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Department of Cellular and Molecular Physiology (V.L.N.,
J.M.M.) and Department of Obstetrics and Gynecology (R.S.L.)
Pennsylvania State University College of Medicine Hershey,
Pennsylvania 17033
Center for Research on Reproduction and
Women’s Health University of Pennsylvania (J.F.S.)
Philadelphia, Pennsylvania 19104
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-hydroxyprogesterone (17OHP4),
and testosterone (T) production per cell were markedly increased
in PCOS theca cell cultures. Moreover, basal and forskolin-stimulated
pregnenolone, P4, and dehydroepiandrosterone metabolism were increased
dramatically in PCOS theca cells. PCOS theca cells were capable of
substantial metabolism of precursors into T, reflecting expression of
an androgenic 17ß-hydroxysteroid dehydrogenase. Forskolin-stimulated
cholesterol side chain cleavage enzyme (CYP11A) and
17-hydroxylase/17,20-desmolase (CYP17) expression were augmented in
PCOS theca cells compared with normal cells, whereas no differences
were found in steroidogenic acute regulatory protein mRNA
expression. Collectively, these observations establish that
increased CYP11A and CYP17 mRNA expression, as well as increased CYP17,
3ß-hydroxysteroid dehydrogenase, and 17ß-hydroxysteroid
dehydrogenase enzyme activity per theca cell, and consequently
increased production of P4, 17OHP4, and T, are stable properties of
PCOS theca cells. These findings are consistent with the notion
that there is an intrinsic alteration in the steroidogenic activity of
PCOS thecal cells that encompasses multiple steps in the biosynthetic
pathway. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The molecular and cellular mechanisms underlying the excessive ovarian
androgen production associated with PCOS remain to be elucidated
(11, 12, 13, 14, 15, 16, 17, 18). There is in vivo evidence to support the concept
that excess androgen production in PCOS results from a primary
abnormality in steroid production by ovarian theca cells (19). In the
human follicle, the androgen-secreting theca cells express
17-hydroxylase/17,20- desmolase (CYP17), cholesterol side chain
cleavage enzyme (CYP11A), 3ß-hydroxysteroid dehydrogenase (3ß-HSD),
and steroidogenic acute regulatory protein (StAR), each of which are
required for androgen and progestin production (20, 21, 22, 23, 24, 25, 26). Gilling-Smith
et al. (19) reported that after GnRH agonist (GnRHa)-induced
suppression of serum LH concentrations, ovarian androgen production in
PCOS patients was significantly higher than in controls. Because CYP17
is the key enzyme required for androgen production in theca cells,
Rosenfield and Barnes (5, 27, 28) and Nestler et al. (29, 30) proposed that excess androgen production in PCOS results from
dysregulation of CYP17 enzyme activity due to an intrinsic ovarian
defect. Subsequent studies of Gilling-Smith et al. (31)
suggested that androgen production per theca cell is increased in PCOS.
However, it is still not known whether the increased androgen
production in PCOS is caused by dysregulation of ovarian theca cell
CYP17. Although it has been repeatedly proposed that CYP17 expression
is elevated in PCOS theca cells, no study has directly compared CYP17
enzyme activity or the regulation of CYP17 mRNA expression in normal
and PCOS theca cells. In addition, it is also possible that changes in
CYP11A, 3ß-HSD activity, or StAR expression contribute to increased
ovarian androgen production in PCOS. Moreover, the question of whether
the excessive androgen production by PCOS theca cells in culture (31)
reflects an intrinsic abnormality or whether it results from the
residual effects of the hormonal milieu to which the cells were exposed
in vivo has not been addressed.
Although a number of theories have been proposed to explain the etiology of excess androgen production by PCOS ovaries, few studies have focused on the regulation of steroidogenic enzyme activity and expression in isolated theca interna cells that have been maintained in culture in the absence of gonadotropins. We have begun to comprehensively examine the regulation of androgen production at the metabolic and molecular level using normal and PCOS theca interna cells isolated from size-matched follicles and propagated for multiple population doublings to determine whether increased androgen production in PCOS results from abnormalities in the regulation of StAR, CYP11A, CYP17, and 3ß-HSD gene expression in response to forskolin (22, 23, 24, 25, 32).
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-hydroxyprogesterone
(17OHP4), and testosterone (T) accumulation in the media of cells
treated with increasing concentrations of forskolin (Fig. 1
). In both normal
and PCOS theca cell cultures there was a dose-dependent increase in
forskolin-stimulated steroid hormone production, which was maximal
72 h after treatment with 20 µM forskolin. The
ED50 for forskolin-stimulated steroidogenesis was 3
µM in both normal and PCOS theca cell preparations. In
normal theca cells, forskolin-stimulated P4 and 17OHP4 production were
increased 40-fold and 22-fold, respectively, over basal values.
Negligible amounts of T were present in the media of normal theca cell
cultures. In PCOS theca cells maximally stimulated with forskolin, P4,
17OHP4, and T production increased 43-fold, 22-fold, and 12-fold,
respectively, over basal values. Under basal conditions, P4, 17OHP4,
and T production by PCOS theca cultures was elevated 20-fold
(P < 0.05), 22-fold (P < 0.05), and
4-fold (P < 0.05), respectively, above normal theca
cell values. Moreover, PCOS theca cells stimulated with 20
µM forskolin produced 10-fold, 25-fold, and 30-fold more
P4, 17OHP4, and T, respectively, than forskolin-stimulated normal theca
cells. Thus, while both normal and PCOS are responsive to forskolin,
PCOS thecal cells consistently produce greater quantities of steroid
hormone and have the capacity to produce substantial amounts of T.
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), [3H]-P4 (Fig. 5), and
[3H]-DHEA (Fig. 6) metabolism were examined
in normal and PCOS theca cells that had been grown for 22–26 (three
passages) and for 31–38 population doublings (four passages), and
treated for 72 h with a 20 µM dose of forskolin.
Although the metabolism profiles of cells from individual patients were
distinct, the results presented show the predominant products of
metabolism that are representative of theca cells isolated from four
normal and five PCOS patients that had been matched for follicle size
(
4 mm) and patient age (38–40 yr). Similar data were also obtained
with theca cells isolated from multiple size-matched follicles from
individual patients (data not shown).
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, in theca cells isolated from normal patients and
cultured under basal conditions, the products of [3H]-P5
metabolism were primarily 17-hydroxypregnenolone (17OHP5), and
DHEA, which are both products of CYP17 enzyme activity.
5-Pregnene,3ß,20-diol (20-OHP5), a product of
20-hydroxysteroid dehydrogenase (20-HSD) activity, was also
produced to a limited extent. After forskolin stimulation, the rate of
[3H]-P5 metabolism to 17OHP5 and DHEA was
increased, as was the production of 17,20-dihydroprogesterone
(4-pregnene-17, 20-diol-3-one, 17,20-DHP4) and
5-pregnene-3ß,17,20-triol (17,20-P5). 17,20-DHP4 and
17,20-DHP5 are produced by the action of 20-HSD on 17OHP4 and
17OHP5, respectively. In contrast, in PCOS theca cells
[3H]-P5 was further metabolized to T, Adione, and
androstenediol (Adiol) as well as to larger amounts of 17OHP4,
17,20-DHP4, and 17,20-DHP5. The rate of [3H]-P5
metabolism was increased after forskolin treatment in both normal and
PCOS theca cells, but was more markedly enhanced in PCOS theca
cells.
To determine whether increased [3H]-P5 metabolism is a
property retained by PCOS theca cells over longer culture periods,
[3H]-P5 metabolism was examined in forskolin-stimulated
theca cells isolated from three normal and three PCOS patients grown
for 22–26 population doublings (Fig. 3)
and 31–38 population doublings (Fig. 4).
The metabolism profiles were similar for cells grown for 22–26 and
31–38 population doublings but PCOS cells differed markedly from
normal theca cells. In normal theca cells, 90% of labeled pregnenolone
was metabolized to 17-hydroxypregnenolone and DHEA in
8–12 h, while at 24–48 h only low levels of Adione were produced
(left panel). In contrast, in PCOS theca cells (right
panel), the rate of [3H]-P5 metabolism was much
faster; more than 90% of labeled P5 was converted to 17OHP5 and
DHEA within 3–6 h, and within 12–24 h it had been
metabolized to T, Adione, and Adiol. These data suggest that 3ß-HSD
and/or CYP17 enzyme activities are elevated in PCOS cells as compared
with normal theca cells. Although 20-HSD activity appeared to be
stimulated by forskolin in both normal and PCOS theca cells, 20-HSD
activity/cell was not elevated in PCOS theca cells.
To further explore differences in CYP17 enzyme activity in PCOS
and normal theca cells, [3H]-P4 metabolism was examined
in cells grown for 22–26 population doublings (Fig. 5) and 31–38 population doublings (data
not shown). In theca cells isolated from normal ovaries, we previously
reported that P4 is metabolized predominantly to 17OHP4, 17,20-DHP4,
and 16-hydroxyprogesterone (16OHP4) (25). 16-Hydroxylation of P4
to 16OHP4 was a side reaction associated with CYP17 enzyme activity. P4
was also metabolized to a limited extent to
4-pregnene-20-hydroxy-3-one (20-OHP4), which is a product of the
20-HSD reaction. In the present studies utilizing normal theca cells
after forskolin stimulation (left panel), 80% of
[3H]-P4 was metabolized to 17-hydroxylated products
within 24–36 h, whereas in PCOS theca cells (right panel)
80% of [3H]-P4 was metabolized to similar products
within 4–8 h. Thus, the rate of labeled P4 metabolism was accelerated
and CYP17 enzyme activity/theca cell was elevated in PCOS cells as
compared with normal theca cells. Moreover, the metabolism profile
presented for theca cells grown for 22–26 population doublings (Fig. 5) was similar to that observed for cells grown for 31–38 population
doublings. These data again indicate that CYP17 enzyme activity per
theca cell is increased in PCOS, and that increased CYP17 activity is a
stable property of PCOS theca cells in long-term culture.
To compare 3ß-HSD activity in normal and PCOS theca cells, as well as
establish the predominant intermediates of androgen biosynthesis,
[3H]-DHEA metabolism was examined in cells
grown for 22–26 population doublings (Fig. 6) and 31–38 population doublings (data
not shown). In normal theca cells (left panel), 30% of
[3H]-DHEA was converted to Adione and, to a
limited extent, Adiol within 48 h. In agreement with the data
presented in Fig. 1 examining de novo T production in normal
theca cells, T was not a product of DHEA metabolism during
the 48-h incubation period, suggesting the absence of androgenic
17ß-hydroxysteroid dehydrogenase (17ß-HSD) activity. In contrast,
in PCOS theca cells (right panel), 60% of
[3H]-DHEA was converted to Adione, Adiol,
and T within 12 h. Further metabolism of T to 5-reduced
steroids was not observed during the 48 h incubation period, indicating
the absence of 5-reductase. Moreover, the metabolism profile
presented for theca cells grown for 22–26 population doublings (Fig. 6) was similar to that observed for cells grown for 31–38 population
doublings (data not shown). These observations confirm that increased
3ß-HSD enzyme activity per theca cell is a stable property of PCOS
theca cells in culture and demonstrate that normal thecal cells are
relatively deficient in androgenic 17ß-HSD. Labeled
DHEA (Fig. 6), P4 (Fig. 5), and P5 (
Figs. 2–4) were not
converted into estradiol by either normal or PCOS thecal cells. The
absence of detectable estradiol formation is consistent with the
lack of granulosa cell contamination of our theca cell
preparations.
Expression of Steroidogenic Enzyme mRNAs
To determine whether the increased production of steroids and
rates of precursor metabolism characteristic of PCOS theca cells
resulted from increased steady state levels of steroidogenic enzyme
mRNAs, Northern analyses were performed. Total mRNA was harvested from
theca cells isolated from four normal and four PCOS patients that were
cultured with and without 20 µM forskolin for 48 h.
In Fig. 7, a representative Northern
analysis of mRNA (50 µg/lane) isolated from theca cells from two
normal and two PCOS patients, hybridized with complementary probes for
human CYP17, CYP11A, StAR, and 28S rRNA, is presented. Results from
these experiments demonstrated that forskolin-stimulated CYP17 and
CYP11A mRNA accumulation is markedly augmented in PCOS cells. As shown
in Fig. 8, 48 h of forskolin
treatment of control theca cells resulted in modest (1.5- to 2-fold)
but significant increases in steady state levels of CYP17 and CYP11A
mRNA over the basal levels. In contrast, under identical conditions
CYP17 mRNA levels were increased 6-fold and CYP11A levels were
increased 5-fold over basal levels in PCOS theca cells. However, StAR
mRNA levels were increased to similar extents in normal and PCOS theca
cells (4-fold) in response to forskolin treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Data from our experiments clearly establish that P4, 17OHP4, and T
production are markedly elevated per cell in PCOS theca cultures. In
these experiments, both androgen and P4 levels were found to be
increased in PCOS theca cells, and the androgen/P4 ratio was elevated,
indicating that androgen production predominates. Since the
ED50 for forskolin-stimulated steroid accumulation in both
normal and PCOS theca cells was identical (3 µM), it
does not appear that the differences in steroidogenic activity can be
attributed to differences in forskolin-stimulated adenylate cyclase
activity. It is notable that the absolute amounts of P4, 17OHP4, and T
produced per PCOS theca cell (passaged for 22–38 population doublings)
were similar to those reported by Gilling-Smith et al. (31),
which were obtained from primary (nonpassaged) PCOS theca cells. In
both our study and that of Gilling-Smith et al. (31),
steroid production as well as the androgen-progestin ratio were
increased in PCOS theca cells. Our findings, however, demonstrate that
the rates of basal and forskolin-stimulated P5, P4, and
DHEA metabolism are all dramatically increased in PCOS
cells. These data definitively demonstrate for the first time that
CYP17 and 3ß-HSD enzyme activities per theca cell are increased under
both basal and forskolin-stimulated conditions in PCOS theca cells. The
metabolic profiles also indicate that an androgenic 17ß-HSD activity
is increased in PCOS theca cells. Thus, the distinctive biochemical
phenotype of PCOS theca cells in long-term culture encompasses
increased activities of multiple steroidogenic enzymes. The evidence
for increased androgenic 17ß-HSD is of particular interest because
normal human ovaries are reported not to express type III 17ß-HSD,
the enzyme responsible for testicular T production (33). Thus, either
PCOS theca cells aberrently express the type III enzyme or an
alternative activity capable of reducing the 17-keto group of C19
steroids must be activated in PCOS.
The data presented in
Figs. 2–6 provide new and significant
information about the principal intermediates and the predominant
steroidogenic pathways involved in steroid biosynthesis in normal and
PCOS theca cells. Specifically, normal and PCOS theca cells do not have
the capacity to convert 17OHP4 to Adione. Androgen production in normal
theca cells, as well as increased androgen production by PCOS theca
cells, evidently involves the initial conversion of cholesterol to P5
(via CYP11A) and the subsequent conversion of P5 to DHEA
(via CYP17). DHEA is then further metabolized to Adione
(via 3ß-HSD) and/or Adiol (via 17ß-HSD), which are finally
converted to T. Thus, in agreement with our previous reports (22, 24),
the 
5-steroid pathway is the predominant pathway used
for androgen biosynthesis by both normal and PCOS theca cells. The
4-steroids, P4 and 17OHP4, are not precursors for Adione
or T production by the normal or PCOS ovary. As we previously reported
(23), estradiol was not found to be a product of steroid metabolism in
normal or PCOS theca cells, substantiating the purity of the theca cell
preparations used in these studies. Of importance is the fact that the
steroid metabolism profiles observed in normal and PCOS theca cells
grown for 22–26 population doublings were similar to those observed
when cells are grown for 31–38 population doublings. These data verify
that increased androgen production is a stable phenotype of the
cultured PCOS theca cells.
The ability to propagate normal and PCOS theca cells in long-term culture has and will continue to facilitate the examination of the molecular basis for increased androgen production in PCOS. In this report we present, for the first time, Northern analyses on RNA obtained from theca cells isolated from individual follicles from normal and PCOS patients. Data from these experiments definitively demonstrate that the magnitude of forskolin-stimulated CYP17 and CYP11A mRNA induction is greater in PCOS than in normal theca cells. These data support the hypothesis that increased steady state levels of CYP17 and CYP11A mRNAs contribute to increased levels of steroidogenic enzymes involved in androgen production by PCOS theca cells. Although StAR mRNA levels were increased in response to forskolin, the magnitude of StAR mRNA induction by forskolin was not different between PCOS and control theca cells. These data suggest that increased androgen production in PCOS does not result from overall differences in cAMP or adenylate cyclase regulation, but rather selective alterations in steroidogenic enzyme expression.
The persistent differences in steroidogenic activity of PCOS theca cells could reflect an intrinsic (i.e. genetic) abnormality in these cells or a stable biochemical imprint resulting from the endocrine milieu experienced by the cells in vivo. Unfortunately, at present, no definitive experiment can distinguish between these two possibilities. However, there is increasing evidence for a genetic basis for the hyperandrogenemia associated with PCOS (8). If the stable biochemical phenotype in PCOS cells that we observed is the result of a genetic variation, it evidently influences the expression of multiple genes in the steroidogenic machinery, suggesting that the putative abnormality most likely involves a signal transduction pathway. PCOS theca cells may generate autocrine factors that enhance steroidogenesis. Alternatively, PCOS cells may have increased sensitivity to some component of the culture medium that stimulates expression of steroidogenic enzymes. The factor is not likely to be insulin since we have found, in unpublished experiments, that both normal and PCOS theca cells respond equivalently to insulin in terms of steroid (170HP4) production per cell and that increased forskolin-stimulated steroid secretion by PCOS cells is observed in the absence of insulin in the culture medium. The thecal cell system we have employed is well suited for the study of the biochemical locus that results in the stable steroidogenic phenotype of PCOS cells.
In conclusion, our analyses of normal and PCOS theca cells maintained in long-term culture suggest that increased expression of CYP17 and CYP11A mRNAs, as well as increased CYP17 and 3ß-HSD and 17ß-HSD activities per theca cell, are stable properties of PCOS theca cells. These data are consistent with the concept that increased androgen production by PCOS theca cells is an intrinsic and, possibly genetically determined, property of the cells. In future studies we will attempt to define the locus of this abnormality through a comprehensive analysis of the molecular mechanisms involved in the transcriptional and posttranscriptional regulation of CYP17, CYP11A, 3ß-HSD, and 17ß-HSD expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Individual follicles were dissected away from ovarian stroma. The isolated follicles were size selected for diameters ranging from 3–5 mm so that theca cells derived from follicles of similar size from normal and PCOS subjects could be compared. The dissected follicles were placed into serum containing medium and bisected. Under a dissecting microscope, the theca interna was stripped from the follicle wall, and the granulosa cells were removed with a platinum loop. The cleaned theca shells were dispersed with 0.05% collagenase I, 0.05% collagenase IA, and 0.01% deoxyribonuclease in medium containing 10% FBS (23). Dispersed cells were placed in culture dishes that had been precoated with fibronectin by incubation at 37 C with culture medium containing 5 µg/ml human fibronectin. The media used for cell plating was a 1:1 mixture of DMEM and Hams F-12 medium containing 10% FBS, 10% horse serum, 2% UltroSer G, 20 nM insulin, 20 nM selenium, 1 µM vitamin E, and antibiotics (23). From each follicle twelve 35-mm dishes of primary theca interna cells were grown until confluent, removed from the dish with neutral protease (pronase-E; protease type XXIV, Sigma Chemical Co., St. Louis, MO) in DMEM/F12 (1:1), frozen, and stored in liquid nitrogen (one 35-mm dish per vial) as previously described (23) in culture medium that contained 20% FBS and 10% dimethyl sulfoxide. In all experiments, cells were thawed and propagated in the growth medium described above.
To obtain successive passages of normal and PCOS theca cells, cells were thawed, propagated, and frozen at consecutive passages. The passage conditions and split ratios for all normal and PCOS cells were identical. Experiments comparing PCOS and normal theca were performed utilizing third passage (i.e. 22–26 population doublings) and fourth passage (31–38 population doublings) theca cells isolated from size-matched follicles obtained from age-matched subjects.
At confluence the cells were transferred into serum-free medium (SFM) containing DMEM/F12, 1.0 mg/ml BSA, 100 µg/ml transferrin, 20 nM insulin, 20 nM selenium, 1.0 µM vitamin E, and antibiotics. Sera and growth factors were obtained as follows: FBS was obtained from Irvine Scientific (Irvine, CA): horse serum was obtained from Gibco BRL (Gaithersburg, MD); UltroSer G was from Reactifs IBF (Villeneuve-la-Garenne, France): other compounds were from Sigma Chemical Co. In all experiments the gas phase used was 5% O2, 90% N2, and 5% CO2. Reduced oxygen tension and supplemental antioxidants (vitamin E and selenium) were employed to prevent oxidative damage to CYP17 and CYP11A (22, 23). Subculture was performed by incubation with neutral protease.
Assays for P5, P4, 17OHP4, and T
For evaluation of steroid production, normal or PCOS theca cells
were grown until subconfluent and transferred into SFM with 5 µg/ml
low-density lipoprotein in the presence and absence of 20
µM forskolin for 72 h to induce full steroidogenic
capacity. At 72 h the media were collected. RIAs for 17OHP4, P,
and T were then performed without organic solvent extraction using RIA
kits from ICN Biochemicals, Inc. (Irvine, CA).
Steroid Metabolism Assays
Long-term theca cultures (normal and PCOS) were grown until
subconfluent and transferred into SFM in the presence or absence of 20
µM forskolin for 72 h to induce full steroidogenic
capacity. The cells were then transferred into medium containing
saturating concentrations of [3H]-pregnenolone (1.0
µM), [3H]-P4 (1.0 µM), or
[3H]-DHEA (1.0 µM). Aliquots
of the medium were obtained at various time intervals (i.e.
3, 6, 12, 24, 36, 48, and 72 h). Steroids were extracted from the
medium with 4 vol dichloromethane (HPLC grade) with an extraction
efficiency greater than 90%. The dichloromethane phase containing
unconjugated steroids was evaporated. The residue was dissolved in
methanol and subjected to reverse-phase HPLC. HPLC was conducted on a
computer-controlled automated chromatogram (Gilson Medical Electronics,
Inc., Middleton, WI) using a Phenomenex 25-cm 5
µm Prodigy C18 column (Milford, MA). The gradient solvent
delivery system consisted of 1:1 acetonitrile/methanol (A/M) and water
(50:50) for 10 min, followed by a 10-min linear gradient to 57% A/M,
and an additional 4-min linear gradient to 73% A/M for 9 min, and then
a 2 min linear gradient to 100% A/M. Radioactive material was detected
by an in-line liquid scintillation spectrophotometer (IN/US System
Inc., Tampa, FL). The retention times of authentic steroid standards
were established for the nonreduced and reduced steroids at 240 and 200
nM, respectively.
Determination of CYP17, CYP11A, StAR, and 3ß-HSD mRNA
Levels
Total RNA was extracted from theca cells as previously described
(23). Specific mRNA levels were quantitated using standard Northern
techniques. Human CYP17, CYP11A, 3ß-HSD, and StAR cDNAs were used as
hybridization probes. Hybridizable mRNA species were identified by
autoradiography and normalized using 28S ribosomal RNA.
Statistical Analysis
Statistical analysis was performed using unpaired two-tailed
t tests after combining the results from individual
patients. Each experiment was performed using triplicate or
quadruplicate replicate dishes. Experiments were repeated several times
with cells obtained from various PCOS and normal patients, that had
been thawed and grown to the appropriate passage.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by NIH Grants U54 HD-34449 (J.F.S. and J.M.M.) and R01 HD-33852 (J.M.M.)
Received for publication February 16, 1999. Revision received March 31, 1999. Accepted for publication April 1, 1999.
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A Corbould Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women J. Endocrinol., March 1, 2007; 192(3): 585 - 594. [Abstract] [Full Text] [PDF]
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R. L. Rosenfield Identifying Children at Risk for Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 787 - 796. [Abstract] [Full Text] [PDF]
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 P. Kempna, G. Hofer, P. E. Mullis, and C. E. Fluck Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2 Mol. Pharmacol., March 1, 2007; 71(3): 787 - 798. [Abstract] [Full Text] [PDF]
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 F. Taniguchi, J. F. Couse, K. F. Rodriguez, J. M. A. Emmen, D. Poirier, and K. S. Korach Estrogen receptor-{alpha} mediates an intraovarian negative feedback loop on thecal cell steroidogenesis via modulation of Cyp17a1 (cytochrome P450, steroid 17{alpha}-hydroxylase/17,20 lyase) expression FASEB J, February 1, 2007; 21(2): 586 - 595. [Abstract] [Full Text] [PDF]
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 F. Alvarez-Blasco, J. I. Botella-Carretero, J. L. San Millan, and H. F. Escobar-Morreale Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med, October 23, 2006; 166(19): 2081 - 2086. [Abstract] [Full Text] [PDF]
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M. Mortensen, R. L. Rosenfield, and E. Littlejohn Functional Significance of Polycystic-Size Ovaries in Healthy Adolescents J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3786 - 3790. [Abstract] [Full Text] [PDF]
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 J. F. Couse, M. M. Yates, K. F. Rodriguez, J. A. Johnson, D. Poirier, and K. S. Korach The Intraovarian Actions of Estrogen Receptor-{alpha} Are Necessary to Repress the Formation of Morphological and Functional Leydig-Like Cells in the Female Gonad Endocrinology, August 1, 2006; 147(8): 3666 - 3678. [Abstract] [Full Text] [PDF]
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S.K. Blank, C.R. McCartney, and J.C. Marshall The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2006; 12(4): 351 - 361. [Abstract] [Full Text] [PDF]
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S. C. Foong, D. H. Abbott, M. A. Zschunke, T. G. Lesnick, J. L. Phy, and D. A. Dumesic Follicle Luteinization in Hyperandrogenic Follicles of Polycystic Ovary Syndrome Patients Undergoing Gonadotropin Therapy for in Vitro Fertilization J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2327 - 2333. [Abstract] [Full Text] [PDF]
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 A. Corbould, H. Zhao, S. Mirzoeva, F. Aird, and A. Dunaif Enhanced Mitogenic Signaling in Skeletal Muscle of Women With Polycystic Ovary Syndrome Diabetes, March 1, 2006; 55(3): 751 - 759. [Abstract] [Full Text] [PDF]
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K. Qin, D. A. Ehrmann, N. Cox, S. Refetoff, and R. L. Rosenfield Identification of a Functional Polymorphism of the Human Type 5 17{beta}-Hydroxysteroid Dehydrogenase Gene Associated with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 270 - 276. [Abstract] [Full Text] [PDF]
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H. F. Escobar-Morreale, J. I. Botella-Carretero, F. Alvarez-Blasco, J. Sancho, and J. L. San Millan The Polycystic Ovary Syndrome Associated with Morbid Obesity May Resolve after Weight Loss Induced by Bariatric Surgery J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6364 - 6369. [Abstract] [Full Text] [PDF]
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C. K. M. Ho, J. R. Wood, D. R. Stewart, K. Ewens, W. Ankener, J. Wickenheisser, V. Nelson-Degrave, Z. Zhang, R. S. Legro, A. Dunaif, et al. Increased Transcription and Increased Messenger Ribonucleic Acid (mRNA) Stability Contribute to Increased GATA6 mRNA Abundance in Polycystic Ovary Syndrome Theca Cells J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6596 - 6602. [Abstract] [Full Text] [PDF]
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 M. Jamnongjit, A. Gill, and S. R. Hammes Epidermal growth factor receptor signaling is required for normal ovarian steroidogenesis and oocyte maturation PNAS, November 8, 2005; 102(45): 16257 - 16262. [Abstract] [Full Text] [PDF]
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E. Diamanti-Kandarakis and C. Piperi Genetics of polycystic ovary syndrome: searching for the way out of the labyrinth Hum. Reprod. Update, November 1, 2005; 11(6): 631 - 643. [Abstract] [Full Text] [PDF]
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J. K. Wickenheisser, V. L. Nelson-DeGrave, K. L. Hendricks, R. S. Legro, J. F. Strauss III, and J. M. McAllister Retinoids and Retinol Differentially Regulate Steroid Biosynthesis in Ovarian Theca Cells Isolated from Normal Cycling Women and Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4858 - 4865. [Abstract] [Full Text] [PDF]
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J. Simard, M.-L. Ricketts, S. Gingras, P. Soucy, F. A. Feltus, and M. H. Melner Molecular Biology of the 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Gene Family Endocr. Rev., June 1, 2005; 26(4): 525 - 582. [Abstract] [Full Text] [PDF]
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H. F. Escobar-Morreale, M. Luque-Ramirez, and J. L. San Millan The Molecular-Genetic Basis of Functional Hyperandrogenism and the Polycystic Ovary Syndrome Endocr. Rev., April 1, 2005; 26(2): 251 - 282. [Abstract] [Full Text] [PDF]
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C. Glister, S. L. Richards, and P. G. Knight Bone Morphogenetic Proteins (BMP) -4, -6, and -7 Potently Suppress Basal and Luteinizing Hormone-Induced Androgen Production by Bovine Theca Interna Cells in Primary Culture: Could Ovarian Hyperandrogenic Dysfunction Be Caused by a Defect in Thecal BMP Signaling? Endocrinology, April 1, 2005; 146(4): 1883 - 1892. [Abstract] [Full Text] [PDF]
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D. Soderlund, P. Canto, S. Carranza-Lira, and J.P. Mendez No evidence of mutations in the P450 aromatase gene in patients with polycystic ovary syndrome Hum. Reprod., April 1, 2005; 20(4): 965 - 969. [Abstract] [Full Text] [PDF]
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 D. A. Ehrmann Polycystic Ovary Syndrome N. Engl. J. Med., March 24, 2005; 352(12): 1223 - 1236. [Full Text] [PDF]
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J. K. Wickenheisser, V. L. Nelson-DeGrave, and J. M. McAllister Dysregulation of Cytochrome P450 17{alpha}-Hydroxylase Messenger Ribonucleic Acid Stability in Theca Cells Isolated from Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1720 - 1727. [Abstract] [Full Text] [PDF]
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 J. R. Wood, V. L. Nelson-Degrave, E. Jansen, J. M. McAllister, S. Mosselman, and J. F. Strauss III Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects Physiol Genomics, February 10, 2005; 20(3): 233 - 243. [Abstract] [Full Text] [PDF]
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 V. L. Nelson-Degrave, J. K. Wickenheisser, K. L. Hendricks, T. Asano, M. Fujishiro, R. S. Legro, S. R. Kimball, J. F. Strauss III, and J. M. McAllister Alterations in Mitogen-Activated Protein Kinase Kinase and Extracellular Regulated Kinase Signaling in Theca Cells Contribute to Excessive Androgen Production in Polycystic Ovary Syndrome Mol. Endocrinol., February 1, 2005; 19(2): 379 - 390. [Abstract] [Full Text] [PDF]
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E. Jansen, J. S. E. Laven, H. B. R. Dommerholt, J. Polman, C. van Rijt, C. van den Hurk, J. Westland, S. Mosselman, and B. C. J. M. Fauser Abnormal Gene Expression Profiles in Human Ovaries from Polycystic Ovary Syndrome Patients Mol. Endocrinol., December 1, 2004; 18(12): 3050 - 3063. [Abstract] [Full Text] [PDF]
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J. M. Adams, A. E. Taylor, W. F. Crowley Jr., and J. E. Hall Polycystic Ovarian Morphology with Regular Ovulatory Cycles: Insights into the Pathophysiology of Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4343 - 4350. [Abstract] [Full Text] [PDF]
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 C. R. McCartney, A. B. Bellows, M. B. Gingrich, Y. Hu, W. S. Evans, J. C. Marshall, and J. D. Veldhuis Exaggerated 17-hydroxyprogesterone response to intravenous infusions of recombinant human LH in women with polycystic ovary syndrome Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E902 - E908. [Abstract] [Full Text] [PDF]
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M. Gaasenbeek, B. L. Powell, U. Sovio, L. Haddad, N. Gharani, A. Bennett, C. J. Groves, K. Rush, M. J. Goh, G. S. Conway, et al. Large-Scale Analysis of the Relationship between CYP11A Promoter Variation, Polycystic Ovarian Syndrome, and Serum Testosterone J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2408 - 2413. [Abstract] [Full Text] [PDF]
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R. J. Norman, M. Noakes, R. Wu, M. J. Davies, L. Moran, and J. X. Wang Improving reproductive performance in overweight/obese women with effective weight management Hum. Reprod. Update, May 1, 2004; 10(3): 267 - 280. [Abstract] [Full Text] [PDF]
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S. Jonard and D. Dewailly The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest Hum. Reprod. Update, March 1, 2004; 10(2): 107 - 117. [Abstract] [Full Text] [PDF]
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J. K. Wickenheisser, V. L. Nelson-DeGrave, P. G. Quinn, and J. M. McAllister Increased Cytochrome P450 17{alpha}-Hydroxylase Promoter Function in Theca Cells Isolated from Patients with Polycystic Ovary Syndrome Involves Nuclear Factor-1 Mol. Endocrinol., March 1, 2004; 18(3): 588 - 605. [Abstract] [Full Text] [PDF]
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V. L. Nelson-DeGrave, J. K. Wickenheisser, J. E. Cockrell, J. R. Wood, R. S. Legro, J. F. Strauss III, and J. M. McAllister Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells Endocrinology, February 1, 2004; 145(2): 799 - 808. [Abstract] [Full Text] [PDF]
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A. Gill, M. Jamnongjit, and S. R. Hammes Androgens Promote Maturation and Signaling in Mouse Oocytes Independent of Transcription: A Release of Inhibition Model for Mammalian Oocyte Meiosis Mol. Endocrinol., January 1, 2004; 18(1): 97 - 104. [Abstract] [Full Text] [PDF]
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V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]
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 J. R. Wood, V. L. Nelson, C. Ho, E. Jansen, C. Y. Wang, M. Urbanek, J. M. McAllister, S. Mosselman, and J. F. Strauss III The Molecular Phenotype of Polycystic Ovary Syndrome (PCOS) Theca Cells and New Candidate PCOS Genes Defined by Microarray Analysis J. Biol. Chem., July 11, 2003; 278(29): 26380 - 26390. [Abstract] [Full Text] [PDF]
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M. Fassnacht, N. Schlenz, S. B. Schneider, S. A. Wudy, B. Allolio, and W. Arlt Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5{alpha}-Reductase Activity in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2760 - 2766. [Abstract] [Full Text] [PDF]
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J. F. Couse, M. M. Yates, V. R. Walker, and K. S. Korach Characterization of the Hypothalamic-Pituitary-Gonadal Axis in Estrogen Receptor (ER) Null Mice Reveals Hypergonadism and Endocrine Sex Reversal in Females Lacking ER{alpha} But Not ER{beta} Mol. Endocrinol., June 1, 2003; 17(6): 1039 - 1053. [Abstract] [Full Text] [PDF]
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L. B. Lutz, M. Jamnongjit, W.-H. Yang, D. Jahani, A. Gill, and S. R. Hammes Selective Modulation of Genomic and Nongenomic Androgen Responses by Androgen Receptor Ligands Mol. Endocrinol., June 1, 2003; 17(6): 1106 - 1116. [Abstract] [Full Text] [PDF]
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S. Jabara, L. K. Christenson, C. Y. Wang, J. M. McAllister, N. B. Javitt, A. Dunaif, and J. F. Strauss III Stromal Cells of the Human Postmenopausal Ovary Display a Distinctive Biochemical and Molecular Phenotype J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 484 - 492. [Abstract] [Full Text] [PDF]
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R. S. Legro, R. Bentley-Lewis, D. Driscoll, S. C. Wang, and A. Dunaif Insulin Resistance in the Sisters of Women with Polycystic Ovary Syndrome: Association with Hyperandrogenemia Rather Than Menstrual Irregularity J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2128 - 2133. [Abstract] [Full Text] [PDF]
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D. A. Dumesic, R. D. Schramm, E. Peterson, A. M. Paprocki, R. Zhou, and D. H. Abbott Impaired Developmental Competence of Oocytes in Adult Prenatally Androgenized Female Rhesus Monkeys Undergoing Gonadotropin Stimulation for in Vitro Fertilization J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1111 - 1119. [Abstract] [Full Text] [PDF]
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G. Cheng, Z. Weihua, S. Makinen, S. Makela, S. Saji, M. Warner, J.-A. Gustafsson, and O. Hovatta A Role for the Androgen Receptor in Follicular Atresia of Estrogen Receptor Beta Knockout Mouse Ovary Biol Reprod, January 1, 2002; 66(1): 77 - 84. [Abstract] [Full Text]
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V. L. Nelson, K.-n. Qin, R. L. Rosenfield, J. R. Wood, T. M. Penning, R. S. Legro, J. F. Strauss III, and J. M. McAllister The Biochemical Basis for Increased Testosterone Production in Theca Cells Propagated from Patients with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5925 - 5933. [Abstract] [Full Text] [PDF]
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L. B. Lutz, L. M. Cole, M. K. Gupta, K. W. Kwist, R. J. Auchus, and S. R. Hammes Evidence that androgens are the primary steroids produced by Xenopus laevis ovaries and may signal through the classical androgen receptor to promote oocyte maturation PNAS, November 9, 2001; (2001) 241471598. [Abstract] [Full Text] [PDF]
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M. L. McMullen, B.-N. Cho, C. J. Yates, and K. E. Mayo Gonadal Pathologies in Transgenic Mice Expressing the Rat Inhibin {alpha}-Subunit Endocrinology, November 1, 2001; 142(11): 5005 - 5014. [Abstract] [Full Text] [PDF]
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O. Barbier, C. Girard, L. Berger, M. El Alfy, A. Belanger, and D. W. Hum The Androgen-Conjugating Uridine Diphosphoglucuronosyltransferase-2B Enzymes Are Differentially Expressed Temporally and Spatially in the Monkey Follicle throughout the Menstrual Cycle Endocrinology, June 1, 2001; 142(6): 2499 - 2507. [Abstract] [Full Text] [PDF]
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R. M. Calvo, M. Asunción, D. Tellería, J. Sancho, J. L. San Millán, and H. F. Escobar-Morreale Screening for Mutations in the Steroidogenic Acute Regulatory Protein and Steroidogenic Factor-1 Genes, and in CYP11A and Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Gene on the X Chromosome, Gene-1 (DAX-1), in Hyperandrogenic Hirsute Women J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1746 - 1749. [Abstract] [Full Text]
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A. J. Jakimiuk, S. R. Weitsman, A. Navab, and D. A. Magoffin Luteinizing Hormone Receptor, Steroidogenesis Acute Regulatory Protein, and Steroidogenic Enzyme Messenger Ribonucleic Acids Are Overexpressed in Thecal and Granulosa Cells from Polycystic Ovaries J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1318 - 1323. [Abstract] [Full Text]
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J. W. M. Martens, D. H. Geller, W. Arlt, R. J. Auchus, V. S. Ossovskaya, H. Rodriguez, A. Dunaif, and W. L. Miller Enzymatic Activities of P450c17 Stably Expressed in Fibroblasts from Patients with the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4338 - 4346. [Abstract] [Full Text]
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G. Zhang, J. C. Garmey, and J. D. Veldhuis Interactive Stimulation by Luteinizing Hormone and Insulin of the Steroidogenic Acute Regulatory (StAR) Protein and 17{alpha}-Hydroxylase/17, 20-Lyase (CYP17) Genes in Porcine Theca Cells Endocrinology, August 1, 2000; 141(8): 2735 - 2742. [Abstract] [Full Text] [PDF]
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J. K. Wickenheisser, P. G. Quinn, V. L. Nelson, R. S. Legro, J. F. Strauss III, and J. M. McAllister. Differential Activity of the Cytochrome P450 17{alpha}-Hydroxylase and Steroidogenic Acute Regulatory Protein Gene Promoters in Normal and Polycystic Ovary Syndrome Theca Cells J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2304 - 2311. [Abstract] [Full Text]
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G. A. Dissen, H. E. Lara, V. Leyton, A. Paredes, D. F. Hill, M. E. Costa, A. Martinez-Serrano, and S. R. Ojeda Intraovarian Excess of Nerve Growth Factor Increases Androgen Secretion and Disrupts Estrous Cyclicity in the Rat Endocrinology, March 1, 2000; 141(3): 1073 - 1082. [Abstract] [Full Text] [PDF]
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B. Imani, M. J. C. Eijkemans, F. H. de Jong, N. N. Payne, P. Bouchard, L. C. Giudice, and B. C. J. M. Fauser Free Androgen Index and Leptin Are the Most Prominent Endocrine Predictors of Ovarian Response during Clomiphene Citrate Induction of Ovulation in Normogonadotropic Oligoamenorrheic Infertility J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 676 - 682. [Abstract] [Full Text]
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J. F. Strauss III and A. Dunaif Molecular Mysteries of Polycystic Ovary Syndrome Mol. Endocrinol., June 1, 1999; 13(6): 800 - 805. [Full Text]
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L. B. Lutz, L. M. Cole, M. K. Gupta, K. W. Kwist, R. J. Auchus, and S. R. Hammes Evidence that androgens are the primary steroids produced by Xenopus laevis ovaries and may signal through the classical androgen receptor to promote oocyte maturation PNAS, November 20, 2001; 98(24): 13728 - 13733. [Abstract] [Full Text] [PDF]
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) and appearance of the
indicated steroid metabolites is presented as a function of
time. Results are presented as means ± SD from
triplicate cultures from representative normal and PCOS theca cells.
