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PubMed1988

Regulation of ovarian cell growth through the local production of transforming growth factor-alpha by theca cells.

The rapid proliferation of a tissue often requires the local production of a specific growth factor. The ovarian follicle is a rapidly growing tissue which contains two primary somatic cell types, granulosa cells and theca cells. Theca cells and granulosa cells were isolated from bovine ovaries and cultured to assess the possible local production of a growth factor within the ovarian follicle. Serum-free conditioned medium from theca cells, but not from granulosa cells, was found to contain a component that specifically bound to the epidermal growth factor (EGF) receptor. Therefore, theca cells appear to produce an EGF-like substance as a potential regulator of follicle cell growth. This result provides physiological significance to the previous observation that granulosa cells contain EGF receptors and respond to EGF to increase cell proliferation. Transforming growth factor-alpha (TGF alpha) is a protein that is structurally and functionally related to EGF and binds to the EGF receptor. Using a molecular probe to TGF alpha, theca cells were found to express the TGF alpha gene, which is consistent with the presence of an EGF-like substance in conditioned medium, but granulosa cells had no detectable TGF alpha gene expression. Similar analysis with a molecular probe to EGF demonstrated the apparent lack of EGF gene expression in theca cells or granulosa cells. As previously demonstrated with granulosa cells, the data presented indicate that theca cells also contain high affinity EGF receptors. TGF alpha was found to stimulate the growth of both granulosa and theca cells. These observations imply that within the ovarian follicle TGF alpha is produced by theca cells, which can subsequently have both a paracrine and an autocrine role in regulating follicle cell proliferation. Results presented demonstrate production of TGF alpha by a normal adult mesenchymal tissue and provide an example of a growth factor-mediated mesenchymal-epithelial cell interaction between theca cells and granulosa cells.

Animals↗
PubMed2005

Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells.

Follicle development in the mammalian ovary requires interactions among the oocyte, granulosa cells, and theca cells, coordinating gametogenesis and steroidogenesis. Here we show that granulosa cells of growing follicles in mouse ovary act as a source of hedgehog signaling. Expression of Indian hedgehog and desert hedgehog mRNAs initiates in granulosa cells at the primary follicle stage, and we find induced expression of the hedgehog target genes Ptch1 and Gli1, in the surrounding pre-theca cell compartment. Cyclopamine, a highly specific hedgehog signaling antagonist, inhibits this induced expression of target genes in cultured neonatal mouse ovaries. The theca cell compartment remains a target of hedgehog signaling throughout follicle development, showing induced expression of the hedgehog target genes Ptch1, Ptch2, Hip1, and Gli1. In periovulatory follicles, a dynamic synchrony between loss of hedgehog expression and loss of induced target gene expression is observed. Oocytes are unable to respond to hedgehog because they lack expression of the essential signal transducer Smo (smoothened). The present results point to a prominent role of hedgehog signaling in the communication between granulosa cells and developing theca cells.

Animals↗
PubMed2000

Expression of parathyroid hormone-related peptide (PTH-rp) and its receptorin the porcine ovary: regulation by transforming growth factor-beta and possible paracrine effects of granulosa cell PTH-rp secretion on theca cells.

Parathyroid hormone-related peptide (PTH-rp) and the PTH-rp receptor are expressed in certain cancers as well as in many normal tissues. To evaluate the expression of this Ca(2+)-regulating hormone and its receptor in porcine ovary, we isolated partial cDNAs encoding homologous PTH-rp and PTH-rp receptor using reverse transcription-polymerase chain reaction (RT-PCR). The cDNA encoding PTH-rp (419 base pairs [bp]) was 92% and 87% homologous to human and rat sequences, respectively, while the PTH-rp receptor clone (167 bp) was 94% and 91% identical to the human and rat genes. Qualitative estimates of PTH-rp mRNA by RT-PCR indicated that the PTH-rp gene is expressed at high levels in the corpus luteum but is undetectable in granulosa and theca cells isolated from small (1-5 mm) and medium-sized (5-8 mm) antral follicles. In contrast, PTH-rp receptor transcripts were most abundant in corpora lutea and theca cells, and least abundant (albeit detectable) in granulosa cells. Regulation of PTH-rp protein production was assessed in serum-free monolayer cultures of porcine granulosa cells. Transforming growth factor (TGF)-beta1 (100 ng/ml) increased PTH-rp concentrations (assayed by two-site immunoradiometric assay of culture media) as well as corresponding PTH-rp mRNA accumulation (assessed by RT-PCR) in a time-dependent manner, with maximal responses of 3- to 5-fold at 96 h. TGF-beta1 dose-response studies revealed an ED(50) of 0. 24-0.38 ng/ml with a maximal effect at 30 ng/ml. Other growth factors and hormones, including insulin, insulin-like growth factor (type I), epidermal growth factor, FSH, estradiol, and interleukin-1, failed to alter PTH-rp secretion. Biological effects of PTH-rp were evident in purified porcine theca cells. Using the Ca(2+)-sensitive fluorescent indicator dye, fura-2, and digital imaging videomicroscopy, we found that PTH-rp (1 microM) stimulated intracellular free calcium ion concentrations ([Ca(2+)](i)) in single porcine theca cells. The [Ca(2+)](i) elevation was characterized by a slow and prolonged rise. After PTH-rp stimulation, theca cells maintained responsiveness to hormone stimulation by LH, which elicited a typical theca cell [Ca(2+)](i) response. Our results allow a hypothesis of a paracrine intrafollicular signaling system involving interaction between theca cell-derived TGF-beta and granulosa cell-derived PTH-rp, with feedback by PTH-rp on theca cells. Alternatively, expression of mRNAs encoding PTH-rp and its receptor in corpora lutea suggests that this peptide may play a role in luteal cell function. The precise role of this intraovarian PTH-rp system will require further study.

Animals↗
PubMed2003

Paracrine effects of oocyte secreted factors and stem cell factor on porcine granulosa and theca cells in vitro.

Oocyte control of granulosa and theca cell function may be mediated by several growth factors via a local feedback loop(s) between these cell types. This study examined both the role of oocyte-secreted factors on granulosa and thecal cells, cultured independently and in co-culture, and the effect of stem cell factor (SCF); a granulosa cell derived peptide that appears to have multiple roles in follicle development. Granulosa and theca cells were isolated from 2-6 mm healthy follicles of mature porcine ovaries and cultured under serum-free conditions, supplemented with: 100 ng/ml LR3 IGF-1, 10 ng/ml insulin, 100 ng/ml testosterone, 0-10 ng/ml SCF, 1 ng/ml FSH (granulosa), 0.01 ng/ml LH (theca) or 1 ng/ml FSH and 0.01 ng/ml LH (co-culture) and with/without oocyte conditioned medium (OCM) or 5 oocytes. Cells were cultured in 96 well plates for 144 h, after which viable cell numbers were determined. Medium was replaced every 48 h and spent medium analysed for steroids. Oocyte secreted factors were shown to stimulate both granulosa cell proliferation (P < 0.001) and oestradiol production (P < 0.001) by granulosa cells throughout culture. In contrast, oocyte secreted factors suppressed granulosa cell progesterone production after both 48 and 144 hours (P < 0.001). Thecal cell numbers were increased by oocyte secreted factors (P = 0.02), together with a suppression in progesterone and androstenedione synthesis after 48 hours (P < 0.001) and after 144 hours (P = 0.02), respectively. Oocyte secreted factors also increased viable cell numbers (P < 0.001) in co-cultures together with suppression of progesterone (P < 0.001) and oestradiol (P < 0.001). In granulosa cell only cultures, SCF increased progesterone production in a dose dependent manner (P < 0.001), whereas progesterone synthesis by theca cells was reduced in a dose dependent manner (P = 0.002). Co-cultured cells demonstrated an increase in progesterone production with increasing SCF dose (P < 0.001) and an increase in oestradiol synthesis at the highest dose of SCF (100 ng/ml). In summary, these findings demonstrate the presence of a co-ordinated paracrine interaction between somatic cells and germ cells, whereby oocyte derived signals interact locally to mediate granulosa and theca cell function. SCF has a role in modulating this local interaction. In conclusion, the oocyte is an effective modulator of granulosa-theca interactions, one role being the inhibition of luteinization.

Androstenedione↗
PubMed2003

Tumor necrosis factor-alpha (TNF alpha) inhibits progesterone and estradiol-17beta production from cultured granulosa cells: presence of TNFalpha receptors in bovine granulosa and theca cells.

The aim of this study was to investigate whether functional tumor necrosis factor-alpha (TNFalpha) receptors are present in the granulosa cells and the cells of theca interna (theca cells), obtained from bovine follicles classified into one of three groups. Each group was defined as either small vesicular ovarian follicles (small follicles; 3-5 mm in diameter), preovulatory mature ovarian follicles (preovulatory follicles) or atretic follicles (12-18 mm) according to gross examination of the corpus luteum in the epsilateral or contralateral ovary and the uterus (size, color, consistency and mucus), and the ratio of progesterone (P(4)) and estradiol-17beta (E(2)) concentrations in follicular fluid. A Scatchard analysis showed the presence of a high-affinity binding site on both granulosa and theca cells from all follicles examined (dissociation constant: 4.7 +/- 0.15 to 6.9 +/- 1.40 nM). Moreover, TNFalpha receptor concentrations in granulosa and theca cells obtained from atretic follicles were significantly higher than those in the cells from preovulatory follicles (P<0.05). Exposure of cultured granulosa cells from small antral follicles to recombinant human TNFalpha (rhTNFalpha; 0.06-6 nM) inhibited E(2) secretion in a dose-dependent fashion (P<0.01), but did not affect P(4) secretion. In addition, rhTNFalpha inhibited follicle stimulating hormone-, forskolin- or dibutylyl cyclic AMP-induced P(4) and E(2) secretion by the cells (P<0.01). These results indicate the presence of functional TNFalpha receptors in bovine granulosa and theca cells in small, preovulatory and atretic follicles, and suggest that TNFalpha plays a role in regulating their secretory function.

Animals↗
PubMed1990

Mesenchymal-epithelial cell interactions in the ovary: estrogen-induced theca cell steroidogenesis.

The role of mesenchymal-epithelial cell interactions in the control of ovarian physiology was investigated Theca cells are the mesenchymal (i.e. stromal) like cells that surround the ovarian follicle and produce androgen in response to the gonadotropin luteinizing hormone (LH). Granulosa cells are the epithelial-like cells that form the follicle, support the developing oocyte, and utilize androgens produced by theca cells as a substrate for the production of estrogen Observations presented indicate that estrogen produced by granulosa cells dramatically stimulates androgen production by theca cells Estrogen was found to have greater stimulatory effect on theca cell androgen production than gonadotropin, and a combination of estrogen and gonadotropin results in a greater than additive response of the two hormones. Regulation of androgen production by estrogen provides a local feedback loop in the follicle that will significantly influence ovarian steroidogenesis. This steroid-mediated theca-granulosa cell interaction provides evidence for the importance of mesenchymal (i.e. stromal)-epithelial cell interactions in adult tissues and implies that epithelial cells can produce paracrine factors that modulate mesenchymal cell function and differentiation. The theca cell-granulosa cell interaction identified is postulated to be a critical mesenchymal-epithelial cell interaction for the control of ovarian physiology and the endocrine status of the female.

Androgens↗
PubMed1991

[The prognostic factors in patients with malignant granulosa-theca cell tumors of the ovaries].

The extent of tumor, as revealed by surgery in 113 primary patients with malignant granulosa-stromal cell tumors of the ovaries (granulosa cell--77, theca cell--17 and mixed theca-granulosa cell tumors--19 patients), was analysed versus duration of disease, laterality of tumor and patient age. Factors which were significantly or as a marked tendency associated with stage III and IV of disease and thus suggested poor prognosis were identified.

Age Factors↗
PubMed2005

Increased transcription and increased messenger ribonucleic acid (mRNA) stability contribute to increased GATA6 mRNA abundance in polycystic ovary syndrome theca cells.

CONTEXT: Polycystic ovary syndrome (PCOS) theca cells secrete increased levels of androgens. The mRNA and protein levels of the transcription factor GATA6, which regulates expression of several steroidogenic enzymes, are increased in PCOS theca cells. Thus, GATA6 is a PCOS candidate gene. OBJECTIVE: The objective of the study was to explore mechanisms by which GATA6 mRNA levels are increased in PCOS theca cells. DESIGN: Theca cell cDNA and genomic DNA from normal individuals and PCOS patients were subjected to quantitative RT-PCR and sequence analysis, respectively. SETTING: The experiments were performed in a university laboratory. PARTICIPANTS: Four hundred sixty-nine families that contain at least one PCOS patient were ascertained for genetic studies. Theca cells were obtained from four normal individuals and four PCOS patients. RESULTS: Nascent GATA6 transcript levels, which reflect GATA6 gene transcription, were significantly increased in PCOS theca cells. In normal theca cells, GATA6 mRNA has a short half-life, which was attributed to an AU-rich 3'-untranslated region sequence. The half-life of GATA6 transcripts was also significantly longer in the PCOS theca cells. However, no sequence variations in the GATA6 gene locus were associated with PCOS. CONCLUSIONS: In PCOS theca cells, GATA6 gene transcription and the stability of the GATA6 mRNA are increased. Because there is no sequence variation in the GATA6 gene locus, which is associated with PCOS, it is likely that the increased gene transcription and mRNA stability are due to intrinsic differences in PCOS theca cells.

Base Sequence↗
PubMed1983

Distinguishing the steroidogenic roles of granulosa and theca cells of the dominant ovarian follicle and corpus luteum.

In order to determine the relative contribution of granulosa cells and follicular fluid of the preovulatory follicle to ovarian and peripheral vein levels of principal steroids in the late follicular phase, as well as the importance of granulosa cells and theca cells in subsequent corpus luteum function, 32 rhesus and cynomolgus monkeys were studied. In group one (n = 10), they were bled from the femoral vein daily throughout the cycle and sera assayed for FSH, LH, estradiol, and progesterone. In addition, they were laparotomized in the late follicular phase when serum estradiol (by rapid assay) had exceeded 150 pg/ml for about 24 h. Ovarian vein blood was taken ipsilateral to the dominant follicle, followed by aspiration of follicular contents and rinsing of the antrum to remove as many granulosa cells as possible without disturbing the thecal layers. Also, blood from the contralateral ovarian vein was obtained, as well as a second collection from the ipsilateral ovarian vein 15 min after follicular aspiration; a second peripheral sample was obtained immediately thereafter. Ovarian vein asymmetry of estradiol, progesterone, and androstenedione, but not 17-OH progesterone, was noted in every case (i.e. higher steroid levels were associated with the putative dominant follicle). After follicular aspiration, high concentrations of estradiol, progesterone, and androstenedione in ovarian venous effluent fell (P less than 0.001) by nearly 70% from preaspiration levels; concurrently, peripheral levels of estradiol and progesterone were reduced by about 40%. Conversely, 17-OH progesterone was unaffected. Integrated progesterone levels throughout the subsequent luteal phase, but not serum estradiol, were significantly (P less than 0.001) less in the experimental monkeys (after aspirating/rinsing) compared to controls, although luteal phase length was unchanged (14.33 vs. 14.83 days). Groups two (n = 7) and three (n = 15) were employed to assess the influence of vascular trauma caused by either continuous cannulation or serial (up to six insults) venipuncture, on the concentrations of the principal ovarian steroids in ovarian vein blood.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstenedione↗
PubMed2000

Differential activity of the cytochrome P450 17alpha-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca cells.

17alpha-Hydroxylase (CYP17) expression in propagated theca cells isolated from the ovaries of women with polycystic ovary syndrome (PCOS) is persistently elevated, compared with theca cells isolated from normal ovaries. To investigate the mechanism for increased CYP17 messenger RNA accumulation in PCOS theca cells, we examined CYP17 and steroidogenic acute regulatory protein (StAR) promoter activities in normal and PCOS theca cells. Conditions were established to transiently transfect human theca cells with reporter gene constructs containing 5' truncations of the human CYP17 and StAR promoters. Cotransfection of a steroidogenic factor-1 expression plasmid was found to be required for detection of basal and forskolin-stimulated CYP17 promoter activity but not for StAR promoter activity. However, cotransfection with a steroidogenic factor-1 expression plasmid augmented both basal and forskolin-stimulated StAR promoter activity. CYP17 reporter activity was compared in theca cells isolated from normal and PCOS patients. Basal and forskolin-stimulated CYP17 promoter activity was 4-fold greater in PCOS cells than in theca cells isolated from normal ovaries. In contrast, StAR promoter activity, and the activity of a reporter construct containing three copies of a cAMP response element (3xCRE), were similar in normal and PCOS theca cells. The results of these studies document: 1) that basal and cAMP-dependent CYP17 gene transcription is increased in PCOS theca cells; 2) that there is differential regulation of promoters of genes required for steroidogenesis in PCOS theca cells; and 3) that passaged normal and PCOS theca cells provide a model system for studying tissue-specific regulation of genes encoding steroidogenic enzymes and identifying the molecular mechanisms involved in increased androgen production in PCOS.

Cells, Cultured↗
PubMed1986

[Endocrinological and clinico-pathologic study of granulosa-theca cell tumors of the ovary].

Nine granulosa-theca cell tumors (four pure theca cell tumors, one granulosa cell tumors, two granulosa-theca tumors and two juvenile granulosa-theca tumors) were studied endocrinologically and clinico-pathologically. The cases of juvenile granulosa-theca tumors developed precocious pseudopuberty. Three of seven other cases were re-feminized and four cases showed no hormonal manifestation clinically. The peripheral vein serum values of estradiol, progesterone, testosterone and prolactin were elevated in six of eight cases, three of four cases, four of six cases, and two of three cases, respectively. The concentration ratios between tumor harboring ovarian vein samples and peripheral vein (or opposite normal ovarian vein) samples was 2.7 to 16.9 for estrone, 8.8 to 28.6 for estradiol, 3.6 to 4.7 for progesterone, 1.6 to 6.6 for testosterone and 0.6 to 1.0 for prolactin. Estradiol was localized in both granulosa cells and theca cells, and testosterone was localized in granulosa cells in half of the cases and in theca cells in 60% of the cases. Also, testosterone was localized in all three cases in which luteinized theca cells were present. There were no cases with positive prolactin localization. These results are compatible with the concept that in granulosa-theca cell tumor, both granulosa and theca cells can produce a wide range of steroid hormones.

Aged↗
PubMed1989

Modulation of 17 alpha-hydroxylase/C17,20-lyase activity in porcine theca cells.

The major source of ovarian androgen is the theca cells. Androgens are produced by the conversion of progestins by the 17 alpha-hydroxylase/C17,20 lyase enzymatic system (lyase). The 3 beta-hydroxysteroid dehydrogenase and aromatase enzymes in the theca cells are modulated by gonadotropins as well as by steroids produced locally. Therefore, the combined effects of hCG plus progesterone, estradiol, or dihydrotestosterone (DHT) on microsomal lyase activity in theca cells from large and medium-sized follicles were determined. Theca cells (3 x 10(6) cells/6 ml/well) were cultured in Medium 199 (M199) containing only insulin (10 micrograms/ml) and transferrin (5 micrograms/ml). At 24 h, theca cells were treated with M199, hCG (15 ng/ml), progesterone, estradiol, or DHT (100 ng/ml) or a combination of hCG + one of the three steroids. Media were removed at various times of culture (27-72 h) and levels of androgen determined by RIA. Microsomes were incubated with 1 microCi [3H]progesterone +0.5 mM NADPH and radioactive conversion products were measured after purification by thin layer chromatography. Administration of progesterone, estradiol, or DHT alone had little effect on lyase activity in theca cells from medium-sized follicles whereas the addition of hCG alone significantly increased lyase activity in these cells. However, concomitant addition of any steroid with hCG inhibited the increase in lyase activity after the addition of hCG alone. Theca cells from large porcine follicles had a higher basal level of lyase activity compared to theca cells from the smaller follicles. Lyase activity in theca cells from large follicles was enhanced by progesterone; estradiol was inhibitory. DHT initially stimulated lyase activity in theca cells from large follicles, but was inhibitory later in culture. In contrast to its marked effect on theca cells from medium follicles, hCG had only a small effect on lyase activity in theca cells from large follicles. Thus, thecal lyase activity increased as the follicle matured, providing more androgen substrate for the production of estrogen. Lyase activity in theca cells of medium follicles appears to be regulated predominantly by gonadotropin from the pituitary while intraovarian regulation of lyase activity by steroids may be more important in larger follicles.

Aldehyde-Lyases↗
PubMed2001

The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome.

Ovarian theca cells propagated from patients with polycystic ovary syndrome (PCOS) convert steroid precursors into T more efficiently than normal theca cells. To identify the basis for increased T production by PCOS theca cells, we examined type I-V 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) isoform expression in long-term cultures of theca and granulosa cells isolated from normal and PCOS ovaries. RT-PCR analysis demonstrated that theca cells express type V 17 beta HSD a member of the aldo-keto reductase (AKR) superfamily (17 beta HSDV, AKR1C3), whereas expression of type I, II, and IV 17 beta HSD, which are members of the short-chain dehydrogenase/reductase superfamily, was limited to granulosa cells. Type III 17 beta HSD, the testicular isoform, was not detected in either granulosa or theca cells. Northern and real-time PCR analyses demonstrated that 17 beta HSDV transcripts were not significantly increased in PCOS theca cells compared with normal theca cells. RT-PCR analysis revealed that theca cells also express another AKR, 20 alpha HSD (AKR1C1). Both basal and forskolin-stimulated 20 alpha HSD mRNA levels were increased in PCOS theca cells compared with normal theca cells. However, 17 beta HSD enzyme activity per theca cell was not significantly increased in PCOS, suggesting that neither AKR1C3 nor AKR1C1 contributes to the formation of T in this condition. In contrast, 17 alpha-hydroxylase/C17,20 lyase and 3 beta HSD enzyme activities were elevated in PCOS theca cells, driving increased production of T precursors. These findings indicate that 1) increased T production in PCOS theca cells does not result from dysregulation of "androgenic" 17 beta HSD activity or altered expression of AKRs that may express 17 beta HSD activity; and 2) increased synthesis of T precursors is the primary factor driving enhanced T secretion in PCOS.

20-Hydroxysteroid Dehydrogenases↗
PubMed2003

Involvement of theca cells and steroids in the regulation of granulosa cell apoptosis in rabbit preovulatory follicles.

Follicular atresia is characterized by a rapid loss of granulosa cells and, to a lesser extent, theca cells, via apoptosis. The aim of this study was to investigate the possible involvement of theca cell secretions in the regulation of apoptosis of rabbit granulosa cells. The annexin-V binding method based on externalization of phosphatidylserine to the outer layer of plasma membrane during apoptosis was used to detect apoptotic granulosa cells in flow cytometry. Regulation of apoptosis of granulosa cells was studied in three different culture systems: (i) isolated cultured granulosa cells, (ii) granulosa cells obtained from cultured preovulatory follicles and (iii) granulosa cells co-cultured with theca cells. The results of this study indicate that: (i) the rate of apoptosis of granulosa cells was significantly reduced when granulosa cells were co-cultured with theca cells or obtained from cultured preovulatory follicles in comparison with isolated cultured granulosa cells; (ii) FSH exerts its anti-apoptotic effect only on granulosa cells issued from cultured preovulatory follicles; (iii) ovarian steroids do not affect the percentage of isolated apoptotic granulosa cells; and (iv) the occurrence of an apoptotic process in rabbit theca cells could be upregulated in vitro by hCG and an analogue of the gonadotrophin second messenger cAMP. The results of this study indicate that in rabbits (i) steroids were ineffective in vitro in protecting isolated granulosa cells against apoptosis in comparison with observations in vivo in rats, and (ii) the presence of theca cells was efficient to reduce granulosa cell apoptosis but not sufficient to allow the anti-apoptotic effect of gonadotrophins observed in cultured follicles.

Animals↗
PubMedDate not supplied

Immunohistochemical and biochemical analysis of a human Sertoli-Leydig cell tumor: autonomous steroid production characteristic of ovarian theca cells.

OBJECTIVE: To ascertain the steroidogenic profile and location of steroidogenic enzymes in a steroid-secreting Sertoli-Leydig cell tumor of the ovary. METHODS: Steroid levels from peripheral, left ovarian (tumor), and right ovarian venous blood were measured. Tumor tissue was examined for the steroidogenic enzymes 17 alpha-hydroxylase (P450c17) and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) by immunohistochemistry. Tumor cells were isolated and incubated in serum-free media. Thereafter, media were analyzed for steroid production, steroidogenic response to effectors, and metabolism of radiolabeled pregnenolone and androstenedione. RESULTS: Levels of C19 steroids and 17-hydroxyprogesterone (17OHP) were elevated in peripheral blood. The majority (80%) of steroids in serum from the left ovarian vein (tumor) were C19 steroids (dehydroepiandrosterone [DHEA], 45%; androstenedione, 27%, testosterone, 7%, with 13% 17OHP, 7% progesterone, and less than 1% estradiol (E2). Immunoreactivity for both P450c17 and 3 beta HSD was identified in clusters of large cells surrounded by nonimmunoreactive cells composing cord-like structures. Of the steroids that accumulated in the incubation medium of unstimulated, freshly isolated tumor cells, 84% were C19 steroids (DHEA, 44%; androstenedione, 36%; testosterone 2%, with 16% 17OHP and less than 1% progesterone and E2. Basal steroid production was not stimulated by LH or FSH. However, treatment with forskolin (10 mumol/L), dibutyryl cAMP (1 mmol/L), or steroid precursors (22-hydroxycholesterol, 1 mumol/L; pregnenolone, 1 mumol/L) increased the production of all steroids measured. Forskolin treatment increased androstenedione (fivefold), DHEA (tenfold), and 17OHP (40-fold) compared with basal levels. Incubation of freshly isolated cells with [3H]pregnenolone demonstrated the ability of these cells to metabolize this C21 steroid precursor to androstenedione, DHEA, and 17OHP. However, [3H]androstenedione was not readily metabolized by these cells to either estrone or testosterone. CONCLUSIONS: The steroidogenic properties of a steroid hormone-producing tumor were described. Cells isolated from this tumor produced steroids similar to those secreted by ovarian theca cells. These properties suggest that certain ovarian steroidogenic tumor cells may be an appropriate model for ovarian theca cells and could be used to develop steroid-secreting cell lines.

3-Hydroxysteroid Dehydrogenases↗