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Biomedical subjects

J Rabinovici

Publications and source records attributed to J Rabinovici.

At least 37 records · Page 2Linked to original sources
PubMed1994

Induction of aromatase in human granulosa cells by both follicle stimulating hormone and insulin-like growth factor-I involves tyrosine phosphorylation.

Evaluation of the intracellular signalling mechanisms of follicle stimulating hormone (FSH) and insulin-like growth factor-I (IGF-I) was performed in luteinized and non-luteinized human granulosa cells. A severalfold increase in estradiol production from androstenedione was induced by both hormones in these cells, while only FSH led to a concomitant increase in cAMP. IGF-I bound specifically to its receptor in these cells. Specific tyrosine kinase inhibitors (tyrphostins) blocked the effects of both FSH and IGF-I on aromatase activity without altering FSH-induced cAMP accumulation. These findings demonstrate an involvement of a tyrosine kinase pathway in the intracellular signalling mechanism of the IGF-I effect on aromatase activity. Furthermore, since FSH induction of aromatase activity can be blocked by a tyrosine kinase inhibitor without affecting the level of cAMP production, it can be suggested that tyrosine kinase(s) act downstream of cAMP production and protein kinase A activation.

Adenylyl Cyclases↗
PubMed1993

Endogenous catecholamines augment the inhibitory effect of opioids on luteinizing hormone secretion during the midluteal phase.

OBJECTIVE: Our purpose was to test the hypothesis that endogenous catecholamines may interact with endogenous opioid peptides to influence gonadotropin secretion during the midluteal phase in normal women. STUDY DESIGN: Normal cycling women studied during the midluteal phase were randomized to one of four treatment groups: (1) alpha-methyl-para-tyrosine, (2) naloxone, (3) alpha-methyl-para-tyrosine and naloxone, and (4) control. Mean treatment luteinizing hormone levels were compared by analysis of variance. Pulse frequency, amplitude, and integrated area under the curve were assessed by CLUSTER analysis and compared by means of nonparametric analyses. RESULTS: Mean luteinizing hormone levels were significantly higher in the naloxone and alpha-methyl-para-tyrosine plus naloxone groups compared with alpha-methyl-para-tyrosine or placebo. Coadministration of alpha-methyl-para-tyrosine and naloxone caused a significant increase in large-burst luteinizing hormone pulses compared with the group receiving naloxone only. CONCLUSION: Endogenous catecholamines augment the inhibitory effect of opioids on luteinizing hormone secretion during the midluteal phase in normal cycling women.

Adolescent↗
PubMed1993

Complete failure of fertilization in couples with unexplained infertility: implications for subsequent in vitro fertilization cycles.

OBJECTIVE: To determine whether complete failure of fertilization of oocytes in couples with unexplained infertility persists during subsequent in vitro fertilization (IVF) cycles. DESIGN: A retrospective study of 120 cycles of IVF in 44 couples with unexplained infertility and complete failure of fertilization during their first IVF trial. SETTING: In vitro fertilization unit of the Sheba Medical Center. PATIENTS: Forty-four couples undergoing IVF for unexplained infertility. MAIN OUTCOME MEASURE(S): Fertilization rate of retrieved oocytes and pregnancy rate. RESULTS: Of the initial 44 couples, 37 underwent additional IVF cycles and 30 (81.1%) achieved fertilization. Seven patients conceived during the study period as a result of IVF and two conceived spontaneously. CONCLUSIONS: Complete failure of fertilization does not necessarily persist during subsequent IVF cycles. Therefore, at least two more IVF cycles should be attempted before reverting to other therapeutic options. However, although fertilization can be achieved in most couples, the mean oocyte fertilization rate during subsequent cycles in this group is low. This suggests an underlying undiagnosed pathology of oocyte/sperm interaction in some of these patients.

Female↗
PubMed1993

The differential effects of FSH and LH on the human ovary.

The basic foundation for normal puberty and adult reproductive function is established during fetal life with the adequate development of the hypothalamus, pituitary and gonads. Further maturation and differentiation of the hypothalamic-pituitary-gonadal axis continues throughout childhood, puberty, adult life and senescence. Pituitary FSH and LH play a central role in the cascade of events in the hypothalamic-pituitary-gonadal axis by mediating between the brain and hypothalamus on one hand and the end-organ, the ovary, on the other. Absent or low pituitary secretion of FSH and LH, as occurs in hypothalamic/pituitary hypogonadism, leads in women to anovulation, amenorrhoea and absent ovarian follicular development. The ability of gonadotrophins to modulate ovarian function depends on their rate of synthesis by the pituitary gonadotrophs, on their circulating concentrations (which vary throughout life and throughout the menstrual cycle), on the relative abundance of the multiple forms of gonadotrophins that have varying biological activity, on the presence of their receptors on the different cell types of the ovary, on the intracellular adenylate cyclase enzyme that causes the production of cAMP, and on the extra- and intragonadal factors that are able to modulate the effects of gonadotrophins in the ovary. Recent clinical and basic research with recombinant gonadotrophins, molecular biological studies on the localization, function and regulation of the long sought after gonadotrophin receptors, as well as research on the interaction between gonadotrophins and local intragonadal factors have widened our knowledge about the function and role of FSH and LH in the ovary and have provided new insights into previously unanswered questions of ovarian physiology and pathophysiology and will provide the basis for the design of new treatment strategies to overcome ovulatory gonadotrophin-dependent dysfunction in the future.

Animals↗
PubMed1992

Activin-A as an intraovarian modulator: actions, localization, and regulation of the intact dimer in human ovarian cells.

The actions, localization, and regulation of activin in the human ovary are unknown. Therefore, the aims of this study were (a) to define the effects of recombinant activin-A and its structural homologue, inhibin-A, on mitogenesis and steroidogenesis (progesterone secretion and aromatase activity) in human preovulatory follicular cells; (b) to localize the activin-A dimer in the human ovary by immunohistochemistry; and (c) to examine regulation of intracellular activin-A production in cultured human follicular cells. In addition to stimulating mitogenic activity, activin-A causes a dose- and time-dependent inhibition of basal and gonadotropin-stimulated progesterone secretion and aromatase activity in human luteinizing follicular cells on day 2 and day 4 of culture. Inhibin-A exerts no effects on mitogenesis, basal or gonadotropin-stimulated progesterone secretion and aromatase activity, and does not alter effects observed with activin-A alone. Immunostaining for dimeric activin-A occurs in granulosa and cumulus cells of human ovarian follicles and in granulosa-lutein cells of the human corpus luteum. cAMP, and to a lesser degree human chorionic gonadotropin and follicle-stimulating hormone, but not inhibin-A, activin-A, or phorbol 12-myristate 13-acetate, increased the immunostaining for activin-A in cultured granulosa cells. These results indicate that activin-A may function as an autocrine or paracrine regulator of follicular function in the human ovary.

Activins↗
PubMed1992

Activin and inhibin in the human adrenal gland. Regulation and differential effects in fetal and adult cells.

Recent experimental data have revealed that activins and inhibins exert pivotal effects on development. As part of our studies on growth and differentiation of the human fetal adrenal gland, we examined the subunit localization, as well as the mitogenic and steroidogenic actions of activin and inhibin in human fetal and adult adrenals. All three activin and inhibin subunit proteins (alpha, beta A, and beta B) were detected in the fetal and adult adrenal cortex. Immunoreactive activin-A dimer was demonstrated in midgestation fetal and neonatal adrenals. ACTH1-24-stimulated fetal adrenal cell expression of alpha and beta A subunit messenger RNA. In addition, ACTH elicited a rise in levels of immunoreactive alpha subunit secreted by fetal and adult adrenal cells. Human recombinant activin-A inhibited mitogenesis and enhanced ACTH-stimulated cortisol secretion by cultured fetal zone cells, but not definitive zone or adult adrenal cells. Recombinant inhibin-A had no apparent mitogenic or steroidogenic effects. Thus, activin selectively suppressed fetal zone proliferation and enhanced the ACTH-induced shift in the cortisol/dehydroepiandrosterone sulfate ratio of fetal zone steroid production. These data indicate that activin-A may be an autocrine or paracrine factor regulated by ACTH, involved in modulating growth and differentiated function of the human fetal adrenal gland.

Activins↗
PubMed1992

Localization and regulation of the activin-A dimer in human placental cells.

Subunits of activin and inhibin and their mRNAs are present in human placental and decidual cells. However, evidence for the presence of intact activin dimers in the human placenta and their regulation has been lacking. Using a monoclonal antibody raised against the human activin-A dimer, we examined the cellular localization of immunoreactive activin-A dimer in human placentas of different gestational ages (8-41 weeks). In addition, we determined the effects of culture and various potential regulators on the cellular accumulation of immunoreactive activin-A dimer in trophoblast cells from human first trimester placentas. Activin-A dimer was found in both cyto- and syncytiotrophoblast cells of all gestational ages studied. Immunoreactive activin-A also was detected in placental Hofbauer cells in first and second trimester placentas as well as in cells of the placental membranes. Exposure of these cells to cAMP, GnRH, activin, inhibin, transforming growth factor-beta, dexamethasone, and interleukin-1 did not significantly change the intensity of immunostaining for activin-A dimer. These results together with previous data suggest that placental cells are a source of activin-A and that activin-A may be a paracrine and/or endocrine regulator of feto-maternal interactions during pregnancy.

Activins↗
PubMed1992

Insulin-like growth factor-I and follicle-stimulating hormone suppress insulin-like growth factor binding protein-1 secretion by human granulosa-luteal cells.

Local regulation of insulin-like growth factor binding protein-1 (IGFBP-1) production in the human ovarian follicle was investigated using cultured human granulosa-luteal cells. Both insulin-like growth factor-I (IGF-I) and follicle-stimulating hormone (FSH) exerted a dual effect on granulosa cells: while estradiol (E2) production was increased by both stimulants, the addition of either of the two hormones led to a reduction in IGFBP-1 secretion by more than 50%. Inhibition of IGFBP-1 production in response to IGF-I was dose-dependent,with the highest effect observed at 5 nM IGF-I. A significant correlation was found between the increase in E2 and inhibition of IGFBP-1 secretion in response to IGF-I. These observations may suggest a novel mechanism, at the follicular level, by which FSH and IGF-I amplify the IGF-I effect in the ovarian follicular cells.

Carrier Proteins↗
PubMed1992

Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (Ganirelix) with minimal histamine-releasing properties: studies in postmenopausal women.

A potent and safe GnRH antagonist has been sought unsuccessfully for the last 2 decades. The recently developed GnRH antagonist RS-26306 or Ganirelix ([N-Ac-D-Nal(2)1,D-pClPhe2,D-Pal(3)3,D-hArg(Et2)6,L-++ +hArg(Et2)8,D-Ala10]GnRH ; Syntex Research, Palo Alto, CA), exhibited high antiovulatory potency and low histamine-releasing properties in preclinical studies. Therefore, we determined the extent to which single sc injections of three doses of RS-26306 (1, 3, and 6 mg) decreased serum concentrations of LH and FSH, the free alpha-subunit of LH/FSH/TSH, PRL, and testosterone in five healthy postmenopausal women. We also examined the pharmacokinetic characteristics of RS-26306 by quantifying serum levels of the drug by RIA. RS-26306 rapidly suppressed serum concentrations of LH, FSH, and free alpha-subunit. RS-26306 (6 mg) maximally decreased serum concentrations (mean +/- SEM) of LH, FSH, and free alpha-subunit by 70.1 +/- 3.6%, 42.3 +/- 2.5%, and 74.6 +/- 3.5%, respectively. RS-26306 also decreased serum testosterone, but not serum PRL, concentrations. RS-26306 concentrations reached peak serum levels at 1.2 +/- 0.3, 1.9 +/- 0.4, and 1.8 +/- 0.5 h, respectively, after 1-, 3-, and 6-mg sc injections. The mean serum half-life values based on the terminal portion of the disappearance curves were 22.8 +/- 2.5 and 26.9 +/- 1.0 h, respectively, after 3- and 6-mg s.c. doses. No systemic side-effects were noted after the administration of RS-26306. Our results demonstrate that the GnRH antagonist RS-26306 has favorable pharmacokinetic characteristics and is a potent suppressor of pituitary gonadotropin secretion in postmenopausal women. These attributes and the lack of systemic side-effects make RS-26306 a promising candidate for future clinical applications.

Aged↗
PubMed1991

Platelet-activating factor induces progesterone secretion and changes in morphological appearance in luteinizing granulosa cells in vitro.

OBJECTIVE: Recent evidence indicates the involvement of platelet-activating factor (PAF) in ovarian periovulatory processes. The objective of this study was to investigate the influence of PAF on ovarian follicular cellular function. DESIGN AND INTERVENTIONS: We examined the effects of PAF on progesterone (P) secretion by cultured human luteinizing granulosa cells obtained from women undergoing in vitro fertilization. Follicular cells were cultured in serum-free conditions for 12 to 36 hours with and without PAF (at dosages of 10(-8) to 10(-14) M). RESULTS: Progesterone secretion was significantly increased at 12 and 36 hours after treatment with 10(-8) M PAF (170% +/- 40% and 210% +/- 40%, respectively) and with 10(-10) M PAF (170% +/- 30% and 180% +/- 10%, respectively). Smaller increases were seen with 10(-12) and 10(-14) M PAF. Maximal increases in P secretion in 10(-10) M PAF-treated wells occurred at 3 to 12 hours. At 36 hours, distinct morphological differences between cells in control wells and those containing PAF were noted. CONCLUSIONS: These results indicate that PAF may influence follicular cell function during ovulation and corpus luteum formation.

Cells, Cultured↗
PubMed1991

Inhibition of endogenous catecholamine synthesis augments early follicular phase luteinizing hormone secretion.

The physiological role of catecholamines, particularly dopamine and norepinephrine, in the regulation of gonadotropin secretion in humans is unclear. We administered the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT, 500 mg at 800 and 1000 h) to five women in the early follicular phase of the menstrual cycle and compared LH secretion patterns to those in five untreated controls. Commencing at 800 h, blood was drawn every 15 min for LH and PRL measurements until 1600 h. AMPT elevated PRL concentrations (mean +/- SEM) from a baseline of 14.72 +/- 2.51 micrograms/L to a peak of 102.2 +/- 24 micrograms/L. LH concentrations [21.97 +/- 0.56 (AMPT) vs. 13.51 +/- 0.16 IU/L (control), P less than 0.0001], LH area under the curve [11014 +/- 1815 (AMPT) vs. 7009 +/- 404 IU.min/L (control), P = 0.05] and LH pulse amplitude [9.99 +/- 2.38 (AMPT) vs. 4.03 +/- 0.61 IU/L (control), P = 0.04] were all greater in the group in which catecholamine synthesis was inhibited. There was no difference in pulse frequency between the groups (7.4 +/- 0.51 vs. 6.6 +/- 0.24 pulses/8 h, P greater than 0.05). We conclude 1) inhibition of endogenous catecholamine synthesis augments LH levels in the early follicular phase, and 2) increased LH secretion during catecholamine synthesis inhibition is due, at least in part, to increased LH pulse amplitude but not increased LH pulse frequency.

Catecholamines↗
PubMed1991

Localization and secretion of inhibin/activin subunits in the human and subhuman primate fetal gonads.

Little is known about the ability of the fetal primate gonads to produce inhibin/activin. We investigated the presence of the alpha-, beta A-, and beta B-subunits of inhibin/activin in fetal human (16-23 weeks gestational age) and rhesus monkey (days 150-157 of gestation; term = 165 days) testes and ovaries by immunocytochemistry. The regulation of alpha-inhibin secretion by gonadotropins was studied in fetal testicular cultures. In the human fetal testis, alpha-subunit immunostaining was found in interstitial and intratubular cells, while beta A- and beta B-subunit immunostaining occurred in clusters of Leydig cells that were clearly demarcated from groups of Leydig cells that were immunonegative. In the late gestational monkey testis, the alpha-subunit was localized in tubular cells, and the beta B-subunit was present in the tubules and interstitium. Testicular cells from midgestation human testes secreted detectable immunoreactive alpha-inhibin in response to FSH and hCG stimulation; alpha-inhibin levels were significantly higher after hCG than FSH. In contrast, levels of alpha-inhibin secreted by rhesus monkey testicular cells were significantly increased by FSH, but not hCG. In the ovary, only weak beta B-subunit immunoreactivity was detected in granulosa cells of a few primary follicles from midgestational human fetal ovaries. In contrast, all three subunits were found in granulosa cells of numerous primary and secondary follicles in the late gestation rhesus monkey ovary. In light of recent evidence that inhibins/activins have actions on gonadal differentiation and growth modulation in vitro, as well as endocrine effects on the fetal pituitary, we propose that these proteins may have intragonadal and endocrine roles in human and subhuman intrauterine gonadal development.

Activins↗
PubMed1990

Insulin-like growth factor I (IGF-I) levels in follicular fluid from human preovulatory follicles: correlation with serum IGF-I levels.

Insulin-like growth factor I (IGF-I) levels were measured in both serum and fluid of preovulatory follicles (n = 156) in 43 women undergoing in vitro fertilization (IVF). The mean IGF-I level in follicular fluid (FF) was significantly lower than in serum (0.52 +/- 0.02 IU/L versus 0.66 +/- 0.23 IU/L), and FF levels were significantly correlated with individual serum IGF-I levels as well as with follicular size and FF volume but not with oocyte maturity, granulosa cell appearance, or IVF. This suggests that FF IGF-I levels cannot serve as a clinical indicator for the degree of oocyte/granulosa cell differentiation or a predictor for IVF. Serum IGF-I levels were inversely correlated with the number of human menopausal gonadotropin ampules administered during treatment, suggesting that IGF-I might enhance ovarian gonadotropic stimulation.

Estradiol↗
PubMed1990

Development and regulation of growth and differentiated function in human and subhuman primate fetal gonads.

We have attempted to summarize the research on primate fetal gonadal development that has occurred over the past three decades. Many similarities exist between fetal gonadal development in human and subhuman primates; therefore, comparisons and analogies between these species can be made. Fetal gonadal development is a complex process dependent on timely maturation and differentiation of several cell types with different functions. Adequate development is important for normal sexual development and intact adult fertility potential as well as for intrauterine priming of neural centers in the central nervous system. While the fetal primate testis is active in steroidogenesis, the fetal ovary seems to be quiescent throughout most of gestation, although some ovarian steroidogenic enzymes have been demonstrated. Growth and development of both gonads are controlled during late gestation at least in part by pituitary hormones, while earlier in gestation other yet undefined regulators (placental, intragonadal) likely also are active. The main goal of this review was to demonstrate that gonadal growth and differentiation, both in males and females, is regulated by endocrine factors as well as by intragonadal, autocrine/paracrine agents. Although many parts of the puzzle are still missing it is probable that, similar to fetal development of other endocrine tissues and to events in postnatal gonads, these local regulators have important functions. Currently, primate fetal gonadal research is lacking in at least two key aspects: 1) the definition of paracrine and autocrine nonsteroidal factors that are involved in the regulation of gonadal growth and differentiation in vitro; and 2) in vivo studies in subhuman primates that might better help to clarify the biological roles of the multiple extra- and intragonadal hormones and their complex interactions. To date, the regulation of gonadal steroidogenesis has been investigated more thoroughly than the regulation of gonadal growth. Most of our knowledge stems from observations of gonadal development in anencephalics or subhuman primates after pituitary ablation. Because of the constraints of small organ size and limitation of material, studies of fetal primate gonadal development have been limited. Given such limitations, new molecular biological techniques, including polymerase chain reaction and in situ hybridization, may provide the means of addressing these questions. Further, because of these limitations, sensitive cell separation techniques need to be developed to achieve enriched primary gonadal cell cultures from individual gonads.

Animals↗
PubMed1990

Steroid secretion by granulosa cells isolated from a woman with 17 alpha-hydroxylase deficiency.

Steroid synthesis in luteal/granulosa cells harvested after follicular aspiration in a patient with 17 alpha-hydroxylase deficiency was investigated. Follicular stimulation with purified FSH after the suppression of ACTH and gonadotropin secretion by corticoid analogs and superactive GnRH agonist permitted ovum pick-up and the study of steroid synthesis in the obtained granulosa cells. Progesterone synthesis was elevated while 17 alpha-hydroxy progesterone, testosterone, androstenedione, and estrogen production was minimal. Aromatase activity was retained in these cells, as demonstrated by the 100-fold increase in estrogen levels after the addition of androgens. Progesterone levels in follicular fluids were in the normal range, while estrogen, 17 alpha-hydroxy progesterone, and androgen levels were minimal. These results provide in vitro evidence of 17 alpha-hydroxylase deficiency in the granulosa cells of this patient.

Adrenal Hyperplasia, Congenital↗
PubMed1990

Recombinant human activin-A promotes proliferation of human luteinized preovulatory granulosa cells in vitro.

Ovarian granulosa cells synthesize and secrete activin, a member of the transforming growth factor-beta (TGF-beta) peptide family, during the follicular phase of the menstrual cycle. We examined the growth-promoting activity of human recombinant activin-A on human luteinized preovulatory granulosa cells obtained from women undergoing in vitro fertilization. Activin-A induced proliferation of granulosa cells on day 5 of culture in a dose-dependent manner. Maximal effects were seen at concentrations greater than or equal to 100 ng/mL with an ED50 of 15 ng/mL. We suggest that activin-A is able to modulate growth of ovarian granulosa cells.

Activins↗