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PubMed1993

Association of immunolocalization of matrix metalloproteinase 1 with ovulation in hCG-treated rabbit ovary.

Matrix metalloproteinase 1, MMP-1, which was previously called interstitial collagenase, is necessary for extracellular matrix reconstruction. The immunolocalization of the latent form of MMP-1 (proMMP-1) was examined in the ovulatory process in hCG-treated (100 iu per animal) rabbit ovaries. Immunoreactive products of proMMP-1 were identified by the avidin-biotin peroxidase complex formation using an anti-rabbit proMMP-1 polyclonal antibody. ProMMP-1 was distributed in the cytoplasm of theca interna cells, theca externa cells, interstitial glands and germinal epithelium throughout ovulation. However, at 9 or 10 h after hCG treatment, this enzyme was identified in several capillary lumina around the apex of preovulatory follicles. In addition, the staining density of immunoreactive products apparently increased in granulosa cells and theca interna cells around the orifice of the ruptured follicle 10 h after the stimulation. These results indicate that the spatiotemporal appearance of proMMP-1 in ovulation may be closely associated with the initiation of rupture of the follicle.

Animals↗
PubMed2005

Insulin and insulin-like growth factors inhibit and luteinizing hormone augments ovarian theca-interstitial cell apoptosis.

Theca-interstitial (T-I) cells play a fundamental role in the control of ovarian function. Steroidogenic activity and growth of the T-I cells are regulated by many paracrine and endocrine factors. However, little is known about the mechanisms controlling T-I death. In an in vitro model of apoptosis, purified rat T-I cells were cultured for 24 h with serum and subsequently for up to an additional 24 h with serum or in serum-free medium with or without insulin, insulin-like growth factors (IGF-I and IGF-II) and LH or 8-bromo-cyclic AMP (8Br-cAMP). Apoptosis was identified by histological assessment of nuclear morphology and by detection of internucleosomal cleavage and quantified by determination of [alpha32P]-dideoxy-ATP 3'-end labeling of low molecular weight DNA. Serum withdrawal resulted in nuclear condensation and fragmentation into apoptotic bodies of T-I cells and led to pronounced DNA cleavage. Insulin (10 nM) protected T-I cells from apoptosis, reducing DNA fragmentation by 39 +/- 8% compared to serum-free controls. IGF-I (10 nM) and IGF-II (10 nM) had comparable antiapoptotic effects, decreasing DNA fragmentation by 55 +/- 9% and 37 +/- 14%, respectively. In contrast, LH (100 ng/ml) and 8Br-cAMP (1 mM) augmented the pro-apoptotic effect of serum withdrawal, increasing DNA fragmentation by 85 +/- 55% and 72 +/- 42%, respectively. The antiapoptotic effects of insulin and IGFs and the pro-apoptotic effect of LH, acting via the cAMP system, may be important in the maintenance of T-I homeostasis. Moreover, excessive levels of insulin and free IGFs may lead to T-I cell hyperplasia characteristic of conditions such as polycystic ovary syndrome.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1977

Cytochemical localization of adenylate cyclase activity in the theca folliculi of the mouse Graafian follicle.

The adenylate cyclase activity in the theca folliculi of the mouse Graafian follicle was investigated using the electron microscopic cytochemistry. Deposits of reaction product are recognized on the plasma membrane of the fibroblast, theca cell and transitional cell from the fibroblast-like cell to the theca cell (partially or incompletely differentiated theca cell) after incubation with adenylyl-imidodiphosphate (AMP-PNP) as an effective substrate for adenylate cyclase. This fact indicates that these cells have the receptor on the plasma membrane, and the adenylate cyclase-cyclic AMP system is important for the steroid secretion or the collagen fiber production. It is difficult to clarify by this method the relationship between the adenylate cyclase activity and the functional differentiation of the theca cell.

Adenylyl Cyclases↗
PubMed2004

Oestrous cycle-regulated expression of inositol 1,4,5-trisphosphate receptor type 2 in the pig ovary.

The inositol 1,4,5-trisphosphate receptor type 2 (IP(3)R-2) is an intracellular Ca(2+) release channel responsible for mobilizing of Ca(2+) from intracellular storage sites and plays a key role in biological processes such as fertilization, cell differentiation, and growth. To study the cell-type-specific IP(3)R-2 expression in porcine ovaries during different phases of the oestrous cycle, we used reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. A total of 24 ovaries from gilts were collected in early luteal, mid-luteal, and follicular phases of the oestrous cycle. When amplified with the primers common to IP(3)R-2, a RT-PCR product of the expected size (approximately 388 bp) was clearly detected in the follicular and early luteal phase of the oestrous cycle, but there was no detectable PCR product in the corpus luteum of the mid-luteal phase of the oestrous cycle. Immunohistochemical studies showed that IP(3)R-2 protein is expressed in granulosa cells and theca cells of growing follicles. IP(3)R-2 immunostaining was first detected during the late pre-antral stage in granulosa and theca cells. Granulosa cell IP(3)R-2 expression increased from the pre-antral to mid-antral stage, but was strongly reduced in pre-ovulatory follicles. In the developing corpus luteum, intense IP(3)R-2 immunostaining was also present in luteal cells, but undetectable in mid-luteal corpora lutea. Furthermore, oocytes, atretic follicles and regressed corpora lutea were negative for IP(3)R-2. Our results indicate that the expression of the IP(3)R-2 protein was downregulated in terminally differentiated granulosa cells of pre-ovulatory follicles when granulosa cells lose follicle-stimulating hormone responsiveness. Therefore, we strongly suggest that IP(3)R-2 may play an important role in the initiation and propagation of intracellular Ca(2+) signals during follicular development of the pig.

Animals↗
PubMed1984

The role of 17 beta-estradiol in the recovery from oviductal prolapse in layers.

Plasma 17 beta-estradiol concentrations, thecal estrogen content, and uterine prostaglandin synthetase activity were measured in healthy and prolapsed hens as well as in layers that recovered after exposure to low intensity lighting (250 or 50 lx). The effect of estradiol benzoate injections (100 ng, 3 X per week) in hens exposed to high intensity light (greater than 500 lx) was also studied. Prolapsed hens had significantly lower plasma 17 beta-estradiol concentrations (60 +/- 12 pg/ml; mean +/- SEM) than recovered (374 +/- 40 pg/ml) or healthy hens (475 +/- 45 pg/ml). Theca cells from recovered hens had a significantly higher content of 17 beta-estradiol (.7 ng/5 X 10(5) cells) than theca cells from normal or prolapsed birds (.3 ng/5 X 10(5) cells). Microsomes prepared from the uteri of prolapsed hens converted significantly less arachidonic acid to prostaglandin metabolites (4.4%) than did microsomes from healthy or recovered birds (9.0%). Treatment of prolapsed hens with estradiol benzoate resulted in 89% of the birds recovering within 3 weeks compared to a 4% recovery rate in the controls. We conclude that restoration of peripheral 17 beta-estradiol concentrations to normal levels was concomitant with recovery in prolapsed birds, and suggest that the estrogen exerts its effect by raising the level of prostaglandin synthetase activity in the uterus.

Animals↗
PubMed1998

Developmental and hormonal regulation of keratinocyte growth factor expression and action in the ovarian follicle.

The developing ovarian follicle is one of the most rapidly proliferating normal tissues in vivo. Mesenchymal-epithelial cell interactions between theca cells and granulosa cells are essential for this follicular expansion. Ovarian hormones (i.e. estrogen and LH) may promote follicular development by regulating the local production of mesenchymal inducer proteins that mediate theca cell-granulosa cell interactions. Recently, theca cells were shown to produce keratinocyte growth factor (KGF) that can act in a paracrine manner to stimulate granulosa cell growth. In this study, the developmental and hormonal regulation of KGF was examined during follicular development in the bovine ovary. Expression of KGF in theca cells and the KGF receptor (KGFR, or splice variant of the fibroblast growth factor family receptor family, FGFR-2) in granulosa cells was examined using RT-PCR. Both KGF and KGFR were detected throughout follicular development in small (<5 mm), medium (5-10 mm), and large (>10 mm) follicles. Quantitative RT-PCR assays were used to determine steady-state levels of KGF and KGFR messenger RNAs. Developmental regulation of KGF and KGFR was analyzed in freshly isolated theca cells and granulosa cells from small, medium, and large follicles. Observations demonstrated that expression of KGF (in theca cells) and KGFR (in granulosa cells) was highest in large follicles. These results suggest that KGF actions are important for the rapid proliferation of granulosa cells in large follicles. Estrogen and LH are the primary endocrine hormones that regulate theca cell function in vivo. Therefore, hormonal regulation of KGF was analyzed by treating serum-free theca cell cultures with estrogen and human CG (hCG, an LH agonist). Results showed that both estrogen and hCG stimulated KGF gene expression in theca cells. These results suggest that estrogen and LH may promote follicular growth (i.e. granulosa cell proliferation), in part, by stimulating the local production of KGF. Effects of KGF on granulosa cell differentiated functions were examined. Treatment with KGF reduced basal levels and FSH-stimulated levels of aromatase activity in bovine and rat granulosa cells. In addition, KGF inhibited the ability of hCG to stimulate progesterone production by granulosa cells. The inhibition of granulosa cell steroid production by KGF was likely the indirect effect of promoting cellular proliferation. Therefore, KGF directly stimulates granulosa cell proliferation and indirectly inhibits granulosa cell differentiated functions. Combined results suggest that theca cell production of KGF may be important for ovarian folliculogenesis. This is the first report of the regulation of KGF expression in the ovary. The developmental and hormonal regulation of KGF and KGFR during folliculogenesis provides evidence that KGF may be important for hormone-induced granulosa cell proliferation. As a result, KGF may be essential for establishing the microenvironment required for oocyte maturation in the ovary.

Animals↗
PubMedDate not supplied

Cellular interactions that control primordial follicle development and folliculogenesis.

Specific factors that mediate local cell--cell interactions in the ovary related to the initiation and progression of follicle development will be discussed. Recently, several factors produced locally by the primordial follicle have been shown to induce primordial follicle development from a quiescent state to promote follicle development. Kit ligand/stem cell factor (KL/SCF) produced by the immature granulosa cells appears to promote theca cell organization. Basic fibroblast growth factor produced predominately by the oocyte, but by all cells at reduced levels, also was found to induce primordial follicle development similar to KL. It is likely that numerous locally produced factors will mediate cellular interactions and interact between each other to control the induction of primordial follicle development and influence processes such as the onset of puberty and menopause. After follicle development has been induced, theca cells and granulosa cells interact through classical mesenchymal-epithelial type interactions to influence the progression of follicle development. Mesenchymally derived theca cells have been shown to produce transforming growth factor alpha (TGF-alpha), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and transforming growth factor beta to regulate granulosa cell growth and function. The epithelial granulosa cells have been show to produce KL/SCF that can feed back on the theca cells to regulate theca cell growth and stimulate the production of the theca cell factors (TGF-alpha, KGF, and HGF). Therefore, a positive feedback loop between the theca cells and granulosa cells appears to exist to promote the dramatic cell growth required during folliculogenesis. Interestingly, hormones such as estrogen and gonadotropins stimulate the expression of these paracrine growth factors. Therefore, the actions of hormones to stimulate follicle development and growth are mediated in part through altering these local cell--cell interactions. In summary, the locally produced paracrine factors that mediate cell-cell interactions involved in primordial follicle development and the progression of follicle development during folliculogenesis are starting to be elucidated.

Cell Communication↗
PubMed1981

The role of gonadotropins and testosterone in progesterone production by human ovarian granulosa cells.

Granulosa and theca cells obtained from patients were isolated and cultivated in a chemically defined medium containing gonadotropins and/or testosterone. Progesterone secretion by granulosa cells was consistently stimulated (2-40-fold) in all 5 patients by the addition of follicle-stimulating hormone (FSH, 0.25 micrograms/ml). In the presence of testosterone (0.5 micro M) alone, progesterone production was stimulated (2-8-fold) in 4 out of the 5 patients and cells of one patient showed a greater response to testosterone than to FSH alone. In 2 of the 5 patients, it was also noted that FSH and testosterone acted in a synergistic manner to stimulate the production of progesterone by granulosa cells. On the other hand, human chorionic gonadotropin (hCG, 1.0 IU/ml) alone failed to exert any significant effect. None of the treatments examined altered the production of progesterone by theca cells. These results suggest a role for FSH and testosterone in regulating progesterone biosynthesis by granulosa cells of the human ovary during follicular development.

Adult↗
PubMed2003

Transforming growth factor-beta isoform expression during bovine ovarian antral follicle development.

Transforming growth factor-beta (TGF-beta) isoforms are important paracrine and autocrine signaling molecules for the regulation of ovarian follicle growth and physiology. Effective communication between the epithelial granulosa cells, the mesenchymal theca cells, and the oocyte is vital for ovarian function and reproductive success. The expression, localization, and regulation of TGF-beta isoforms in the developing bovine follicle was examined using both immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (RT-PCR) procedures. TGF-beta1 protein was found to be present in the granulosa cells of early pre-antral, early antral, and 1-2 mm follicles. Interestingly, there was no visible staining of granulosa cells of 3-5 or 5-10 mm follicles. There was also no TGF-beta1 staining of theca cells. TGF-beta2 and TGF-beta3 staining were present in the granulosa and theca cells of all follicle stages examined. The levels of TGF-beta mRNA expression in granulosa and theca cells from antral follicles was measured using quantitative RT-PCR. For each isoform mRNA expression levels did not change in different sized antral follicles. TGF-beta3 mRNA levels were much higher than those of TGF-beta1 and TGF-beta2 in both granulosa and theca. Expression levels were higher in theca than in granulosa for TGF-beta2 and TGF-beta3. FSH was found to decrease TGF-beta1 mRNA expression in granulosa cells, but had no effect on TGF-beta2 and TGF-beta3. Bovine ovarian follicles were found to have a unique pattern of TGF-beta isoform expression and regulation when compared to other species (i.e., rodent, pig, quail, and human). The similarities and differences between the various species is discussed to help elucidate common functions of TGF-beta in the ovary. In summary, observations demonstrate that as antral follicles develop, TGF-beta3 is the most abundant TGF-beta isoform and TGF-beta1 protein levels decline in large follicles. Granulosa cell TGF-beta1 expression was decreased by FSH and this correlated with reduced levels in large antral follicles. TGF-betas involved in antral follicular growth and development appear to act as paracrine/autocrine signaling molecules having a species-specific pattern of expression.

Animals↗
PubMed2005

The role of cyclic AMP response element binding protein in transactivation of scavenger receptor class B type I promoter in transfected cells and in primary cultures of rat theca-interstitial cells.

In the ovary, lutropin (LH) stimulates the selective uptake and transport of cholesterol for steroid biosynthesis from HDL particles via the scavenger receptor class B type I (SR-BI). Furthermore the expression of SR-BI mRNA in the ovary is stimulated by LH and cyclic AMP (cAMP). Since the promoter of the rat SR-BI gene is devoid of consensus cyclic AMP response element (CRE) sequences, this study examined if cAMP response element binding protein (CREB) plays a role in the transactivation of SR-BI promoter (SR-BIpr). The transactivation of SR-BIpr was examined in transfected 293T cells and human granulosa SVOG-4o cells, and in primary cultures of rat theca-interstitial cells infected with adenoviral constructs containing the SR-BIpr and a luciferase reporter gene. Dose-related increases in SR-BRpr activity ranging from 2- to 4-fold was induces by 293T cells co-transfected with the catalytic subunit of protein kinase A (cPKA). Co-transfections with CREB and cPKA produced a concentration-dependent increase ranging from 6- to 32-fold. The cAMP-mediated transactivation was significantly attenuated by co-transfection with CREB M1, a non-phosphorylatable, dominant-negative form of CREB. An increase in transactivation of SR-BIpr activity was also seen in SVOG-4o cells co-transfected with CREB. In primary cultures of rat theca-interstitial (T-I) cells infected with an adenoviral construct of SR-BIpr, forskolin produced a marked increase in promoter activity. These data indicate that stimulation of the cAMP-PKA-CREB pathway enhances rat SR-BIpr activity and substantiate the role of CREB as an intermediary in this process. The absence of canonical CRE sequences in the rat SR-BIpr suggests that the activation of SR-BI by CREB may occur either through non-canonical CRE sequences or through additional transcription factors that cooperate with CREB in the activation of SR-BI promoter activity.

Animals↗
PubMed2000

Growth differentiation factor-9 stimulates rat theca-interstitial cell androgen biosynthesis.

Growth differentiation factor-9 (GDF-9) was shown recently to be essential for early follicular development, including the appearance of the theca layer. Theca cells provide the androgen substrate for aromatization and estrogen production by granulosa cells. Using biologically active recombinant GDF-9 (rGDF-9) and an androgen-producing immortalized theca-interstitial cell (TIC) line or primary TIC, we have examined the action of this paracrine hormone on theca cell steroidogenesis. The effect of GDF-9 on TIC progesterone synthesis was marginal and inconsistent in the primary cultures. In immortalized theca cells, GDF-9 attenuated the forskolin-stimulated progesterone accumulation. More significantly, this oocyte-derived growth factor enhanced both basal and stimulated androstenedione accumulation in the primary and transformed TIC cultures. The effects of GDF-9 on steroidogenesis by preovulatory follicles were relatively modest. Likewise, it did not affect the maturation of follicle-enclosed oocytes. The effect of GDF-9, an oocyte product, on TIC androgen production suggests a regulatory role of the oocyte on theca cell function and hence on follicle development and differentiation. This direct effect of GDF-9 on thecal steroidogenesis is consistent with its recently demonstrated actions on thecal cell recruitment and differentiation.

Androgens↗
PubMed1995

Detection of in situ localization of long form prolactin receptor messenger RNA in lactating rats by biotin-labeled riboprobe.

Biotinylated riboprobe that specifically hybridized with messenger RNAs (mRNAs) encoding the long form of prolactin receptor (PRLRL) was transcribed from 269 bp Hind III and Xho I fragment of the cytoplasmic domain of PRLRL complementary DNA (cDNA). The probe was used for in situ hybridization to identify tissue localization of PRLRL mRNA in the mammary gland, liver, ovaries and kidneys from lactating rats at 24-36 h after delivery. Histochemical detection of signals by means of horseradish peroxidase (HRP)-labeled streptavidin revealed that the PRLRL gene was expressed on the alveolar epithelial cells and mammary ductal epithelium in the mammary gland, and hepatocytes in the liver. In the ovary, the PRLRL gene was expressed on the luteal cells in the newly formed corpus luteum, granulosa cells and theca cells of follicles at various stages of development, hypertrophied theca cells in the atretic follicle, and secondary interstitial cells, but no signal was observed in the kidney. Biotinylated sense RNA probe did not detect any signals in any of the tissues examined. In situ hybridization with non-radiolabeled probe provided the identification of PRLRL mRNA in the fine tissues, such as follicular epithelium in the ovary, and showed the morphology of individual cells expressing the PRLRL gene. In particular, the diversity of signal intensity in the same mammary gland with different appearances suggested the existence of a local mechanism controlling PRLRL gene expression.

Animals↗
PubMed1993

[Oxygen radicals-superoxide dismutase system and reproduction medicine].

Reactive oxygen species such as superoxide anion (O2-), hydrogen peroxide (H2O2) and hydroxy radical (OH) possess potent oxygen toxicity to cells. Superoxide dismutases (SODs) are metalloenzymes that are essential for dismutation of O2- to H2O2 and O2. SODs are important initial components in the cellular defense against oxygen toxicity since O2- can react with H2O2 to generate single oxygen and hydroxy radicals, which are even more reactive and cytotoxic than O2- or H2O2. In mammalian tissues three superoxide dismutases (SODs) designated Cu,Zn-SOD, Mn-SOD and extracellular SOD exist. These enzymes play an important role in the antioxidant defense system against superoxide anion (O2-) generated in vivo and may be involved in various pathophysiological processes including inflammation, cancer diabetes, aging and ischemia. (1) The role of superoxide anion in ovulation and luteal function was investigated the localization of Cu, Zn-SOD and Mn-SOD in rat and human ovary by immunohistochemical methods. Cu,Zn-SOD was present in granulosa cells of mature Graafian follicles and growing follicles and Mn-SOD was present in luteal cells of the corpus luteum in rat. (2) To investigate the relationship between active oxygen radical-scavenge system and ovulatory mechanism in human. Mn-SOD was found in granulosa cells and theca cells of mature follicles, luteal cells of corpus luteum and epithelial cells of fallopian tubes. Cu,Zn-SOD was localized in theca cells of mature follicles, margin of corpus luteum and epithelial cells of tubal isthmus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

TGF-beta superfamily members and ovarian follicle development.

In recent years, exciting progress has been made towards unravelling the complex intraovarian control mechanisms that, in concert with systemic signals, coordinate the recruitment, selection and growth of follicles from the primordial stage through to ovulation and corpus luteum formation. A plethora of growth factors, many belonging to the transforming growth factor-beta (TGF-beta ) superfamily, are expressed by ovarian somatic cells and oocytes in a developmental, stage-related manner and function as intraovarian regulators of folliculogenesis. Two such factors, bone morphogenetic proteins, BMP-4 and BMP-7, are expressed by ovarian stromal cells and/or theca cells and have recently been implicated as positive regulators of the primordial-to-primary follicle transition. In contrast, evidence indicates a negative role for anti-Mullerian hormone (AMH, also known as Mullerian-inhibiting substance) of pre-granulosa/granulosa cell origin in this key event and subsequent progression to the antral stage. Two other TGF-beta superfamily members, growth and differentiation factor-9 (GDF-9) and BMP-15 (also known as GDF-9B) are expressed in an oocyte-specific manner from a very early stage and play key roles in promoting follicle growth beyond the primary stage; mice with null mutations in the gdf-9 gene or ewes with inactivating mutations in gdf-9 or bmp-15 genes are infertile with follicle development arrested at the primary stage. Studies on later stages of follicle development indicate positive roles for granulosa cell-derived activin, BMP-2, -5 and -6, theca cell-derived BMP-2, -4 and -7 and oocyte-derived BMP-6 in promoting granulosa cell proliferation, follicle survival and prevention of premature luteinization and/or atresia. Concomitantly, activin, TGF-beta and several BMPs may exert paracrine actions on theca cells to attenuate LH-dependent androgen production in small to medium-size antral follicles. Dominant follicle selection in monovular species may depend on differential FSH sensitivity amongst a growing cohort of small antral follicles. Changes in intrafollicular activins, GDF-9, AMH and several BMPs may contribute to this selection process by modulating both FSH- and IGF-dependent signalling pathways in granulosa cells. Activin may also play a positive role in oocyte maturation and acquisition of developmental competence. In addition to its endocrine role to suppress FSH secretion, increased output of inhibin by the selected dominant follicle(s) may upregulate LH-induced androgen secretion that is required to sustain a high level of oestradiol secretion during the pre-ovulatory phase. Advances in our understanding of intraovarian regulatory mechanisms should facilitate the development of new approaches for monitoring and manipulating ovarian function and improving fertility in domesticated livestock, endangered species and man.

Animals↗
PubMed1978

Hormonal regulation of ovarian cellular proliferation.

The steroid hormone estradiol, and the glycoprotein hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are known to be essential for the growth and differentiation of follicles in the ovary. The present study was conducted to determine quantitatively the effects of estradiol, FSH and LH on proliferation of different ovarian cell types (granulosa and theca cells). The immature female hypophysectomized rate sequentially primed with estradiol, FSH and LH was used as the experimental model. Proliferation was assessed by examining changes in total DNA, incorporation of 3H-thymidine into DNA and labeling index in specific cell types. Estradiol and FSH each acted on follicles at different stages of development to stimulate proliferative activity of both granulosa and theca cells. Continued administration of either hormone caused a decrease in the proliferative activity of both cell types. These observations have been interpreted to indicate that estradiol and FSH can each alter the length of the specific phases of the cell cycle. A luteinizing dose of LH caused a cessation of proliferation in luteinizing granulosa cells while stimulating a limited proliferation of theca cells. Absence of the appropriate hormonal stimulus caused both granulosa and theca cells to stop proliferating and the follicles to undergo atresia. These results indicate that, depending upon the state of differentiation of granulosa and theca cells, estradiol, FSH and LH can stimulate or inhibit the ability of these cells to proliferate.

Cell Division↗
PubMed1986

Synergism between granulosa and theca-interstitial cells in estrogen biosynthesis by gonadotropin-treated rat ovaries: studies on the two-cell, two-gonadotropin hypothesis using steroid antisera.

In mammalian ovaries, luteinizing hormone (LH) induces androgen biosynthesis by theca interna cells, whereas both follicle-stimulating hormone (FSH) and LH stimulate aromatase activity by granulosa cells. The joint action of these two types of cell and pituitary hormones forms the basis of a 2-cell, 2-gonadotropin hypothesis for biosynthesis of estrogen. We tested the synergism between these cell types using antisera against the estrogen precursors progesterone and testosterone. Ovaries were obtained from immature rats two days after a single injection of pregnant mare serum gonadotropin (PMSG). Granulosa cells were obtained by puncturing the follicles, and ovarian remnants were dissociated with collagenase to derive cells from the theca interstitium. Granulosa and theca interstitial cells were cultured alone or in combination for 20 h. Granulosa cells secreted negligible amounts of estrogen and testosterone, but contained high aromatase activity. Treatment with both FSH and human chorionic gonadotropin (hCG) increased production of progesterone in granulosa cells. In contrast, theca interstitial cells had negligible aromatase activity. Treatment with hCG, but not FSH, increased androgen production by theca interstitium; the hCG action was further augmented by the inclusion of exogenous progesterone. Furthermore, co-culture of gonadotropin-treated granulosa and theca interstitial cells resulted in substantial increases in estrogen production, indicating synergism between the two types of cell. The increases in estrogen production in the co-cultures were accompanied by decreases in progesterone content. To test the possibility that progesterone released by granulosa cells may serve as a substrate for production of androgen in theca cells, specific antiserum was used to adsorb progesterone present in the medium. Addition of the progesterone antibody inhibited gonadotropin-stimulated production of testosterone (39% decrease) and estrogen (64% decrease) by the combined cell cultures. The inhibitory effect on estrogen production could be reversed by the addition of progesterone (10(-6) M) or testosterone (10(-6) M) but not by the addition of a synthetic progestin, R5020. Since testosterone released from theca cells may serve as the substrate for aromatases in granulosa cells, specific testosterone antiserum was also used. Production of estrogens by the combined cell cultures was inhibited (78%) by the testosterone antiserum, but the inhibitory effect was completely reversed by exogenous testosterone or progesterone. Thus, synergistic interactions between granulosa and theca interstitial cells are important in effecting maximal estrogen biosynthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

[Molecular basis of polycystic ovarian syndrome].

Polycystic ovarian syndrome (PCO) is a relatively poorly defined type of steroidogenic abnormality, dependent on an overproduction of lutropin (LH). The PCO is characterized by infertility, amenorrhea or oligomenorrhea, obesity and hirsutism. The clinical symptoms are associated with typical morphological changes of the ovaries. It has been suggested that hyperplastic secondary interstitial cells and theca cells are the main site of excess androgen production. In PCO the elevation of androgens is observed, while the estrogen level is normal or slightly decreased. In the ovarian sex steroidogenic pathways, 17 alpha-hydroxylase, which produces androgens and aromatase, which converts androgens to estrogens are important regulatory enzymes. Major components of 17 alpha-hydroxylase and aromatase are cytochromes P450 17 alpha and P450 arom. Histochemical investigations revealed increased immunoreactivity with the antibody directed against P450 17 alpha in theca cells. In this review data from literature are presented and discussed regarding endocrinological and molecular background of PCO.

Androgens↗
PubMed1994

Regulation of cell proliferation and estrogen synthesis by ovine LH, IGF-I, and EGF in theca interstitial cells of the domestic hen cultured in defined media.

There is relatively little information on the factors which regulate the proliferation and alterations in the steroidogenic capacity of avian theca cells during follicular maturation. The development of culture conditions for these cells to determine the effects of gonadotrophin (LH) and the growth factors epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) on DNA synthesis and estrogen production is reported. Cultures were established in serum-supplemented (with fetal calf serum or chicken serum) or ITS+ (insulin, transferrin, and selenium plus additives) supplemented serum-free media. Cell replication occurred throughout the 72-hr culture period as indicated by a linear increase in the DNA content of the culture dishes. Aromatase activity of the cells as defined by conversion of androstenedione to estrogen was best maintained in serum-free medium while sera inhibited this activity. Ovine LH enhanced the aromatase activity of cultured cells from medium and small-sized follicles, while IGF-I and EGF inhibited both basal and LH-stimulated aromatase activity. LH, IGF-I, and EGF all stimulated cell proliferation as reflected by increased DNA. The responses of cells to these peptides varied with the size of the follicle, with the greatest effects on cells from F4/5.

Androstenedione↗