as the polycystic ovary (PCO) syndrome (1, 2), recurrent miscarriages (3, 4), androgenic alopecia, hirsutism, acne (5), reduced libido (6), and various psychiatric conditions (7). Of particular interest in this context are the accumulating data suggesting that elevated levels of androgens may be a major risk factor for the development of noninsulin-dependent diabetes mellitus in women (8).
The androgen receptor (AR) belongs to a family of nuclear transcription factors. The AR gene is located on chromosome Xq11–12. A polymorphic polyglutamine stretch in the amino-terminal domain of the AR, encoded by the nucleotides cysteine, adenine, and guanine (CAG), appears to influence the function of the receptor as a transcription factor, so that relatively long fragments are associated with a low level of receptor function (9, 10, 11). The polyglutamine region is assumed to be involved in interactions between the AR and different coactivators; recent data suggest that long repeat regions are inhibitory to these interactions, which could explain the lower activity of the receptor (12).
Clinical studies support the functional importance of the CAG repeat sequence of the AR gene. Relatively few (<22) CAG repeats in the AR gene are hence associated with a higher risk of prostate cancer (13, 14), benign prostate hyperplasia (15, 16), and young-onset rheumatoid arthritis (17) and with a lower risk of infertility (18). A substantial expansion (40–72 repeats) of the CAG repeat sequence is the cause of a rare X-linked form of motor neuron disorder in men, termed Kennedy’s disease (spinal and bulbar muscular atrophy) (19), that is associated with some degree of androgen insensitivity (20). Data on the functional importance of the number of CAG repeats in the AR gene in women is sparse, but associations between this polymorphism and hirsutism, acne, androgenic alopecia (21, 22), bone mass density (23), and breast cancer (24, 25) have been suggested.
In men, the inhibitory feedback influence of the AR on serum levels of androgens is well established and is illustrated by the marked elevation of testosterone levels after the administration of an AR antagonist (26) and by the reduction in endogenous androgen production after intake of exogenous androgens (27). The report by Krithivas and co-workers (28) that a relatively long CAG repeat sequence counteracts the age-related decline in serum androgen levels hence supports the idea that many CAG repeats are associated with low AR responsiveness. In line with this, patients with Kennedy’s disease are reported to fail to suppress LH and testosterone levels after the administration of a synthetic androgen (20). In women, the hypothalamus-pituitary-gonadal axis is mainly regulated by female sex steroids; to what extent and by which mechanisms androgen receptors may influence serum androgen levels in women are thus less obvious.
Two estrogen receptors (ERs) have been identified, the subtype and
the more recently discovered ß subtype (29). The ER
gene is located on chromosome 6q25–27. Its promoter region contains a
polymorphic TA repeat (30) that has been associated with
coronary heart disease (31) and anxiety (32)
in men and with bone mineral density (33, 34), familiar
premature ovarian dysfunction (35), and endometriosis
(36) in women. The ERß gene is located on chromosome
14q23–24. Recently, a polymorphic dinucleotide CA repeat in the
noncoding 3'-portion of the gene was identified (37) and
was suggested to be associated with bone mineral density in women
(38). The functional importance of these two polymorphisms
has as yet not been clarified; however, as suggested (39),
there are reasons to believe that repeat nucleotide sequences
(micro/minisatellites), even when situated in untranslated regions,
per se may influence the expression of a gene.
The idea that estrogens may influence serum androgen levels in women
gains support from the reduction in serum levels of ovarian and adrenal
androgens observed in women receiving estrogen replacement therapy
during menopause (40, 41) or oral contraceptives
(42). The involvement of the and ß receptor
subtypes, respectively, in the tentative effect of estrogens on
androgen levels is not known however.
In this study we explored to what extent serum levels of sex steroids,
sex hormone-binding globulin (SHBG), LH, and FSH in a population-based
cohort of women are related to the number of CAG repeats of the AR
gene, the number of TA repeats of the ER gene, and the number of CA
repeats of the ERß gene.
Subjects and Methods
Subjects
All women born on uneven days in 1956 and living in Goteborg, Sweden, constituted the primary cohort (n = 1137) (43, 44). Of these subjects, 80% responded to questionnaires and reported self-measurements of body weight, height, and circumferences over the waist and hips. The participants in the present study were originally recruited to elucidate the relationship between the waist/hip circumference ratio (WHR) and various metabolic and endocrine parameters. To ensure that the subjects included displayed a considerable variation with respect to WHR, self-measured WHR (as reported by the subjects) was used for selection of subjects; thus, one third reported low (<0.738) self-rated WHR, one third reported a self-measured WHR around the median (0.798–0.822), and one third reported high (>0.895) self-measured WHR. Women who had not experienced menstruation during the past 6 months were excluded. In total, 450 women were invited to participate. Two hundred and seventy (60%) of these agreed to provide blood samples for hormone analyses and genotyping. Probably due to the fact that 1) the inclusion of subjects was based on self-rated rather than verified WHR, 2) 2 yr had elapsed between the return of the questionnaire and the assessment of WHR in the laboratory, and 3) 40% of those selected refused to provide blood samples, the laboratory-assessed WHR data in the studied population appeared to be normally distributed, with a median corresponding to that of the normal population. It is hence reasonable to assume that this cohort of women does not differ substantially from the normal population with respect to WHR. Moreover, as reported in previous publications (43, 44), the subjects included did not differ to any greater extent from those 40% who refused to participate with respect to parameters such as body mass index, somatic health, mental health, and a number of socioeconomic factors. Subjects using oral or im hormone-containing contraceptives (n = 26) were excluded from analysis; these are hence based on a total number of 244 participants. All but 17 subjects (7%) were from Europe and of probable Caucasian origin. Of the non-Europeans, 14 were from the Middle East, 2 were from South America, and 1 was from South-East Asia. No attempt to further analyze the ethnicity of the participants was made. Fasting blood samples for hormonal measurements (serum) and genetic analyses (whole blood) were obtained in the follicular phase of the menstrual cycle (days 5–10). All women provided written informed consent. The study was approved by the ethical committee of Goteborg University.
Genotyping
Genomic DNA was isolated using the QIAamp DNA Blood Mini Kit (QIAGEN, Valencia, CA). The three different regions were amplified by PCR. The PCR of the CAG repeat in the AR gene was performed in a total volume of 25 µL containing 50 ng DNA, 1.5 mmol/L MgCl2, 0.625 U AmpliTaq DNA polymerase (Perkin-Elmer Corp., Norwalk, CT), and 0.2 µmol/L of each of the primers (5'-GTG CGC GAA GTG ATC CAG A-3' and 5'-GTT TCC TCA TCC AGG ACC AGG TA-3', selected with Primer Express, Perkin-Elmer Corp.). The forward primer was fluorescently labeled with 6-carboxy fluorescein. Nucleotides promoting the nontemplated addition of adenine by Taq DNA polymerase was added to the 5'-end of the reverse primer (45). Thermal cycling was performed in a Perkin-Elmer Corp. GeneAmp PCR System 9700 with the following temperature profile: 95 C for 5 min, followed by 35 cycles of 95 C for 30 s, 57 C for 30 s, 72 C for 30 s, and a final incubation at 72 C for 7 min.
The PCR of the TA repeat of the ER gene was performed in a total
volume of 15 µL containing 50 ng DNA, 1.5 mmol/L
MgCl2, 1 U HotstarTaq polymerase
(QIAGEN), and 0.3 µmol/L of each of the primers
described by Comings and co-workers (32). The forward
primer (5'-AGA CGC ATG ATA TAC TTC ACC-3') was labeled with 6-carboxy
fluorescein and used together with the reverse primer (5'-GTT
CAC TTG GGC TAG GAT AT-3'). The temperature profile was 95 C for 15
min, followed by 35 cycles of 95 C for 30 s, 60 C for 30 s,
72 C for 30 s, and a final incubation at 72 C for 7 min.
The PCR of the CA repeat polymorphism of the ERß gene was performed in a total volume of 25 µL containing 50 ng DNA, 1.5 mmol/L MgCl2, 1 U AmpliTaq DNA polymerase (Perkin-Elmer Corp.), and 0.3 µmol/L of each of the primers described by Tsukamoto and co-workers (37). The forward primer (5'-GGT AAA CCA TGG TCT GTA CC-3') was labeled with Hexachloro-6-carboxy fluorescein and used together with the reverse primer (5'-AAC AAA ATG TTG AAT GAG TGG G-3'). The temperature profile was 95 C for 12 min, followed by 35 cycles of 95 C for 30 s, 60 C for 30 s, 72 C for 30 s, and a final incubation at 72 C for 7 min.
The fluorescently labeled DNA fragments were analyzed by size with automated capillary electrophoresis using an ABI PRISM 310 Genetic Analyzer (Perkin-Elmer Corp.).
Hormone determination
17ß-Estradiol, total testosterone, SHBG, and FSH were analyzed
using a chemiluminescent enzyme immunoassay; androstenedione,
dehydroepiandrosterone sulfate (DHEA-S),
17-hydroxyprogesterone, 3-androstanediol glucuronide (3--diol-G),
and LH were analyzed by RIA. All assays were performed in accordance
with the instructions provided by the manufacturer (3--diol-G:
Diagnostics Systems Laboratories, Inc., Webster, TX; LH:
MAIA Clone, Serono Diagnostics, Braintree, MA; all other:
Diagnostic Products, Los Angeles, CA).
Data analysis
Prompted by previous studies suggesting an inverse relation
between the number of CAG repeats in the AR and receptor activity, we
divided all alleles into two groups of approximately equal size; those
with 19 or fewer repeats were defined as short (S), whereas those with
more than 19 repeats were defined as long (L). The subjects studied
could thus be divided into three groups [those with two short alleles
(SS), those with two long alleles (LL), and those with one short and
one long allele (SL)] that were compared with respect to serum hormone
levels. Given the fact that the AR gene is located on the X-chromosome,
resulting in a random inactivation of one of the two alleles in women
(46), we also decided to analyze the tentative importance
of carrying at least one allele with a short CAG repeat fragment (a
more active receptor); to this end, all subjects were divided into two
groups, based on the length of the shortest of the two alleles they
displayed. So that these two groups should be of approximately the same
size, the cut-off used for this operation was 17 (
17 = short).
Likewise, a division based on the length of the longest of the two
alleles was performed, with 20 as the cut-off (20 = short).
For the ER and ERß gene polymorphisms studied, no relationship
between repeat number and function has as yet been found. Prompted by
the tentative assumption that there is a relationship between the
length of microsatellites and function (39), the ER and
ERß alleles were examined using the same strategy as that applied for
the AR gene data, i.e. by splitting the subjects into
subgroups comprising those with 2 short alleles (SS), those with 2 long
alleles (LL), and those with 1 short and 1 long allele (SL). Splitting
of groups was undertaken with the median as the cut-off, hence yielding
groups of approximately the same size. These cut-off limits were 191
(alleles containing 191 bp = short) for ER and 159 (alleles
containing 159 bp = short) for ERß.
Data are presented as the mean ± SE. Comparisons of
groups were undertaken using t test (two groups) or ANOVA,
followed by Fischer’s protected least significant difference test (
2
groups). P = 0.05 was considered statistically
significant.
Results
AR
The CAG repeats in the AR receptor ranged from 4 to 33 CAGs, with
a median length of 19 (Fig. 1
). As shown
in Fig. 2, a relatively low number of CAG
(19) repeats in the AR gene was associated with relatively high
levels of total testosterone. Comparison of the SS (n = 84), LL
(n = 46), and SL (n = 109) groups with respect to the levels
of 17-hydroxyprogesterone (nanomoles per L) also revealed a
significant difference (SS, 3.8 ± 0.2; LL, 3.3 ± 0.2; SL,
4.0 ± 0.2; SS vs. LL, P = NS; SS
vs. SL, P = NS; SL vs. LL,
P = 0.05); in contrast, free testosterone (picomoles
per L; SS, 4.8 ± 0.3; LL, 4.4 ± 0.3; SL, 4.8 ± 0.2),
androstenedione (nanomoles per L; SS, 7.6 ± 0.4; LL, 7.0 ±
0.4; SL, 7.4 ± 0.3), DHEA-S (micromoles per L; SS,
4.0 ± 0.2; LL, 3.9 ± 0.3; SL, 3.8 ± 0.1), 3-diol-G
(nanomoles per L; SS, 6.5 ± 0.4; LL, 6.0 ± 0.6; SL,
6.4 ± 0.4), 17ß-estradiol (picomoles per L; SS, 199.5 ±
16.7; LL, 209.4 ± 31.8; SL, 223.2 ± 17.8), and SHBG
(nanomoles per L; SS, 45.1 ± 2.3; LL, 43.2 ± 2.7; SL,
45.5 ± 2.0) did not differ significantly. Serum levels of LH were
lower in subjects with short CAG repeats (international units per L;
SS, 3.5 ± 0.2; LL, 5.3 ± 0.8; SL, 4.2 ± 0.3; SS
vs. LL, P = 0.006; SS vs. SL,
P = NS; SL vs. LL, P =
0.09). Levels of FSH reached borderline significance between groups
(international units per L; SS, 12.1 ± 0.6; LL, 15.6 ± 2.6;
SL, 14.2 ± 1.0; SS vs. LL, P = 0.08;
SS vs. SL, P = NS; SL vs. LL,
P = NS).
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Comparison of the two groups formed by dividing the subjects with
respect to the length of the shortest of the two AR gene CAG repeat
polymorphisms carried by each individual revealed a significant
difference between those with a short (17) shortest allele (n =
116) and those with a long (>17) shortest allele (n = 123), not
only with respect to total testosterone (short, 2.3 ± 0.1; long,
1.8 ± 0.1; P = 0.002), but also with respect to
free testosterone (short, 5.2 ± 0.3; long, 4.3 ± 0.2;
P = 0.005) and 17-hydroxyprogesterone (short,
4.2 ± 0.2; long, 3.4 ± 0.1; P = 0.003).
Androstenedione levels were also higher in the group displaying at
least one short allele, but this difference failed to reach statistical
significance (short, 7.8 ± 0.4; long, 7.0 ± 0.2;
P = 0.06). Serum levels of DHEA-S,
3-diol-G, 17ß-estradiol, LH, FSH, and SHBG did not differ between
groups (data not shown). The corresponding analysis after splitting for
the longest allele in each individual (cut-off limit, 20; short allele,
n = 115; long allele, n = 124) revealed a significant
difference with respect to total testosterone (short, 2.2 ± 0.1;
long, 1.9 ± 0.08; P = 0.008) and LH (short,
3.6 ± 0.2; long, 4.7 ± 0.4; P = 0.03), but
with respect neither to the other hormones nor to SHBG (data not
shown).
ER
Eighteen different alleles of the ER gene were identified,
comprising 183–217 bp (Fig. 3). Cut-off
limit was 191. Comparison of the SS (n = 78), LL (n = 67),
and SL (n = 99) groups with respect to the levels of total
testosterone (SS, 2.0 ± 0.1; LL, 2.0 ± 0.1; SL, 2.1 ±
0.1), free testosterone (SS, 4.7 ± 0.3; LL, 4.9 ± 0.3; SL,
4.6 ± 0.2), androstenedione (SS, 7.4 ± 0.4; LL, 7.2 ±
0.3; SL, 7.6 ± 0.3), DHEA-S (SS, 3.8 ± 0.2;
LL, 3.8 ± 0.2; SL, 4.0 ± 0.2), 17-hydroxyprogesterone
(SS, 3.7 ± 0.2; LL, 3.6 ± 0.2; SL, 3.9 ± 0.2),
3-diol-G (SS, 6.0 ± 0.3; LL, 5.9 ± 0.4; SL, 6.7 ±
0.4), 17ß-estradiol (SS, 193.7 ± 18.3; LL, 223.4 ± 19.5;
SL, 216.3 ± 20.7), SHBG (SS, 44.8 ± 2.3; LL, 45.2 ±
2.7; SL, 44.7 ± 1.9), LH (SS, 4.5 ± 0.5; LL, 4.1 ±
0.5; SL, 3.9 ± 0.3), and FSH (SS, 14.6 ± 1.3; LL, 13.7
± 1.2; SL, 12.9 ± 1.1) revealed no significant differences.
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Fourteen different alleles of the ERß gene were identified,
comprising 145–171 bp (Fig. 4). The
cut-off limit was 159. Comparison of the SS (n = 43), LL (n =
74), and SL (n = 124) groups revealed a significant difference
with respect to total testosterone (Fig. 5), free testosterone (SS, 5.5 ±
0.5; LL, 4.2 ± 0.2; SL, 4.7 ± 0.2; SS vs. LL,
P = 0.007; SS vs. SL, P =
0.07; SL vs. LL, P = NS), androstenedione
(SS, 8.2 ± 0.6; LL, 6.9 ± 0.3; SL, 7.4 ± 0.3; SS
vs. LL, P = 0.05; SS vs. SL,
P = NS; SL vs. LL, P = NS),
and SHBG (SS, 39.1 ± 2.9; LL, 46.1 ± 2.4; SL, 46.1 ±
1.8; SS vs. LL, P = 0.07; SS vs.
SL, P = 0.05; SL vs. LL, P =
NS). In contrast, no significant differences were observed with respect
to DHEA-S (SS, 4.1 ± 0.3; LL, 3.6 ± 0.2; SL,
4.0 ± 0.2), 17-hydroxyprogesterone (SS, 4.2 ± 0.4; LL,
3.6 ± 0.2; SL, 3.7 ± 0.2), 3-diol-G (SS, 6.6 ±
0.6; LL, 5.8 ± 0.3; SL, 6.6 ± 0.3), or 17ß-estradiol (SS,
198.6 ± 23.1; LL, 226.6 ± 24.3; SL, 206.9 ± 15.5). No
associations between variants of the ERß gene and serum levels of FSH
or LH were observed (data not shown).
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Subgroup analyses
The fact that self-measured WHR was used as an inclusion criterion when initially recruiting this cohort of women (see Materials and Methods) prompted us to investigate to what extent the observed relationships between genotypes and hormonal levels were restricted to women with high or low WHR, respectively. These analyses, however, showed that WHR seems not to be a factor of importance in this context; similar associations were hence observed in women with low or high WHR, respectively (data not shown). In addition, all calculations were repeated after excluding those 17 subjects that were not of European origin; in no case did the exclusion of these subjects influence the level of significance (data not shown).
Discussion
The data presented in this paper suggest that serum androgen levels in women are associated with a CAG repeat polymorphism in the AR gene and by a CA repeat polymorphism in the ERß gene. To our knowledge, such an association between receptor genes and androgen levels in women has previously not been reported.
The observation that variants of the AR gene coding for a more active receptor (few CAG repeats) are associated with higher levels of androgens is the opposite of what has previously been reported in men (28) and suggests that the major influence of ARs on androgen production in women is stimulatory rather than inhibitory.
Serum levels of LH were significantly lower in subjects with few CAG repeats in the AR gene, suggesting that ARs in women exert an inhibitory influence on LH release during the follicular phase. This observation indicates that the relative increase in serum androgen levels in these subjects is not mediated by the hypothalamus, but is due to a direct effect of ARs in the adrenal glands or the ovaries. It should, however, be underlined that LH is secreted in a pulsatile fashion; any information based on a single sample should hence be interpreted with caution.
ARs have been demonstrated in the adrenal gland (47). Administration of testosterone to women has been shown to cause increased serum levels of adrenal androgens (48, 49, 50, 51), which may explain the increase in adrenal androgens observed in women with the PCO syndrome (52, 53). The assumption that the observed positive relationship between a gene polymorphism coding for a more active receptor and high levels of testosterone should be due to an increase in adrenal androgen production is, however, to some extent challenged by the observation that serum levels of an androgen that is generally regarded as a marker of adrenal androgen production, DHEA-S, did not seem to be related to the AR gene.
Human thecal cells, which are thought to be the primary site of androgen biosynthesis in the ovarian stroma, have been shown to express ARs (54). Recent data suggest that short-term androgen treatment stimulates follicle development by various mechanisms (55, 56, 57). Supporting the idea that androgens may induce ovarian overgrowth, leading to further hyperandrogenism, androgen-producing tumors, congenital hyperplasia, and exogenous androgen treatment have all been associated with the development of PCO. On the other hand, AR blockade has been shown to cause a reduction in follicle number and ovarian size in women with this condition (58). The present observation that women expressing a more active AR display higher serum levels of androgens may thus reflect an enhanced androgenic influence on androgen-producing cells in the ovary. No examination of ovarian morphology was undertaken in this trial; the possible relationship between the genes studied and PCO was hence not the subject of this investigation. It should however be underlined that women with amenorrhea, which is a common feature of a manifest PCO syndrome, were not included in this study.
Lending further support for the idea that the AR indeed exerts a stimulatory influence on androgen production in women, administration of the AR antagonist flutamide has been shown to reduce androgen levels (58, 59, 60). Whether this effect is exerted within the adrenal gland or within the ovaries, however, remains to be clarified. Also, results obtained with flutamide should be interpreted with caution, because a direct, non-AR-mediated influence of flutamide on testosterone synthesis cannot be excluded (61, 62).
The present data suggest that the ERß gene influences androgen
levels. Women with a short CA repeat region of the ERß gene hence
displayed higher serum levels of total and free testosterone than women
with many CA repeats. In contrast, no associations between the ER
polymorphism studied and serum levels of sex steroids were
observed.
Several studies suggest that estrogen replacement therapy (ERT) of postmenopausal women (63) or administration of oral contraceptives (42) reduces androgen levels. This effect may be mediated by the hypothalamus, but direct effects on the ovaries have been suggested as well. Notably, ERß receptors have been detected in the ovaries, adrenals, pituitary, and hypothalamus of humans (64) and monkeys (65).
Our finding that SHBG levels seem related to the ERß gene is in agreement with previous studies reporting a profound stimulatory influence of estrogens on SHBG production (40, 41, 63). The observed association between a low number of CA repeats in the ERß gene and low levels of SHBG may explain the finding that free testosterone levels seemed more strongly associated with this gene than did total levels of testosterone.
The apparent association between a short CA repeat region of the ERß gene and high and low levels of testosterone and SHBG, respectively, would suggest that this variant of the gene leads to a less active receptor (which contrasts with the fact that a short repeat region of the AR is known to lead to a more active receptor). Needless to say, a detailed discussion of the possible mechanisms underlying the apparent association between the ERß gene polymorphism studied and hormone levels must await a further clarification of the putative influence of this polymorphism on receptor function.
As discussed above, the apparent influence of the AR and ERß genes on androgen levels may be explained by acute effects of these receptors on the hormonal production in the adrenal glands and/or the ovaries. As both AR and ERß are probably involved in the prenatal sexual differentiation (66, 67), the possibility that the effects observed are due to early organizational effects of these receptors, however, may not be excluded. The possibility that a relatively pronounced influence of androgens during development leads to an increase in serum androgen levels in the adult woman should be considered.
It should be noted that all blood samples were obtained in the
follicular phase of the menstrual cycle. The fact that no relationship
between the three gene polymorphisms studied and serum levels of
17ß-estradiol was observed does not preclude that such associations
would have been found if hormonal levels had been followed throughout
the menstrual cycle. Moreover, although androgen levels are more stable
than are the levels of female sex steroids, the possibility that serum
levels of androgens are also regulated by different mechanisms during
different phases of the cycle cannot be excluded. The possibility that
the ER genotype are more important for hormonal levels in phases of
the cycle when estrogen levels are high than during the early
follicular phase also should not be excluded.
In conclusion, our results suggest that serum levels of androgens in premenopausal women may be influenced by certain variants of the AR gene and the ERß gene, respectively. Given the likely involvement of androgens for somatic and psychiatric morbidity in women, a further elucidation of the genetic determinants for serum androgen levels is clearly warranted.
Acknowledgments
We thank technicians Inger Oscarsson, Gunilla Bourghardt, and Anna Nilsson for skillful assistance.
Footnotes
1 This work was supported by grants from the Swedish Medical Research
Council (Grants 8668 and 251), Lundberg’s Foundation, Wallenberg’s
Foundation, Thuring’s Foundation, and Lundbeck’s Foundation. 
Received September 1, 2000.
Revised March 2, 2001.
Accepted March 20, 2001.
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the prostate. J Steroid Biochem. 28:619–622.[CrossRef][Medline]
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S. Wedren, C. Magnusson, K. Humphreys, H. Melhus, A. Kindmark, F. Stiger, M. Branting, I. Persson, J. Baron, and E. Weiderpass Associations between Androgen and Vitamin D Receptor Microsatellites and Postmenopausal Breast Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1775 - 1783. [Abstract] [Full Text] [PDF]
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A. Beleza-Meireles, I. Kockum, F. Lundberg, C. Soderhall, and A. Nordenskjold Risk Factors for Hypospadias in the Estrogen Receptor 2 Gene J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3712 - 3718. [Abstract] [Full Text] [PDF]
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M. Hietala, T. Sandberg, A. Borg, H. Olsson, and H. Jernstrom Testosterone levels in relation to oral contraceptive use and the androgen receptor CAG and GGC length polymorphisms in healthy young women Hum. Reprod., January 1, 2007; 22(1): 83 - 91. [Abstract] [Full Text] [PDF]
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N. Xita and A. Tsatsoulis Fetal Programming of Polycystic Ovary Syndrome by Androgen Excess: Evidence from Experimental, Clinical, and Genetic Association Studies J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1660 - 1666. [Abstract] [Full Text] [PDF]
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M. L. Slattery, C. Sweeney, M. Murtaugh, K. N. Ma, R. K. Wolff, J. D. Potter, B. J. Caan, and W. Samowitz Associations between ER{alpha}, ER{beta}, and AR Genotypes and Colon and Rectal Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2005; 14(12): 2936 - 2942. [Abstract] [Full Text] [PDF]
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 L. Gennari, D. Merlotti, V. De Paola, A. Calabro, L. Becherini, G. Martini, and R. Nuti Estrogen Receptor Gene Polymorphisms and the Genetics of Osteoporosis: A HuGE Review Am. J. Epidemiol., February 15, 2005; 161(4): 307 - 320. [Abstract] [Full Text] [PDF]
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 I. S. Brum, P. M. Spritzer, F. Paris, M. A. Maturana, F. Audran, and C. Sultan Association Between Androgen Receptor Gene CAG Repeat Polymorphism and Plasma Testosterone Levels in Postmenopausal Women Reproductive Sciences, February 1, 2005; 12(2): 135 - 141. [Abstract] [PDF]
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 S. Walsh, J. M. Zmuda, J. A. Cauley, P. R. Shea, E. J. Metter, B. F. Hurley, R. E. Ferrell, and S. M. Roth Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men J Appl Physiol, January 1, 2005; 98(1): 132 - 137. [Abstract] [Full Text] [PDF]
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 C. Zhao, L. Xu, M. Otsuki, G. Toresson, K. Koehler, Q. Pan-Hammarstrom, L. Hammarstrom, S. Nilsson, J.-A. Gustafsson, and K. Dahlman-Wright Identification of a functional variant of estrogen receptor beta in an African population Carcinogenesis, November 1, 2004; 25(11): 2067 - 2073. [Abstract] [Full Text] [PDF]
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D. Lattuada, P. Vigano, E. Somigliana, M. P. Odorizzi, M. Vignali, and A. M. Di Blasio Androgen Receptor Gene Cytosine, Adenine, and Guanine Trinucleotide Repeats in Patients With Endometriosis Reproductive Sciences, May 1, 2004; 11(4): 237 - 240. [Abstract] [PDF]
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L. Ibanez, K. K. Ong, N. Mongan, J. Jaaskelainen, M. V. Marcos, I. A. Hughes, F. de Zegher, and D. B. Dunger Androgen Receptor Gene CAG Repeat Polymorphism in the Development of Ovarian Hyperandrogenism J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3333 - 3338. [Abstract] [Full Text] [PDF]
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N. M. Suter, K. E. Malone, J. R. Daling, D. R. Doody, and E. A. Ostrander Androgen Receptor (CAG)n and (GGC)n Polymorphisms and Breast Cancer Risk in a Population-Based Case-Control Study of Young Women Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 127 - 135. [Abstract] [Full Text] [PDF]
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H. O. D. Critchley, T. A. Henderson, R. W. Kelly, G. S. Scobie, L. R. Evans, N. P. Groome, and P. T. K. Saunders Wild-Type Estrogen Receptor (ER{beta}1) and the Splice Variant (ER{beta}cx/{beta}2) Are Both Expressed within the Human Endometrium throughout the Normal Menstrual Cycle J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5265 - 5273. [Abstract] [Full Text] [PDF]
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I. Stavrou, C. Zois, J.P.A. Ioannidis, and A. Tsatsoulis Association of polymorphisms of the oestrogen receptor{alpha} gene with the age of menarche Hum. Reprod., April 1, 2002; 17(4): 1101 - 1105. [Abstract] [Full Text] [PDF]
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 C. A. Haiman, M. Brown, S. E. Hankinson, D. Spiegelman, G. A. Colditz, W. C. Willett, P. W. Kantoff, and D. J. Hunter The Androgen Receptor CAG Repeat Polymorphism and Risk of Breast Cancer in the Nurses' Health Study Cancer Res., February 1, 2002; 62(4): 1045 - 1049. [Abstract] [Full Text] [PDF]
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