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Original Studies |
-Reductase Activity in Women with Polycystic Ovary Syndrome1
Department of Obstetrics and Gynecology, Cedars-Sinai Burns and Allen Research Institute, Cedars-Sinai Medical Center/University of California School of Medicine (S.R.W., D.A.M.), Los Angeles, California 90048; and the Department of Obstetrics and Gynecology, Second Clinic of Surgical Gynecology, University School of Medicine (A.J.J.), 20-090 Lublin, Poland
Address all correspondence and requests for reprints to: Dr. Denis A. Magoffin, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: magoffin{at}cshs.org
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-androstane-3,17-dione in the follicular fluid of polycystic
ovaries suggests a potential role for 5-reduced androgens in the
etiology of polycystic ovary syndrome (PCOS). The purpose of the
present study was to determine whether there is increased
5-reductase activity or messenger ribonucleic acid (mRNA) expression
in polycystic ovaries. 5-Reductase 1 and 5-reductase 2 mRNAs were
measured in thecal (TC) and granulosa (GC) cells from individual
follicles of 18 women with PCOS and 26 regularly cycling control women.
Both 5-reductase 1 and 2 mRNA expression was higher in GC than in
TC, and 5-reductase 2 mRNA levels were approximately 3-fold higher
than 5-reductase 1 mRNA. 5-Reductase 1 and 2 mRNA expression were
similar in GC from PCOS and control women, but 5-reductase mRNA was
decreased in TC from PCOS follicles. In control women, 5-reductase 2
mRNA was highest in GC from 3- to 5-mm follicles and decreased to
undetectable levels in GC from 7-mm follicles. A similar pattern of
expression was present in GC from PCOS follicles, but detectable levels
of 5-reductase 2 mRNA were present in GC from 7-mm follicles.
5-Reductase activity was measured in whole follicles by measuring
the conversion of radiolabeled testosterone to dihydrotestosterone.
Kinetic analysis of total 5-reductase activity at physiological pH
revealed a Km of 1.46 µmol/L and a maximal velocity of
0.31 nmol/min·mg protein, indicating predominantly type 1 activity.
The total 5-reductase activity was approximately 4-fold higher in
PCOS follicles than in control follicles. These data demonstrate
elevated 5-reductase activity in polycystic ovaries and support the
hypothesis that 5-reduced androgens may play a role in the
pathogenesis of PCOS. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The cause of arrested follicular growth in PCOS remains unknown,
but recent evidence suggests a role for 5-reduced androgens. The
concentration of 5-androstane-3,17-dione in women with PCOS is
elevated compared with that in regularly cycling women in both serum
and follicular fluid, with 1000-fold higher levels in follicular fluid
than in serum (5). The elevated concentrations of
5-androstane-3,17-dione in polycystic ovaries are capable of
markedly inhibiting human granulosa cell (GC) aromatase activity in the
presence of physiological concentrations of androgen substrate (5) by
functioning as a competitive inhibitor (6). These data indicate a
potential role for 5-androstane-3,17-dione in the pathogenesis of
PCOS.
5-Androstane-3,17-dione can be produced from androstenedione
by the 5-reductase enzymes (7). There are two 5-reductase
isoenzymes, type 1 and type 2, that are expressed in a developmentally
regulated and tissue-specific manner (8, 9). 5-Reductase 1 has a
broad pH optimum around pH 8 and is mainly expressed in liver,
hypothalamus, cerebellum, and pons (10, 11). The type 2 isoenzyme has a
narrow, acidic pH optimum of 5.5 (11, 12) and is prominently expressed
in prostate, liver, skin, scalp, pituitary, and epididymis (13).
Although 5-reductase 2 messenger ribonucleic acid (mRNA) was not
detected by Northern blot analysis, 5-reductase activity was
observed in both follicular and stromal tissue at pH 5.5 and 8.0,
indicating that both isoenzymes are expressed in the human ovary (14).
5-Reductase activity was higher in human GC from follicles smaller
than 10 mm than in follicles larger than 10 mm in diameter, and thecal
cells (TC) contained less 5-reductase activity with increasing
follicle size (7). Taken together, these data demonstrate that
5-reductase activity is present in the granulosa, thecal, and
stromal compartments of the human ovary, but the distribution of
5-reductase isoenzymes in the ovary is unclear.
In light of the elevated 5-reduced androgen concentrations in the
follicular fluid of polycystic ovaries, it is reasonable to propose
that expression of one or more of the 5-reductase isoenzymes may be
increased in polycystic ovaries, causing elevated 5-reductase
activity in small antral follicles. The purpose of the present studies
was to test this hypothesis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ovarian tissue specimens were obtained from 18 women with PCOS undergoing wedge resection or before electrocauterization of the ovarian surface for the treatment of infertility. Control tissues were obtained from 26 regularly cycling premenopausal women undergoing total abdominal hysterectomy and bilateral oophorectomy in the follicular phase for nonovarian indications unrelated to the study. The indications for oophorectomy were uterine leiomyoma and cervical cancer. Women in both control and PCOS groups ranged from 22–44 yr of age. Women with PCOS were identified based on a history of oligo/amenorrhea, hirsutism, and typical morphological appearance of polycystic ovaries (normal or enlarged ovarian volume with multiple subcapsular cysts <8 mm in diameter) at laparotomy or laparoscopy with no evidence of hyperprolactinemia, Cushing’s syndrome, congenital or nonclassical adrenal hyperplasia, thyroid disease, or hormone-secreting tumors. No subject had received hormonal treatment or ovarian suppression for at least 3 months before obtaining the samples. Informed consent was obtained from all subjects participating in the study, which was approved by the ethics committee at the University School of Medicine in Lublin. These studies were also approved by the institutional review board at Cedars-Sinai Medical Center.
GC and TC collection
The ovarian specimens were immediately placed into ice-cold medium 199 (Life Technologies, Gaithersburg, MD) containing 25 mmol/L HEPES and 1 mg/mL BSA. After washing off the blood, the ovaries were placed under a dissecting microscope, and the follicular fluid was completely aspirated from the visible follicles using a Hamilton syringe (Reno, NV). The follicular fluid volume was measured, and the GC were collected by centrifugation for 5 min at 250 x g. The follicular fluid was frozen at -80 C until hormone assays were performed. The follicle diameter was calculated from the volume of aspirated fluid. The follicle was opened with microscissors, and the GC were gently scraped from the follicle wall with a platinum loop and collected by flushing with medium. The GC were centrifuged, and the pellet was pooled with the GC collected from the follicular fluid. The theca interna was microdissected from the follicle wall after the GC had been removed. The isolated GC and TC were frozen at -80 C until nucleic acids and protein were extracted.
For the experiments measuring 5-reductase activity in ovarian
follicles, whole follicles were dissected from the ovarian stroma after
aspiration of the follicular fluid. The follicles were frozen at -80 C
until microsomes were prepared.
DNA assay
Total cellular DNA and total RNA were isolated from the GC and TC of individual follicles using Tri-Reagent (MRC, Cincinnati, OH) according to the manufacturer’s protocol. The DNA pellet was dissolved in 50 µL phosphate-buffered saline buffer (0.1 mol/L NaPO4, pH 7.4, and 0.15 mol/L NaCl) at 37 C for 10 min. The DNA concentration of the samples was measured by a sensitive fluorescence assay as previously described (15). Briefly, 50 µL sample were added to 1.5 mL 100 ng/mL Hoechst 33258 dye (Sigma Chemical Co., St. Louis, MO), and the fluorescence was then measured in a fluorometer (Hoefer Scientific, San Francisco, CA). Sample concentrations were interpolated from a standard curve calculated by linear regression of the fluorescence of known concentrations of herring sperm DNA.
Measurement of 5-reductase 1 and 2 mRNA
5-Reductase 1 and 5-reductase 2 mRNAs were measured by
semiquantitative assays based on RT-PCR amplification of the
complementary DNA (cDNA). Total RNA isolated with Tri-Reagent was
resuspended in 20 µL diethylpyrocarbonate-treated water, then frozen
at -80 C. Aliquots of RNA (4 µL) were transcribed into cDNA by
incubating (37 C) for 30 min in 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L
KCl, 5 mmol/L MgCl2, 1 mmol/L deoxy (d)-ATP, 1 mmol/L dCTP,
1 mmol/L dGTP, 1 mmol/L dTTP, 5 µg
oligo(deoxythymidine)12–18 (Pharmacia Biotech, Piscataway, NJ), 20 U RNAsin (Promega Corp., Madison, WI), and 200 IU Moloney murine leukemia
virus-reverse transcriptase (Life Technologies) in a total
volume of 20 µL. The reaction was then heated to 95 C (5 min) and
cooled to 4 C. One picogram of mutant control DNA, 50 pmol of each PCR
primer, 8 µL of 10 x PCR buffer (100 mmol/L Tris-HCl, pH 8.3,
and 500 mmol/L KCl), 9.6 µL 25 mmol/L MgCl2, 10 µCi
[32P]dCTP (3000 Ci/mmol; DuPont-NEN, Boston,
MA), and 2.5 U Taq DNA polymerase (Perkin Elmer/Cetus, Norwalk, CT) were added, and the volume was
adjusted to 100 µL. 5-Reductase type 1 cDNA was amplified for 25
cycles (94 C for 30 s, 55 C for 20 s, 72 C for 30 s).
5-Reductase type 2 cDNA was amplified for 30 cycles (94 C for 1 min,
50 C for 2 min, 72 C for 3 min). The amplification products were
ethanol precipitated and digested with EcoRI to cut the
control products, then separated on a 2% agarose gel. The DNA was
visualized with ethidium bromide staining, and the bands were cut from
the gel and counted in a scintillation counter. The counts per min in
the bands amplified from the cellular mRNA were normalized to the
counts per min in the bands amplified from the mutant DNA to control
for procedural variations. The data were also normalized to total
cellular DNA to control for variations in the number of GC in each
sample.
The oligonucleotide primers were synthesized in our laboratory using a
PE Applied Biosystems model 391 DNA synthesizer (Foster
City, CA). A specific 540-bp fragment of 5-reductase 1 cDNA was
amplified using primers corresponding to bases 337–357 and 857–877 of
the published sequence (16). The primers for 5-reductase 2 cDNA
corresponding to bases 328–348 and 758–778 of the published sequence
(17) amplified a 450-bp fragment. To control for PCR variations, an A
was substituted for a T at base 608 in the 5-reductase 1 sequence
and at base 553 in the 5-reductase 2 sequence, respectively, by
site-directed mutagenesis (18) to introduce a unique
EcoRI site. The control template (1 pg) was included in each
PCR reaction, and all samples for each experiment were amplified at the
same time.
5-Reductase activity
Follicular 5-reductase activity was measured at physiological
pH by modification of previously published methods (16, 19). Individual
microdissected follicles containing oocytes, GC, and TC were
homogenized in 10 vol ice-cold 10 mmol/L potassium phosphate (pH 7.0),
150 mmol/L KCl, and 1 mmol/L ethylenediamine tetraacetate. The
homogenates were centrifuged at 100,000 x g for 30 min
at 4 C, and the pellets were resuspended in 500 µL homogenization
buffer. Homogenate (400 µL) was incubated in a total volume of 500
µL containing 1 µmol/L testosterone, 0.75 µCi
[1,2,6,7-3H]testosterone (85 Ci/mmol), and 5 mmol/L NADPH
at 37 C for 30 min. After the incubation, the steroids were extracted
with chloroform, and the extract was dried under a stream of air. The
steroids were resuspended in a small volume of ethanol and were
separated by high performance liquid chromatography using a 25-cm
reverse phase C18 column and isocratic elution with
tetrahydrofuran-methanol-water (16:28:56) (20). The column was
calibrated with authentic standards. Fractions (1 mL) were collected,
and the radioactivity was measured in a scintillation counter. Areas
under the testosterone and dihydrotestosterone (DHT) curves were
calculated using Peakfit software (SPSS, Inc., Chicago,
IL). The data were corrected for recovery and are expressed as
femtomoles of DHT produced per min/µg protein.
Statistical analysis
Multiple comparisons were performed using one-way ANOVA with
post-hoc comparisons employing Tukey’s test. The unpaired
t test was used to compare 5-reductase activities in
follicles from control subjects and those with PCOS. The paired
t test was used to compare 5-reductase mRNA levels
between TC and GC from the same follicles. Statistical significance was
considered to be P 
0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase 1 and 2 mRNAs
We first attempted to determine the expression pattern of
5-reductase mRNAs in the various endocrine compartments of the ovary
using the technique of in situ hybridization. The signals
were too weak to yield a convincing result (data not shown). To
overcome the inherently weak signals of the in situ
hybridizations, we developed a RT-PCR assay with the sensitivity to
measure 5-reductase 1 and 2 mRNAs in GC and TC from individual
follicles. As shown in Fig. 1
, both
5-reductase 1 and 2 mRNAs were detectable in the GC and TC from
regularly cycling women. The levels of both 5-reductase 1 and 2
mRNAs were higher in GC than in TC. There was no difference in either
5-reductase 1 or 2 mRNA in the GC from women with PCOS compared to
controls; however, theca from women with PCOS expressed less
5-reductase mRNA (Fig. 1). It was apparent that 5-reductase 2
mRNA levels were approximately 3-fold higher in both TC and GC than
5-reductase 1 mRNA.
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-reductase mRNA
expression, 5-reductase 2 mRNA levels were compared in GC from PCOS
follicles between 3–7 mm in diameter and in those from size-matched
follicles from regularly cycling control women. In control women, the
expression of 5-reductase 2 mRNA expression was highest in 3- to
5-mm follicles and decreased to undetectable levels in 7-mm follicles
(Fig. 2). In GC from women with PCOS, the
pattern of 5-reductase 2 mRNA expression was similar to that in
controls, except that detectable levels were present in 7-mm follicles.
It should be noted that 5-reductase 2 mRNA was detectable in some,
but not all, follicles larger than 7 mm in control women (data not
shown). 5-Reductase 1 mRNA expression was similar in GC from
follicles of all sizes (data not shown). Similarly, there were no
significant differences in either 5-reductase 1 or 2 mRNAs in TC
from follicles of different sizes.
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-Reductase activity
Measurement of 5-reductase 1 and 2 mRNAs did not reveal any
significant differences in either the pattern or the relative amount of
mRNA in follicles from women with PCOS compared to those in regularly
cycling controls. Nevertheless, there are significantly higher
concentrations of 5-androstane-3,17-dione in the follicular fluid
from polycystic ovaries (5). It was therefore critical to measure
5-reductase activity. The two 5-reductase isoenzymes have
different pH optima, and the activity of each isoenzyme varies markedly
with pH. 5-Reductase 1 has a broad, slightly basic pH optimum, and
5-reductase 2 has a narrow acidic optimum (17). Due to the limited
amount of follicular tissue that was available for study, it was
decided to measure total 5-reductase activity at physiological pH.
Kinetic analysis of the total 5-reductase activity demonstrated a
Km of 1.46 µmol/L and a maximum velocity
(Vmax) of 0.31 nmol/min·mg protein (Fig. 3). These values are consistent with the
majority of activity being from the type 1 isoenzyme. As shown in Fig. 4, the total 5-reductase activity was
approximately 4-fold higher in PCOS follicles than in control
follicles.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase activity may be elevated in women with PCOS.
Measurements of urinary steroid metabolites indicated that women with
PCOS appear to have increased 5-reductase activity compared to
regularly cycling women (21). A 5-reduced androstenedione
metabolite, 5-androstane-3,17-dione, was shown to be elevated in the
serum and follicular fluid of women with PCOS (5). The concentrations
of 5-androstane-3,17-dione in the follicular fluid were 1000-fold
higher than those in the circulation, indicating that there might be
increased 5-reductase activity in polycystic ovaries. Although
5-reductase activity has been demonstrated in the ovaries of
regularly cycling women (7, 14), the present study is the first to
demonstrate increased 5-reductase activity in polycystic
ovaries.
It is unclear why 5-reductase activity is increased in polycystic
ovaries, but there are several alterations in the endocrine milieu in
women with PCOS that might play a role. Based on rodent and human
studies, it appears that LH and insulin-like growth factor I (IGF-I)
stimulate and FSH inhibits 5-reductase activity (22, 23, 24). Elevated
serum LH concentrations are observed in some women with PCOS (25), and
the follicular fluid concentration of IGF-I is higher in PCOS than in
normal follicles (26). The potential exists that elevated LH and/or
IGF-I could stimulate 5-reductase activity in PCOS. Another
important characteristic of PCOS is hyperandrogenism. Studies in the
prostate (27) demonstrate that small concentrations of DHT can increase
5-reductase activity, presumably by a mechanism involving the
androgen receptor. Elevated androgen concentrations in PCOS could play
a role in stimulating ovarian 5-reductase activity.
The expression patterns of 5-reductase 1 and 2 within the human
ovarian follicle were previously unknown. Our results demonstrate that
both 5-reductase isoenzymes are expressed in GC and TC. The levels
of mRNA were significantly higher in GC than TC. Interestingly, the
levels of 5-reductase mRNA were highest in small antral follicles,
where it has been shown that androgens promote follicle growth (28, 29).
In regularly cycling women, 5-reductase expression declines to
undetectable levels by the time follicles achieve 7 mm in diameter.
These findings are in agreement with those of a previous study
demonstrating higher 5-reductase activity in human GC from follicles
smaller than 10 mm compared to follicles larger than 10 mm in diameter
(7). Interestingly, 7-mm diameter follicles are the first to begin to
express increased levels of aromatase mRNA (30). A similar inverse
relationship between 5-reductase and aromatase was described in the
rat (31).
Although the levels of 5-reductase activity in the human ovary are
low relative to those in prostate, liver, and hair follicles, there was
considerably more activity in follicles from polycystic ovaries than in
those from controls. There were no significant increases in
5-reductase mRNA expression in polycystic ovaries, indicating that
the increased activity is the result of increased translation of the
5-reductase mRNA, reduced enzyme turnover, and/or posttranslational
regulation. Interestingly, tissue-specific effects of androgens on
5-reductase mRNA expression have been reported. Testosterone was
shown to increase 5-reductase mRNA expression in prostate tissue,
but not liver, in castrated male rats (32). Understanding the specific
mechanisms of 5-reductase regulation in the ovary will require
further study.
The physiological significance of our result is unclear, but
5-reduced androgens may play a role in blocking selection of the
dominant follicle. An essential feature of dominant follicles destined
to ovulate is the estrogenic microenvironment (33, 34). To the best of
our knowledge, every follicle that fails to develop an estrogenic
microenvironment undergoes atresia. The development of an estrogenic
microenvironment is critically dependent on expression of aromatase
activity in the GC. Elevated 5-reductase activity in PCOS appears to
increase the production of 5-androstane-3,17-dione from
androstenedione in the ovarian follicles. The concentrations of
5-androstane-3,17-dione that are achieved in PCOS are sufficient to
markedly inhibit aromatase activity by a competitive mechanism (5).
The consequences of inhibiting aromatase activity in developing
follicles are not clear. It is unknown whether increased estrogen
concentrations are necessary for dominant follicles to develop normally
or whether the estrogens produced by dominant follicles are only
required to communicate the developmental state of the dominant
follicle to other endocrine organs, such as the hypothalamus,
pituitary, and endometrium. It is clear that follicles can be induced
to ovulate in the absence of estrogen production, but only in the
presence of pharmacological concentrations of exogenous FSH (35). The
potential exists that estradiol plays an important role in sensitizing
the GC to FSH. If estradiol is important for selection of the dominant
follicle, suppression of the emerging aromatase activity in 7-mm
follicles might play a significant role in the genesis of polycystic
ovaries by preventing the follicles from achieving the heightened
sensitivity to FSH that is characteristic of dominant follicles.
Further studies will be required to establish the physiological role of
estrogen in human follicle development and to clarify the role of
5-reduced androgens in the genesis of PCOS.
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Acknowledgments |
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Footnotes |
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2 Supported by a Kosciuszko Foundation fellowship.
Received December 30, 1998.
Revised March 9, 1999.
Accepted April 9, 1999.
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References |
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