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Original Studies |
Department of Obstetrics and Gynecology, CSMC Burns and Allen Research Institute, University of California School of Medicine (S.R.W., A.N., D.A.M.), Los Angeles, California 90048-0750; and 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, Davis 2066, Los Angeles, California 90048-0750. E-mail: magoffin{at}cshs.org
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Abstract |
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-hydroxylase/C17–20 lyase cytochrome P450 (CYP17)
mRNAs were measured by RT-PCR. There was no difference between 3- to
7-mm control follicles and dominant follicles with respect to LH
receptor mRNA expression in either thecal or granulosa cells. CYP11A
and CYP17 mRNAs were higher in thecal cells from 3- to 7-mm follicles
than in dominant follicles, but StAR expression was not different. In
granulosa cells, StAR and CYP11A mRNA expression was higher in dominant
follicles than in 3- to 7-mm follicles. The mean levels of LH receptor,
StAR, CYP11A, and CYP17 mRNA expression were higher in thecal cells
from PCOS follicles than in size-matched control follicles. In
granulosa cells, the mean levels of LH receptor and CYP11A, but not
StAR, mRNA expression were higher in PCOS than in control follicles.
These data demonstrate that regulatory protein and steroidogenic enzyme
mRNAs are overexpressed in thecal and granulosa cells from polycystic
ovaries and support the conclusions that the thecal cells are
hyperstimulated and the granulosa cells may be prematurely luteinizing. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is well known that the steroidogenic cells in the theca interna are the source of androgen biosynthesis in the human ovary (7). However, the mechanisms causing increased androgen secretion by polycystic ovaries remain unclear. Although there is evidence that some follicles in polycystic ovaries exhibit thecal hyperplasia, not all follicles contain increased numbers of thecal cells (8). Overall, it is not known whether there are more thecal cells in polycystic ovaries that produce a relatively normal amount of androgen per cell or whether there is a near-normal number of thecal cells in the ovary that have an increased steroidogenic capacity per cell.
In a significant proportion of women with PCOS there are elevations in circulating LH concentrations (9, 10), and mild hyperinsulinemia caused by insulin resistance is a common finding in obese women with PCOS (11). Either of these changes would be expected to increase thecal androgen production (12, 13). In support of the concept that the thecal cells may be hyperstimulated is the observation that primary cultures of thecal cells from polycystic ovaries secrete more androstenedione in vitro than thecal cells from control ovaries (14).
The molecular basis for thecal hyperactivity is unknown. It has been suggested that certain alleles could enhance the expression of steroidogenic enzyme messenger ribonucleic acids (mRNAs) in the thecal cells of women carrying those alleles (15, 16, 17). In support of this concept is the observation that thecal cells from polycystic ovaries propagated in vitro harbor a stable hyperandrogenic phenotype (18) and that these cells have increased CYP17 promoter activity (19). However, a direct comparison of the endogenous expression levels of steroidogenic enzyme mRNAs in thecal cells from women with PCOS relative to regularly cycling controls has not been performed.
The follicles in polycystic ovaries arrest their development at the small antral stage (4–7 mm) just before expression of aromatase cytochrome P450 mRNA in the granulosa cells (20) and well before the beginning of luteinization when LH receptor and CYP11A mRNAs are expressed. Interestingly, when granulosa cells from polycystic ovaries are cultured in vitro, they exhibit an increased steroidogenic response to LH compared with granulosa cells from comparably sized follicles of regularly cycling control women (21). These data support the hypothesis that the granulosa cells in polycystic ovaries are more differentiated than is appropriate for the stage of follicle development.
The purpose of this study was to test the hypothesis that key genes involved in androgen biosynthesis are overexpressed in the thecal cells of polycystic ovaries and to determine whether the granulosa cells are prematurely expressing genes characteristic of luteinization. To accomplish this goal, the steady state levels of LH receptor, steroidogenic acute regulatory protein (StAR), CYP11A, and CYP17 mRNAs were measured in freshly isolated thecal and granulosa cells from polycystic ovaries and the ovaries of regularly cycling control women.
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Subjects and Methods |
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Thirty-four individual follicles, 4.3–8.8 mm in diameter, were
obtained from the ovaries of 12 women with PCOS who were 44 yr of age
or younger and were undergoing electrocauterization of the ovarian
surface or wedge resection for treatment of infertility. 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.
Nineteen individual control follicles, 4.2–8.7 mm in diameter, with
follicular fluid 
4-androstenedione
(A4)/estradiol (E2) ratios
greater than 4 were obtained from the ovaries of 19 control women. and
22 individual dominant follicles 9.1–23.2 mm in diameter with
follicular fluid A4/E2
ratios less than 4 were obtained from the ovaries of 22 control women.
Control subjects were age-matched premenopausal women in the follicular
phase of their menstrual cycles who were undergoing total abdominal
hysterectomy with bilateral oophorectomy for nonovarian indications
unrelated to the study. None of the subjects 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 as approved by the ethics committee at the
University School of Medicine in Lublin and the institutional review
board at Cedars-Sinai Medical Center.
Granulosa and thecal cell collection
The ovarian specimens were immediately placed into ice-cold medium 199 (Life Technologies, Inc., 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 granulosa cells were collected by centrifugation for 5 min at 250 x g. The follicular fluid was frozen at -80 C until A4 and E2 were measured by RIA (Diagnostic Products, Los Angeles, CA). The follicle diameter was calculated from the volume of aspirated fluid. The follicle was opened with microscissors, and the granulosa cells were gently scraped from the follicle wall with a loop and collected by flushing with medium. The granulosa cells were centrifuged, and the pellet was pooled with the granulosa cells collected from the follicular fluid. The theca interna was microdissected from the follicle wall after the granulosa cells had been removed. The isolated granulosa and thecal cells were frozen at -80 C until nucleic acids were extracted.
DNA assay
Total cellular DNA was isolated from the granulosa and thecal
cells of individual follicles using Tri-Reagent (MRC, Cincinnati, OH)
according to the manufacturer’s protocol. The DNA pellet was
resuspended in 50 µL 8 mmol/L NaOH at 37 C for 10 min, then the pH
was adjusted to 7.4 with 1 mol/L HEPES. The DNA concentration of the
samples was measured using a sensitive fluorescence assay (PicoGreen
dsDNA Quantitation Kit, Molecular Probes, Inc., Eugene,
OR). Briefly, 20 µL sample were diluted with 2 mL PicoGreen solution,
and the fluorescence was measured in a Turner Designs fluorometer
(Sunnyvale, CA). Sample concentrations were interpolated from a
standard curve calculated by linear regression of the fluorescence of
known concentrations of 
DNA standard.
Measurement of mRNA
LH receptor, StAR, CYP11A, and CYP17 mRNAs were measured by
RT-PCR assays as previously described (22). Total RNA was
isolated with Tri-Reagent, resuspended in 20 µL
diethylpyrocarbonate-treated water and transcribed into complementary
DNA (cDNA) by incubation (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, Inc.) in a total
volume of 100 µL. One picogram of mutant control DNA (Table 1
), 50 pmol of each PCR primer (Table 1),
8 µL 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; NEN Life Science Products, Boston, MA), and 2.5 U Taq DNA polymerase
(Perkin-Elmer Corp./Cetus, Norwalk, CT) were added to
individual aliquots of sample cDNA (4 µL), and the volume was
adjusted to 100 µL. cDNA was amplified for 25 cycles (94 C, 1 min; 55
C, 1 min; 72 C, 1 min). Control templates were synthesized by
site-directed mutagenesis (23) to create unique
restriction sites with the substitutions and at the positions listed in
Table 1. After amplification, the products were ethanol precipitated
and digested with the appropriate restriction enzyme (Table 1) to cut
the control products, then separated on a 2% agarose gel. The bands
visualized with ethidium bromide 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 cDNA to control for procedural variations.
The data were also normalized to total cellular DNA to control for
variations in the number of cells in each sample. All samples from each
cell type were amplified for each gene at the same time. The amount of
mRNA in each sample was interpolated from the standard curve and
expressed as picograms of full-length mRNA per µg total cellular DNA.
The standard concentrations were chosen to obtain a linear range
spanning 2 orders of magnitude. The volumes of sample were adjusted to
yield data within the linear range of the standard curve.
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Comparisons of the means were made using one-way ANOVA with
post-hoc Tukey’s test. Linear regression analysis was
performed by least squares linear regression. 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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shows the standard curves for each of
the assays used in these experiments.
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. There was an approximately 100-fold
difference in expression levels among the various mRNAs. LH receptor
mRNA expression was lowest, and those of CYP17 and CYP11A mRNAs were
the highest. StAR mRNA was expressed at intermediate levels. There was
little difference in the expression levels of LH receptor mRNA among
follicles of different diameters. The expression of StAR, CYP11A, and
CYP17 mRNAs tended to be higher in many small follicles and low in
dominant follicles.
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, the mean levels of LH
receptor, StAR, CYP11A, and CYP17 mRNA expression were higher in the
thecal cells of PCOS follicles than in size-matched control follicles.
The expression of CYP11A and CYP17 mRNAs in thecal cells from 3- to
7-mm follicles was higher than that in thecal cells from dominant
follicles. There was no significant difference between 3- to 7-mm
control follicles and dominant follicles with respect to LH receptor
and StAR expression.
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, LH receptor mRNA did not vary
significantly, as CYP17 mRNA increased in the thecal cells of both
control (r2 = 0.06; P = 0.32) and
PCOS (r2 = 0.003; P = 0.78)
follicles. The regression line was shifted up for PCOS thecal cells
relative to controls. StAR (control: r2 = 0.28;
P = 0.02; PCOS: r2 = 0.17;
P = 0.02) and CYP11A (control: r2
= 0.49; P = 0.003; PCOS: r2 =
0.49; P < 0.001) mRNAs increased with increasing CYP17
mRNA (Fig. 4). Although the regression lines for control and PCOS
thecal cells were virtually superimposable for CYP11A mRNA, the line
for StAR was shifted up in PCOS thecal cells relative to that in
controls.
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, the pattern of LH
receptor, StAR, and CYP11A mRNA expression in granulosa cells varied
from the pattern in thecal cells. LH receptor mRNA expression was
comparable in 3- to 7-mm control follicles and dominant follicles, but
was markedly elevated in granulosa cells from polycystic ovaries. In
contrast, StAR mRNA expression was similar in granulosa cells from
polycystic ovaries compared with that in size-matched control
follicles. StAR mRNA was significantly increased in dominant follicles.
CYP11A mRNA expression was increased in granulosa cells from polycystic
ovaries to levels comparable to those found in dominant follicles (Fig. 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although there was an apparent 100-fold difference in the level of expression from the lowest (LH receptor) to the highest (CYP11A) individual mRNA, there was a similar percentage of overexpression of LH receptor, StAR, CYP11A, and CYP17 mRNAs. Although our data do not directly test the hypothesis that specific alleles in the CYP11A and CYP17 genes may play a role in ovarian hyperandrogenism (15, 16, 17), it seems unlikely that genetic abnormalities could simultaneously be the cause of overexpression in all four genes. A simpler explanation is that alterations in a regulatory element such as a transcription factor gene substantially contributes to the overexpression of all of the genes in thecal cells as opposed to separate mechanisms operating for each gene. Another alternative is that polycystic ovaries contain alterations in one or more intracellular signaling pathways that mediate the expression of steroidogenesis-related mRNAs.
The observation that the mRNAs measured were expressed at higher specific concentrations in thecal cells from polycystic ovaries is the first evidence that individual thecal cells are hyperstimulated in polycystic ovaries in vivo and that the follicles produce excessive amounts of androgens regardless of whether theca hyperplasia is evident. For us to get an accurate measurement of the steady state mRNA levels in thecal cells from polycystic ovaries, it was necessary to rapidly isolate the RNA from the freshly isolated specimens. This methodology prevented us from determining the steroidogenic capacity of the limited number of thecal cells obtained from each follicle. It is likely, however, that the increased mRNA expression translates directly into increased steroidogenic capacity on a per thecal cell basis. This concept is supported by the observation that primary thecal cell cultures from polycystic ovaries produce more A4 in vitro than thecal cells from control ovaries (14) and by observations that thecal cells from polycystic ovaries maintain a higher degree of forskolin responsiveness than control thecal cells when propagated in vitro (18).
There are two hormonal mechanisms that are likely to contribute significantly to hyperstimulation of the thecal cells and overexpression of thecal mRNAs. Both LH (24, 25) and insulin concentrations are elevated in many women with PCOS (9). Expression of each of the mRNAs that were overexpressed in thecal cells, with the exception of StAR mRNA, has been shown to be stimulated by LH and insulin or IGF-I in studies with rat thecal cells (26). Taken together, the data strongly suggest that the endocrine abnormalities present in PCOS play a primary role in hyperstimulating both thecal gene expression and steroidogenesis. It is probable that genetic mechanisms modulate the susceptibility of a woman to endocrine abnormalities, such as insulin resistance (27) and the sensitivity of thecal cells to LH and insulin stimulation.
If an endocrine mechanism such as mild hyperinsulinemia is primarily responsible for overexpression of thecal mRNAs, it is likely that removing the excessive hormonal stimulus can control ovarian hyperandrogenism. In vitro studies have shown that ovarian thecal cell androgen production is stimulated by insulin acting through the insulin receptor and not the type I IGF receptor (13). A role for hyperinsulinemia in stimulating ovarian androgen production is supported by the observation that the insulin-sensitizing drugs metformin and troglitazone can decrease androgen concentrations in insulin-resistant women with PCOS (28, 29). In many women this led to an improvement in their fertility and can result in resumption of menstrual cycles (29). It is apparent that the decline in androgen concentrations caused by metformin is related to a decrease in ovarian CYP17 activity (30, 31). It remains unclear whether hyperinsulinemia per se causes ovarian hyperandrogenism or whether ovarian insulin resistance plays a role. The finding that inhibition of insulin secretion by treatment with diazoxide caused a decline in ovarian androgen concentrations supports the conclusion that it was the hyperinsulinemia that increased androgen concentrations and not ovarian insulin resistance (32).
Although insulin resistance is a common finding in women with PCOS, only about 50% of women with insulin resistance develop PCOS (33), indicating that hyperinsulinemia is likely to be important in many women with PCOS, but that other factors are important as well. This conclusion is supported by recent evidence demonstrating that thecal cells from polycystic ovaries propagated in vitro have inherently higher rates of CYP17 gene transcription than thecal cells propagated from control ovaries (19). These cells are not LH responsive, yet they appear to retain metabolic differences that presumably originated in vivo. Thus, the relative contributions of genetic and endocrine mechanisms to thecal mRNA overexpression in PCOS remain to be elucidated.
In contrast to thecal cells, there was not a general overexpression of LH receptor, StAR, and CYP11A mRNA in granulosa cells from polycystic ovaries. Only LH receptor and CYP11A mRNA were overexpressed. In previous studies we demonstrated that the granulosa cells from polycystic ovaries do not express the increased aromatase mRNA characteristic of dominant follicles (20). These new data indicate that the granulosa cells may be beginning to luteinize at a premature stage of follicle development. This conclusion is supported by the observation that granulosa cells from polycystic ovaries have an exaggerated responsiveness to LH compared with granulosa cells in control follicles of similar diameter (21). Because terminally differentiated cells lose their proliferative capacity, disruption of the normal developmental program could explain the paucity of granulosa cells and the failure to express aromatase that are observed in polycystic ovaries. Understanding the mechanisms leading to the apparent premature luteinization in PCOS will require further investigation.
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Footnotes |
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2 Supported by a Kosciuszko Foundation fellowship.
Received March 24, 2000.
Revised July 17, 2000.
Revised October 17, 2000.
Accepted November 16, 2000.
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References |
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C (-34 bp) of gene CYP17 promoter in
Greek patients with polycystic ovary syndrome. Fertil Steril. 71:431–435.[CrossRef][Medline]
-hydroxylase and steroidogenic acute regulatory
protein gene promoters in normal and polycystic ovary syndrome theca
cells. J Clin Endocrinol Metab. 58:2304–2311.
-Reductase activity in women with polycystic ovary syndrome. J
Clin Endocrinol Metab. 48:2414–2418.
activity and serum androgens. J Clin
Endocrinol Metab. 82:4075–4079.This article has been cited by other articles:
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