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PubMed2006

Identification of a stage-specific permissive in vitro culture environment for follicle growth and oocyte development.

The availability of viable oocytes is the limiting factor in the development of new reproductive techniques. Many attempts have been made to grow immature oocytes in vitro during recent decades. Recently, a modified alginate-based three-dimensional culture system was designed to support the growth and maturation of multilayered secondary follicles. This system was able to produce oocytes that successfully completed meiosis, fertilization, and development to the blastocyst stage. Subsequent attempts to culture two-layered secondary follicles were unsuccessful under the original conditions. Herein, we investigated the effect of alginate consistency on two-layered follicle growth and oocyte developmental competence by encapsulating follicles into alginate scaffolds of various concentrations. Although there were no significant differences in survival rates, 0.25% and 0.5% alginate supported more rapid growth of follicles and antrum formation compared with 1.5% and 1.0% alginate after 8 days of culture. Alginate scaffold concentration also affected the proliferation and differentiation of somatic cells (theca and granulosa cells), measured in terms of morphological changes, steroid profiles (androstenedione, estradiol, and progesterone), and specific molecular markers (Fshr, Lhcgr, and Gja1). Theca cell proliferation and steroid production were hindered in follicles cultured in 1.5% alginate. In vitro fertilization and embryo culture revealed that oocytes obtained from 0.25% alginate retained the highest developmental competence. Overall, the present study showed that the alginate scaffold consistency affects folliculogenesis and oocyte development in vitro and that the alginate culture system can and should be tailored to maximally support follicle growth depending on the size and stage of the follicles selected for culture.

Androstenedione↗
PubMed1994

Steroidogenic cytochrome P450 enzyme messenger ribonucleic acids and follicular fluid steroids in individual follicles during preovulatory maturation in the pig.

Changes in follicular concentrations of steroidogenic cytochrome P450 enzyme mRNAs were determined during preovulatory maturation. RNA was isolated from 59 individual follicles dissected from 18 pigs during altrenogest-synchronized preovulatory follicular maturation: at Day 1 (pre-follicular phase), Day 3 (early follicular phase), Day 5 (mid-follicular phase), and Day 7 (late follicular phase, 24-36 h after the onset of the LH surge). Follicular fluid was aspirated for steroid RIA. RNA was also isolated from pooled granulosa cells, theca tissue, and luteal tissue. RNA was analyzed by Northern and slot-blot procedures using cDNA probes to human aromatase cytochrome P450 (P450arom), porcine 17 alpha-hydroxylase cytochrome P450 (P450(17) alpha), and porcine cholesterol side-chain cleavage cytochrome P450 (P450scc). P450arom mRNA was expressed in both granulosa and theca interna cells but was not detectable in luteal tissue from Day 13 of the estrous cycle. Follicular P450arom mRNA concentration tended to increase between Days 1 and 5 and decreased (p < or = 0.05) by 92% between Days 5 and 7. Follicular fluid estradiol-17 beta concentration increased 17-fold between Days 1 and 5 and then decreased (p < or = 0.05) by 96% between Days 5 and 7. P450(17) alpha mRNA was present in theca interna but was not detected in granulosa cells or luteal tissue. Follicular P450(17) alpha mRNA concentrations did not differ significantly among days, but the content per follicle increased (p < 0.05) between Days 1 and 5 and decreased (p < 0.05) between Days 5 and 7.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Lipoprotein enhancement of ovarian theca-interstitial cell steroidogenesis: relative contribution of scavenger receptor class B (type I) and adenosine 5'-triphosphate- binding cassette (type A1) transporter in high-density lipoprotein-cholesterol transport and androgen synthesis.

The theca-interstitial cells take up plasma high-density lipoprotein (HDL)- and low-density-lipoprotein-derived cholesterol to convert into steroid hormones. The uptake of HDL-derived cholesterol is mediated by the scavenger receptor, class B, type I (SR-BI). In nonsteroidogenic cells, HDL-stimulated efflux of cholesterol has been shown to be mediated by the ATP-binding cassette A1 (ABCA1) transporter. Its expression has not been documented in steroidogenic cells. The goal of the present study was to determine: 1) the role of SR-BI in theca-interstitial cell androgen production; 2) whether theca-interstitial cells express ABCA1 transporter mRNA; and 3) the relative roles of SR-BI and ABCA1 transporter in androgen production. The ABCA1 transporter mRNA expression in rat theca-interstitial cells was shown using RT-PCR and Northern blot analyses. The role of SR-BI and ABCA1 in androstenedione production was also examined by treating cells with anti-SR-BI and 2-hydroxypropyl-beta-cyclodextrin in the presence and absence of human chorionic gonadotropin and/or human HDL(3). The treatment of theca-interstitial cells with anti-SR-BI antibody blocked more than 90% of HDL plus human chorionic gonadotropin-stimulated androstenedione production, and selective HDL-CE uptake. On the other hand, the use of inhibitors of ABCA1 transporter function had no discernible effect on HDL-supported androgen production. These data demonstrate that, although theca-interstitial cells express both SR-BI and ABCA1 transporter mRNA, the SR-BI pathway supplies the majority of the cholesterol required for androgen production. Furthermore, the present study presents evidence for a crucial role for SR-BI in HDL-mediated androgen production.

ATP Binding Cassette Transporter 1↗
PubMed1983

Steroidogenesis by avian ovarian cells: effects of luteinizing hormone and substrate availability.

The production of progesterone (P) and estrogen (E) by enzymatically dispersed granulosa and theca cells from chicken preovulatory follicles was examined in 3-h incubations. Accumulation of the P produced by granulosa cells was significantly reduced by the addition of theca cells, whereas E production was increased. The decrease in P accumulation was shown to be due to extensive metabolism of P by theca cells. There were no synergistic effects of luteinizing hormone (LH) and any substrate tested on E production by theca cells. Maturation of granulosa cells was characterized by an increased sensitivity to LH stimulation of P production, but there was no change in pregnenolone conversion to P. Conversely, maturation of theca cells was accompanied by decreased in both sensitivity to LH and the ability to convert substrates to E. The results are discussed in terms of the contribution of each cell type in the production of steroids by chicken follicles during maturation.

Animals↗
PubMed2003

Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common disorder of unknown etiology, but several lines of evidence suggest that there is an underlying genetic cause for PCOS. Studies of first-degree relatives of women diagnosed with PCOS reveal familial clustering of the disease, particularly hyperandrogenemia. A prospective study of first-degree female relatives of PCOS women found that 46% of ascertainable sisters of PCOS women were hyperandrogenemic. The serum bioavailable testosterone in the cohort of sisters showed a bimodal distribution. These observations suggest a dominantly inherited trait controlling androgen levels. Studies on cultures of human theca cells derived from follicles isolated from the ovaries of PCOS and normal women demonstrated that PCOS theca cells produce greater amounts of testosterone, 17alpha-hydroxyprogesterone, and progesterone than normal theca cells, despite the fact that cells were cultured under identical conditions for multiple population doublings. Examination of the metabolism of radiolabeled steroid hormone precursors and steady-state levels of mRNAs encoding steroidogenic enzymes revealed that there are multiple alterations in the steroidogenic machinery of PCOS theca cells, including elevated expression of the CYP11A, 3BHSD2, and CYP17 genes. The increased mRNA levels are the result, in least in part, of increased gene transcription. Interestingly, the STAR gene is not expressed at a higher level in PCOS theca cells. The stable up-regulation of steroidogenesis in PCOS thecal cells indicates either a genetic abnormality in these cells or a persistent metabolic imprint established in vivo. Linkage and association studies conducted by the National Cooperative Program in Infertility Research using affected sib-pair analysis and the transmission/disequilibrium test to explore candidate genes point a finger at a region on chromosome 19p13.3. The putative PCOS gene lying in this region has yet to be identified. However, existing data suggest that it is probably involved in signal transduction mechanisms leading to altered expression of a suite of genes that affect theca cell steroidogenic activity as well as the metabolic phenotype of other cell types, including muscle and fat.

Cholesterol Side-Chain Cleavage Enzyme↗
PubMed1979

[Granulosa cell and thecacell tumors in 25 cases (author's transl)].

Granulosa cell tumors are derived from specific ovarion stroma and have the ability to produce hormones. In the 25 cases of granulosa cell tumors no concommitant endometrial carcinoma was found. Because of the varying degree of malignancy tumors which contain granulosa cells must be differentiated from pure theca cell tumors. Granulosa cell tumors are frequently malignant. Theca cell tumors are benign. The treatment of granulosa cell tumors is fundamentally the same as that of epithelial cancers of the ovary. The treatment of theca cell tumors is conservative.

Adult↗
PubMed1998

Keratinocyte growth factor expression by the bovine corpus luteum.

Communication between cells of the corpus luteum (CL) is thought to be necessary for normal luteal function. Keratinocyte growth factor (KGF) is produced by mesenchymally derived cells in numerous tissues and acts on epithelial cells. In bovine follicles, theca cells produce KGF, which can stimulate granulosa cell proliferation. Whether KGF is produced by ovarian cells after luteinization is unknown. Our objective was to determine whether KGF mRNA and protein were present in bovine luteal tissue, and if so, to determine what type(s) of luteal cells contains KGF. CL (n = 3-4/day) were obtained from specific days throughout diestrus. Presence of KGF mRNA in CL was determined using a porcine KGF anti-sense cRNA probe. Northern analyses of luteal tissue poly(A)+ RNA revealed a single transcript (approximately 2.0 kilobases), the quantity of which did not change throughout diestrus. Western analysis revealed an immunoreactive band (28 kDa) in luteal tissues and theca cell homogenates that was absent from granulosa cell homogenates. Immunocytochemistry showed KGF predominantly in theca and small luteal cells. Results indicate that bovine CL produce and contain KGF, which is primarily localized in small luteal cells. Therefore, KGF may participate in paracrine communication within the bovine CL.

Animals↗
PubMed2000

Type VI collagen expression during growth of human ovarian follicles.

OBJECTIVE: To identify type VI collagen expression in human ovarian follicles during follicular growth. DESIGN: In vitro experiment. SETTING: Department of Obstetrics and Gynecology, Wakayama Medical College, Japan. PATIENT(S): Regularly cycling women who underwent adnexectomy. INTERVENTION(S): Immunohistochemistry and in situ hybridization for human type VI collagen. MAIN OUTCOME MEASURE(S): Expression of type VI collagen. RESULT(S): Expression of type VI collagen was observed in the theca cell layers during folliculogenesis, whereas no expression of type VI collagen was observed in the granulosa cell layers at the mRNA and protein levels. As the follicles grew, immunostaining for type VI collagen became intense in the theca cell layers, especially the theca externa. In preovulatory follicles, however, weak, fragmented, or discontinuous immunostaining of the theca cell layers was observed. This fragmented or discontinuous immunostaining was evident predominantly in the apical area of preovulatory follicles rather than in the basal area. CONCLUSION(S): Type VI collagen is present in the theca cell layers of follicles during folliculogenesis and plays an important role in interactions between the theca cells and extracellular matrix. These interactions may lead to changes in the shape, proliferation, migration, or differentiation of follicular cells during follicular development, maturation, and ovulation.

Adult↗
PubMed1987

Ovarian transforming growth factor-alpha gene expression: immunohistochemical localization to the theca-interstitial cells.

Rat ovaries were examined for the presence of transforming growth factor-alpha (TGF-alpha). Immature diethylstilbestrol-primed rats were treated for 3 days prior to sacrifice with or without FSH. Their ovaries were either fixed in formaldehyde for immunohistochemistry or the RNA was extracted for northern blot analysis. Hybridization with a rat TGF-alpha cDNA probe revealed a 4.5 kilobase mRNA whose abundance was markedly stimulated in the rats treated with FSH. Immunohistochemical staining, using a sequence specific monoclonal antibody to TGF-alpha, MF9, detected immunoreactive TGF-alpha only in the interstitial and theca cells. FSH treatment resulted in no appreciable change in the immunostaining. These results suggest that TGF-alpha is synthesized in the ovary, perhaps in the theca-interstitial compartment.

Animals↗
PubMed2002

Effect of type 3 and type 4 phosphodiesterase inhibitors on the maintenance of bovine oocytes in meiotic arrest.

The use of broad-spectrum inhibitors first suggested that phosphodiesterases (PDEs) are involved in the maturation of bovine oocytes. Modulation of individual PDE families is now possible with the use of newly developed type-specific PDE inhibitors. This study evaluated the role of type 3- and type 4-specific PDE inhibitors on the meiotic arrest of bovine cumulus-oocyte complexes (COCs) and denuded oocytes (DOs). It also evaluated the role of these specific inhibitors on meiotic arrest when COCs are incubated in the presence or absence of theca cell monolayers. Bovine COCs were aspirated from ovaries collected at the abattoir. Denuded oocytes and COCs were incubated for 12 h in culture medium alone or culture medium containing the type 3 PDE inhibitors cilostamide (10 and 20 microM) or milrinone (10 and 50 microM) or the type 4 PDE inhibitor rolipram (10 and 50 microM). Oocytes were then fixed and classified according to the status of nuclear maturation. Cumulus-oocyte complexes were coincubated with untreated theca cell monolayers or theca cell monolayers treated with the different specific PDE inhibitors. Bovine COCs or DOs incubated in culture medium resumed meiosis, but supplementation of the culture medium with the PDE3 inhibitors cilostamide or milrinone resulted in meiotic arrest. On the other hand, supplementation of the culture medium with rolipram did not prevent oocyte maturation. Furthermore, PDE3 inhibitors, but not PDE 4 inhibitors, had an additive effect on the inhibitory action of theca cell monolayers on oocyte maturation. These data support the hypothesis that inhibition of PDE3 prevents the meiotic resumption of bovine oocytes, whereas inhibition of PDE4 does not block oocyte maturation even under normally inhibitory conditions. The additive effect of PDE3 inhibitors on the ability of theca cells to maintain bovine oocytes in meiotic arrest suggests that type 3 PDE has an important role in meiotic resumption of bovine oocytes.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Follicle dynamics and aromatase activity in high-ovulating Meishan sows and in Large-White hybrid contemporaries.

This study compared the dynamics of follicle development during the follicular phase in Meishan sows (n = 10) with a high ovulation rate, with those in contemporary Large-White hybrid sows (n = 12) (ovulation rates: 27.7 and 17.6, respectively; p < 0.01). Ovaries were recovered on Day 16 or 19 of the cycle, and all follicles > or = 1 mm in diameter were dissected. Fluid was aspirated from all those > or = 2 mm, and the granulosa and theca cells were incubated to estimate aromatase activity and estradiol production. The total number of follicles dissected was higher in Meishan than in Large-White hybrid animals (p < 0.001), and whereas the number decreased (p < 0.01) between Days 16 and 19 in Large-White hybrid sows, there was no significant change in Meishan animals. The mean diameter of Meishan follicles recovered on each of Days 16 and 19 was smaller (p < 0.001) than that of those recovered from Large-White hybrids. Total estradiol production in vitro was higher (p < 0.01) by follicles > or = 2 mm from Meishan sows. There was an interaction (p < 0.01) between day of the cycle, breed, and follicle diameter in aromatase activity in both granulosa cells and theca tissue, and in follicular fluid estradiol concentrations in follicles > or = 2-< 6 mm. The largest three size categories of follicles recovered on Day 19 from each breed were classified as preovulatory (29.0 and 17.7 for Meishan and Large-White hybrid, respectively), and the mean diameter was smaller (p < 0.001) in Meishan animals. Follicular fluid estradiol concentrations and total estradiol synthesis by granulosa and theca combined were higher (p < 0.05) in Meishan than in Large-White hybrid sows. In conclusion, high-ovulating Meishans maintained a higher number of follicles during the follicular phase, which overall synthesized more estradiol in vitro, than did Large-White hybrid animals.

Animals↗
PubMed1995

Transforming growth factor alpha gene expression and peptide localization in porcine ovarian follicles.

The present study was undertaken to determine transforming growth factor alpha (TGF alpha) gene expression in various components of medium-sized porcine ovarian follicles by reverse transcription-polymerase chain reaction, and to localize the peptide during folliculogenesis by immunocytochemistry. A strong signal for TGF alpha transcript was detected in cumulus and granulosa cells, whereas the signal in theca cells was very weak but detectable. No TGF alpha mRNA was detected in the oocyte. Immunolocalization studies revealed intense TGF alpha staining in cumulus and granulosa cells of all stages of follicular development. TGF alpha immunostaining was also observed in the oocytes of primordial and primary follicles. In antral follicles, immunostaining was observed only in cumulus and mural granulosa cells, whereas theca cells and oocytes exhibited very little or no detectable staining. TGF alpha immunostaining was absent in follicles undergoing atresia. No TGF alpha immunostaining was observed when the antibody was omitted from the procedure, and the staining was substantially reduced when the primary antibody was preabsorbed with the same mass of TGF alpha peptide, suggesting the specificity of the staining procedure. These results suggest a local follicular production of TGF alpha in the porcine ovary and thus a role for TGF alpha of follicular origin in the regulation of follicular development in an autocrine/paracrine fashion.

Animals↗
PubMed1999

Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary.

Growth differentiation factor-9 (GDF-9), a secreted member of the transforming growth factor-beta superfamily, is expressed at high levels in the mammalian oocyte beginning at the type 3a primary follicle stage. We have previously demonstrated that GDF-9-deficient female mice are infertile because of an early block in folliculogenesis at the type 3b primary follicle stage. To address the molecular defects that result from the absence of GDF-9, we have analyzed the expression of several important ovarian marker genes. The major findings of our studies are as follows: 1) There are no detectable signals around GDF-9-deficient follicles for several theca cell layer markers [i.e. 17alpha-hydroxylase, LH receptor (LHR), and c-kit, the receptor for kit ligand]. This demonstrates that in the absence of GDF-9, the follicles are incompetent to emit a signal that recruits theca cell precursors to surround the follicle; 2) The primary follicles of GDF-9-deficient mice demonstrate an up-regulation of kit ligand and inhibin-alpha. This suggests that these two important secreted growth factors, expressed in the granulosa cells, may be directly regulated in a paracrine fashion by GDF-9. Up-regulation of kit ligand, via signaling through c-kit on the oocyte, may be directly involved in the increased size of GDF-9-deficient oocytes and the eventual demise of the oocyte; 3) After loss of the oocyte, the cells of the GDF-9-deficient follicles remain in a steroidogenic cluster that histologically resembles small corpora lutea. However, at the molecular level, these cells are positive for both luteal markers (e.g. LHR and P-450 side chain cleavage) and nonluteal markers (e.g. inhibin alpha and P-450 aromatase). This demonstrates that initially the presence of the oocyte prevents the expression of luteinized markers, but that the absence of GDF-9 at an early timepoint alters the differentiation program of the granulosa cells; and 4) As demonstrated by staining with either proliferating cell nuclear antigen (PCNA) or Ki-67 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) labeling, the granulosa cells of GDF-9-deficient type 3b primary follicles fail to proliferate but also fail to undergo cell death. This suggests that granulosa cells of type 3b follicles require GDF-9 for continued growth and also to become competent to undergo apoptosis, possibly through a differentiation event Thus, these studies have enlightened us as to the paracrine roles of GDF-9 as well as the normal steps of granulosa cell and theca cell growth and differentiation within ovarian follicles.

Activins↗
PubMed1997

Ovarian granulosa and theca interstitial cells: a morphological and physiological analysis in guanethidine denervated rats at pre-puberty.

Since ovary denervation causes delayed puberty, we investigated the relative importance of ovary innervation on the morphology and physiology of theca interstitial cells (TIC) and granulosa cells (GC) in female rats at pre-puberty. Elimination of the sympathetic innervation was performed by long term post natal treatment with guanethidine (GD), an adrenergic blocking agent. The sympathectomized rats exhibited: reductions in follicular volume (40%), granulosa cells area (43%) and theca interstitial cell volume (50%). Ovarian concentrations of pregnenolone (P5) and progesterone (P4) were decreased whereas no differences were observed in androstenedione (A) and estradiol (E2). The intensity of the immunocytochemical reaction for 3 beta hydroxysteroid dehydrogenase (3 beta-HSD) detected only in interstitial cells, did not show any difference. These in vivo results include the TIC in the bulk of ovarian structures affected by GD denervation at pre-puberty as it was already observed for GC. The reduced area/volume occupied by these cells in the GD treated ovary is associated to a blockade of the initial steps of the steroidogenic pathway, probably at the level of the cholesterol side chain cleavage enzyme (P450 s.c.c.), previously to P5 synthesis, since P5 is reduced. Similar intra ovarian concentrations of androgens are discussed in terms of possible pineal deafferentation promoted by GD at high doses.

Adrenergic Antagonists↗
PubMed2003

Activation of the cAMP-dependent protein kinase signaling pathway by luteinizing hormone in trout theca layers.

In the fish ovary, LH is the main factor regulating the production of steroids during the periovulatory period and its effects are believed to be mediated, at least partially, through the cAMP-dependent protein kinase (PKA) signaling pathway. However, there is no direct evidence for the presence of PKA in the fish ovary nor on the regulation of its activity by fish LH. Here, we show the identification of regulatory (R) and catalytic (C) subunits of PKA in trout theca cells by immunoblotting. DEAE-cellulose chromatography of theca cell extracts indicated the presence of PKA type I and II and showed that trout theca cells display PKA-specific phosphotransferase and cAMP-binding activities. Salmon LH (sLH) stimulated PKA activity and increased the levels of immunoreactive RIIalpha, RIIbeta and C subunits in trout theca layers. These observations, coupled with the sLH-dependent decrease in the half-life of the C subunit, as shown by pulse-chase experiments, strongly suggest that sLH activates PKA in trout theca cells. Furthermore, our results suggest that ovarian PKA activity and its regulation by LH has been well conserved from fish to humans.

Animals↗
PubMed1992

Immunocytochemical localization of transforming growth factors (TGFs) TGF-alpha and TGF-beta in human ovarian tissues.

Light microscopic immunocytochemical technique was utilized in order to elucidate the presence and cellular distribution of transforming growth factors alpha and beta (TGF-alpha and TGF-beta) in human ovarian tissues in different reproductive states using polyclonal antibodies to TGF-alpha and TGF-beta. The results indicated that the ovarian tissue immunostained for both TGF-alpha and TGF-beta. The immunostaining for TGF-alpha was associated with oocytes in the primary follicles, granulosa and theca cell layers, as well as small and large luteal cells. The granulosa cell layers in the small follicles were immunostained for TGF-alpha, but there was very little staining association to the theca cell layers. However, the immunostaining intensity increased in both granulosa and theca cell layers as the size of the follicles increased. The ovarian stroma cells always showed moderate immunostaining. In luteal tissue, both small and large luteal cells immunostained for TGF-alpha and the intensity was similar in both cell types. The immunostaining intensity was similar in both early and midluteal phases and was less than that seen in the granulosa-theca cell layers of the large follicles, and decreased in the late luteal phase. Both corpora albicans and ectopic pregnancy corpora lutea showed a weak immunostaining. Immunostaining of ovarian tissues for TGF-beta indicated that the oocytes of the small preantral follicles stained faintly in the cytoplasm; however, they stained strongly around the nuclear periphery. In small, medium, and large follicles granulosa and theca cell layers immunostained with similar intensity for TGF-beta and its intensity increased with follicular size. The ovarian stroma cells also immunostained for TGF-beta, but with a moderate to low intensity compared with other regions. In luteal tissue, both small and large luteal cells immunostained for TGF-beta and its intensity was similar in early and midluteal phases and reduced during the late luteal phase. This immunostaining was reduced as compared to the granulosa-theca cell layers of the follicles. Corpora albicans and ectopic pregnancy corpora lutea also immunostained for TGF-beta; however, the immunostaining intensity was lower than that seen in luteal tissues of early, mid, or late luteal phases. There was strong immunostaining of the luteal fibroblasts and, interestingly, in small and medium size arterioles; endothelial and smooth muscle cells also immunostained strongly for TGF-beta, whereas the large arterioles showed very little or no immunostaining.(ABSTRACT TRUNCATED AT 400 WORDS)

Epidermal Growth Factor↗
PubMed2006

Mevastatin inhibits proliferation of rat ovarian theca-interstitial cells by blocking the mitogen-activated protein kinase pathway.

OBJECTIVE: To evaluate mechanisms involved in mevastatin-induced inhibition of proliferation of ovarian theca-interstitial cells. DESIGN: In vitro study. SETTING: Academic laboratory. ANIMAL(S): Immature Sprague-Dawley female rats. INTERVENTION(S): Ovarian theca-interstitial cells were cultured without and with mevastatin in the presence and absence of serum, mevalonic acid, and/or insulin. MAIN OUTCOME MEASURE(S): Proliferation was assessed by determination of DNA synthesis by thymidine incorporation assay. Activation of extracellular signal-regulated kinase (Erk1/2) and of Akt/protein kinase B (PKB) was determined by ELISA. RESULT(S): Mevastatin induced a concentration-dependent inhibition of theca-interstitial cell proliferation in the absence and in the presence of serum. Inhibitory effects of mevastatin were partly abrogated by mevalonic acid and by insulin. Mevastatin blocked basal and insulin-induced phosphorylation of ERK1/2. In contrast, mevastatin had no significant effect on either basal or insulin-induced phosphorylation of Akt/PKB. CONCLUSION(S): Mevastatin inhibits proliferation of theca-interstitial cells by a mechanism that involves depletion of mevalonic acid and selective inhibition of basal and insulin-induced activity of Erk1/2 pathway, but not Akt/PKB pathway. These effects of mevastatin may be a result of decreased isoprenylation of small GTPases.

Animals↗
PubMed1990

[Autoradiographic study on the distribution of gonadotropin-releasing hormone receptor in the rat ovary].

Autoradiographic studies were undertaken to clarify the distribution and regulatory mechanisms of GnRH receptors in the ovary of the immature rat during sexual maturation. Iodinated GnRH analog (GnRHa) was injected intravenously and the uptake and distribution of the GnRHa in the ovary were examined. The uptake rate for GnRHa in the ovary increased gradually from 7 days to 21 days of age and declined by 49 days of age. The uptake of GnRHa increased in the ovary of the hypophysectomized rat (28 days old) treated with GnRH and decreased in those treated with PMSG. In the autoradiographic study, silver grains were detected in the ovary, that is the theca cells and the interstitial tissue as well as the granulosa cells. GnRHa bound predominantly to the interstitial tissues before 21 days of age, but GnRHa bound to the granulosa cells more than the theca cells and the interstitial tissue after 28 days of age, corresponding with the prepubertal decrease in GnRHa uptake in the ovary. These results suggest that the distribution of GnRH receptor in the ovary changes with follicular development during sexual maturation.

Animals↗