PubMed Health⌕ Search

Biomedical subjects

R H Asch

Publications and source records attributed to R H Asch.

At least 127 records · Page 7Linked to original sources
PubMed1985

The antiprogesterone steroid RU-486 does not impair gonadotropin-stimulated luteal adenylyl cyclase activity or gonadotropin release by pituitary cells.

Administration of the antiprogesterone synthetic steroid RU-486 (17 beta-hydroxy-11 beta-[4-dimethylaminophenyl-1]-17 alpha-[prop-l-ynyl]-estra-4,9-dien-3-one) in human and non-human primates induces menstruation and is promising as a new approach to fertility control. To explore the sites of action of RU-486, we investigated in this study the effects of RU-486 upon gonadotropin-stimulable adenylyl cyclase in membrane preparations obtained from human corpus luteum and upon LH and FSH release by a dispersed rat anterior pituitary cell culture. In the presence of a wide range of concentrations (10(-10) to 10(-6) M), RU-486 failed to alter basal or hCG-stimulated adenylyl cyclase activities under conditions allowing either maximal or submaximal hormonal activation. Additionally, enzyme stimulation by GMP-P(NH)P (100 microM), NaF (10 mM) or forskolin (100 microM) was not affected by a high concentration (10(-6) M) of RU-486. These data indicate that RU-486 does not affect gonadotropin receptor binding nor does it interfere with cAMP generation. It is unlikely, therefore, that the compound may modulate human luteal function through changes in plasma membrane lipid mobility or modifications of reactions occurring in plasma membranes as suggested for other steroids in several membrane systems. The present observations are compatible with previously published in vivo studies suggesting that RU-486 activity does not involve a direct antigonadotropic effect at the primate corpus luteum level. We also found that RU-486 (10(-12) to 10(-7) M) did not alter the basal release of gonadotropins by the pituitary cells, nor did the compound impair the response of these cells to maximally or submaximally effective concentrations of LHRH. Thus, these data suggest that the anti-reproductive actions of RU-486 involve no direct effect upon pituitary function. Taken together, these findings support the concept that RU-486 exerts its effects on the luteal phase exclusively by a local action upon the endometrium.

Adenylyl Cyclases↗
PubMed1985

The effects of RU486 on the luteal phase of the rhesus monkey.

RU486 is a steroid which possesses great affinity for the progesterone (P) receptor, but which has no P activity. It has been shown to be, as a result, a potent P antagonist. In the present study, we investigated the effect of this compound on the luteal phase of the rhesus monkey. The day of ovulation was diagnosed with a +/- 12 h accuracy, using serial laparoscopies and serum estradiol (E2) determinations, in regularly cycling rhesus monkeys. RU486 was administered by gavage (10 mg daily) in different regimens during the luteal phase: Group 1, days 1-5; Group 2, days 5-9; Group 3, days 9-13; and Groups 4, days 9-13, plus hCG (30, 60, 90, 180 and 360 IU i.m. on days 6-10). RU486 induced vaginal bleeding within 24-72 h after the initial administration in Groups 1-3. Animals of Group 4 presented luteal lengths ranging from 9-12 days. Progesterone concentrations at the onset of vaginal bleeding were 2.1 +/- 0.3, 4.9 +/- 0.6, 2.6 +/- 0.4 and 11.2 +/- 1.5 ng/ml (x +/- SEM) for animals of Groups 1-4, respectively. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), E2 and P levels were not altered during treatment. The availability of a compound such as RU486, that consistently induces vaginal bleeding due to its action at the target level (endometrium) without affecting the hormonal events of the menstrual cycle, opens a new approach to post-coital and interceptive contraception.

Abortifacient Agents, Steroidal↗
PubMed1985

Opposite effects of ethanol on the activation of adenylyl cyclase in human corpus luteum membranes.

The influence of an acute exposure to ethanol on adenylyl cyclase activity in membrane fractions prepared from human corpus luteum was investigated. Ethanol up to a concentration of 5% (v/v) was without effect on basal luteal adenylyl cyclase activity, but markedly potentiated stimulation of NaF and hCG in a dose-dependent manner. In contrast, ethanol progressively inhibited forskolin stimulation at the same range of ethanol concentrations. Maximal NaF and hCG responsiveness of adenylyl cyclase activity was observed at 5% ethanol and reached values 80% and 100% higher than controls without ethanol, respectively. However, at the same ethanol concentration, forskolin-stimulated enzymatic activity was reduced by 40% relative to controls. Equilibrium binding studies involving [125I]hCG interaction with luteal membranes in the presence of the concentration of ethanol showing maximal hCG responsiveness indicated that ethanol slightly affected (15% increase) the hCG binding compared to controls, without any appreciable change on the Kd for the hormone. This minor effect of ethanol on gonadotropin binding sites contrasted greatly with the extent at which ethanol maximally potentiated the gonadotropin-stimulated adenylyl cyclase. GTP was found to be less effective than GMP-P(NH)P in sustaining ethanol potentiation, suggesting that ethanol is unlikely to act by inhibiting GTPase activity. These data indicate that the acute effects of ethanol inhibit forskolin-stimulated adenylyl cyclase at concentrations potentiating stimulatory effects of NaF and of hCG, and that the synergistic interaction of ethanol and gonadotropin stimulation of adenylyl cyclase is, at least in part, due to an increase in the functional coupling of the occupied hCG-receptor complex with the components of the enzyme system.

Adenylyl Cyclases↗
PubMed1985

Studies of a controlled-release microcapsule formulation of an LH-RH agonist (D-Trp-6-LH-RH) in the rhesus monkey menstrual cycle.

It has been shown that continuous administration of LH-RH agonists inhibits ovulation in many species, including human and nonhuman primates. However, the need of daily injections or intranasal application of the LH-RH agonists makes this contraceptive approach impractical. In addition, due to the repeated daily administration of the LH-RH analogues and their bioavailability, serum levels of gonadotropins and estradiol present wide variations and are often associated with irregular bleeding and/or endometrial hyperplasia. This experiment was designed to study the effects on ovulation and the hormonal profile during the rhesus monkey menstrual cycle of a system that continuously delivers a potent agonist of LH-RH (D-Trp-6-LH-RH encapsulated in poly [DL-lactide-co-glycolide]). Subjects were divided into two groups: On day 1 of the cycle, monkeys received a single subcutaneous injection of microcapsules containing D-Trp-6-LH-RH at a release rate of 13.6 micrograms/day (Group 1) or placebo microcapsules (Group 2). Ovulation dates were significantly delayed in animals from Group 1 (50 +/- 3 days) as compared to those in group 2 (20 +/- 2 days). Luteal phases following ovulation were normal in animals of both groups, as determined by length and serum progesterone levels. No significant differences on baseline levels of FSH and LH were observed between the two groups of animals. Post-treatment cycles were ovulatory and presented normal luteal phases and hormone concentrations as compared to the non-treated animals of our colony. The present data show for the first time that a controlled-release microcapsule formulation that delivers an agonist of LH-RH can effectively suppress ovulation when injected in a single dose in non-human primates.

Animals↗
PubMed1984

Etiology of infertility in monkeys with endometriosis: measurement of peritoneal fluid prostaglandins.

To study the relationship between peritoneal fluid prostaglandins and infertility associated with endometriosis, we autografted endometrial or adipose tissue to the pelvic peritoneum in 21 monkeys. Peritoneal washings were collected prior to tissue transplantation and during a subsequent laparotomy performed for biopsy of the implants. Monkeys were mated and peritoneal washings were collected during three subsequent cycles. The content of prostaglandin F2 alpha (PGF2 alpha) in adipose tissue autografts was significantly less (p less than 0.05) than in endometrial tissue autografts. The PGF2 alpha concentration in peritoneal fluid increased significantly (p less than 0.05) only in monkeys that developed moderate or severe endometriosis. Prostaglandin E levels in tissue autografts or peritoneal fluid were similar in all animals. Infertility in monkeys with endometriosis was associated with luteinized unruptured follicles, luteal phase defects, and pelvic adhesions. Although PGF2 alpha concentrations in peritoneal washings obtained during these cycles were increased in comparison with those of ovulatory cycles, the difference was not significant. A relationship between spontaneous abortion and prostaglandin concentrations in peritoneal fluid was not established.

Animals↗
PubMed1984

Day:night variations of melatonin, 5-hydroxyindole acetic acid, serotonin, serotonin N-acetyltransferase, tryptophan, norepinephrine and dopamine in the rabbit pineal gland.

Pineal tryptophan, serotonin, serotonin-N-acetyltransferase (NAT), melatonin, 5-hydroxyindole acetic acid (5HIAA), norepinephrine and dopamine were measured in 5 castrated rabbits each at 11.00, 00.30 and 03.00 hours. The rabbits were housed in an L:D 14:10 (lights on 07.00 hours). Significant day:night variations were found in NAT, melatonin, dopamine and norepinephrine. These results were compared to data concerning rhythms of pineal constituents in other species.

Acetyltransferases↗
PubMed1984

The effects of porcine follicular fluid in the postcastration rise of gonadotropins in the rabbit.

The effects of repeated administration of porcine follicular fluid (PFF) on the follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels after castration were studied in rabbits. Steroid-free dextran-charcoal extracted PFF was administered to male and female adult rabbits at 0800 and 1600 h for four days immediately following castration. Serum levels of FSH and LH were measured before, during and after the PFF administration and compared to controls. A significant increase in FSH and LH was observed within 24 h following castration in the controls. In the PFF-treated group, a clear suppression of serum FSH levels was observed during PFF administration in both males and females. FSH concentrations returned to the control levels within 24 h after PFF withdrawal. Even through LH levels showed no differences during PFF injection, compared to controls, a significant increase was observed following discontinuation of PFF administration.

Animals↗
PubMed1984

The effects of chronic administration of LH-RH agonists and antagonists on the menstrual cycle and endometrium of the rhesus monkey.

Regularly cycling rhesus monkeys (Macaca mulatta) were used to study the effects of prolonged administration of LH-RH analogs on the menstrual cycle and the endometrium. According to the treatment, animals were divided into: Group 1, vehicle; Group 2, LH-RH agonist (D-Trp6 LH-RH, 20 micrograms/day); and Group 3, LH-RH antagonist [( N-Ac-D-Trp1,3, D-p-Cl-Phe2,D-Arg6,D- Ala10 ]-LH-RH,200 micrograms/day) for 90 days. Follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and progesterone (P) were measured every second day until thirty days past the discontinuation of drug administration. Endometrial biopsies were obtained on days 10, 40, 90 and 120 and processed for histologic exam and determination of estrogen (E) and progesterone receptors. Animals of Group 1 presented regular cycles, while those in Groups 2 and 3 remained anovulatory throughout the treatment. Animals of Group 2 presented different degrees of endometrial hyperplasia during treatment and animals of Group 3 showed either resting or atrophic endometrium. Administration of LH-RH agonist produced a marked increase in E and P endometrial receptors and the antagonist produced a decrease in P receptors. In both instances, reversal of the effects on the menstrual cycle and in the endometrium was observed 30 days after discontinuation of drug administration.

Animals↗
PubMed1984

Estriol modifies the absorption of estrone and estradiol in castrated rhesus monkeys: a new therapeutic approach for the use of natural estrogens in the menopause?

In order to study the effects of estriol (E3) on estradiol (E2) and estrone (E1) absorption in the rhesus monkey the following study was performed. Chronically ovariectomized animals were divided in four groups of five each according to the treatment protocol (1) E1: 0.7 mg (2) E1: 0.7 mg + E3: 0.135 mg (3) E2: 0.3 mg, (4) E2: 0.3 mg + E3: 0.135 mg (5) E1: 0.7 mg + E2: 0.3 mg and (6) E1: 0.7 mg + E2: 0.3 mg + E3: 0.135 mg. Monkeys received daily drug administration (DA) for 10 consecutive days. Serum E1, E2 and E3 were determined by RIA on a daily basis. In addition, during the first day of treatment blood samples were obtained at hourly intervals. Results were analyzed by comparing the areas under the curve (Integral tests). The data shows that during treatment serum concentrations of E1 and E2 in groups 1, 3 and 5 were significantly higher than in groups 2, 4 and 6 (2-4-fold greater). Serum levels of E1 and E2 rose 5-fold from baseline in animals from group 1 within 1 h, while they increased only 2-fold in those from group 2 at 3-6 h after DA. Similarly, serum levels of E1 and E2 increased 30- and 10-fold respectively 1 h after DA in group 3, while they rose 12- and 5-fold respectively 4 h after DA in animals of group 4. Estriol levels were similar in animals from group 2 and 4 throughout the study (250 +/- 80 pg/ml). It may be concluded therefore that the oral administration of estriol diminishes the absorption of both E1 and E2 and alters their bioavailability, perhaps modulating their biological activity.

Absorption↗
PubMed1984

Etiology of infertility in monkeys with endometriosis: luteinized unruptured follicles, luteal phase defects, pelvic adhesions, and spontaneous abortions.

To elucidate the etiology of infertility due to endometriosis, we autografted endometrial or adipose tissue to the pelvic peritoneum of 21 cynomolgus monkeys. These primates were divided into five groups: control animals with adipose tissue autografts (n = 5), animals with microscopic endometriosis (n = 5), animals with mild endometriosis (n = 5), animals with moderate endometriosis (n = 4), and animals with severe endometriosis (n = 2). During three subsequent menstrual cycles, each animal underwent (1) serial assay of peripheral serum gonadotropins and steroids; (2) mating timed according to daily serum 17 beta-estradiol; and (3) laparotomy to document an ovulatory stigma. The chemical and term pregnancy rates were lower among monkeys with moderate or severe endometriosis, as compared with control animals. The impaired fertility in monkeys with endometriosis appeared to be mediated primarily by failure of follicular rupture and/or pelvic adhesions.

Abortion, Spontaneous↗
PubMed1984

Successful in vitro fertilization and embryo transfer in cynomolgus monkeys.

We have started an in vitro fertilization program in cynomolgus monkeys in an effort to develop an appropriate animal model to improve our knowledge of early embryonic development. In 16 of 25 animals treated with menopausal gonadotropins, preovulatory follicles developed. Follicular aspiration was performed at laparotomy after human chorionic gonadotropin injection. A total of 299 follicles were aspirated, and 251 oocytes were recovered. Oocytes were cultured in 1 ml of growth medium or 100 microliter droplets of medium under mineral oil. Semen samples were obtained by electroejaculation, and the oocytes were inseminated 4 to 24 hours after aspiration. Culture under mineral oil significantly increased the fertilization and cleavage rates. Of 68 embryos produced, 24 have been used in 10 embryo transfers, resulting in two pregnancies.

Animals↗
PubMed1984

Properties of gonadotropin-stimulable adenylyl cyclase of the human corpus luteum: regulation of hormonal responsiveness by guanyl nucleotide and magnesium ion.

We studied the properties of a gonadotropin-responsive adenylyl cyclase in membrane preparations obtained from human corpus luteum and explored the nature of guanyl nucleotide and Mg ion involvement in activation of the enzyme. Maximal adenylyl cyclase activity required ATP concentrations of 1-2.5 mM, total MgCl2 concentrations of 8-10 mM, and 1 mM EDTA. Optimal hCG responsiveness, however, required lower (approximately 5 mM) MgCl2 concentrations. Both GTP and its hydrolysis-resistant analog guanyl 5'-yl imidodiphosphate [GMP-P(NH)P] increased enzyme activity, but the response to each nucleotide had distinct characteristics. The rate and the extent of activation were greater in the presence of GMP-P(NH)P than in that of GTP. Moreover, enzyme activation by GMP-P(NH)P was hysteretic in nature, requiring about 8 min to reach steady state velocity in the absence of hormonal stimuli. The slow rate of activation by GMP-P(NH)P was accelerated by either hCG or increases (3-10 mM) in the concentration of MgCl2. Thus, both gonadotropin and Mg ion are inherently antihysteretic in the human luteal adenylyl cyclase system. Basal and hCG stimulation were under the control of guanine nucleotides. Dose-response curves showed that the apparent activation constants for GTP and GMP-P(NH)P were 0.30 and 0.51 microM, respectively; these values did not shift after the addition of hCG. At a higher concentration of guanyl nucleotides (1000 microM), basal and hCG-stimulated activities were markedly reduced, suggesting bimodal regulation of the enzyme by the nucleotides. We also found that enzyme responsiveness to prostaglandin E2 was small and that, in contrast to a number of other nonprimate species, adenylyl cyclase from the human corpus luteum was not stimulated by isoproterenol. Taken together, these data support the usefulness of the cell-free model for studying the role of adenylyl cyclase in the regulation of luteal function in the human.

Adenosine Triphosphate↗
PubMed1984

Effect of porcine follicular fluid on the postcastration secretion of gonadotropins in rhesus monkeys.

Porcine follicular fluid (pFF) contains a nonsteroidal factor(s) that modifies pituitary secretion of both FSH and LH under certain physiological and experimental conditions. The aim of this study was to further define the activity of pFF on basal and pulsatile gonadotropin secretion after bilateral oophorectomy in monkeys. Sexually mature female rhesus monkeys underwent bilateral oophorectomy during the early follicular phase of the menstrual cycle. For 10 consecutive days, beginning on the day of surgery, monkeys were given twice daily sc injections of 2.5 ml normal saline (group I, control; n = 3), 2.5 ml steroid-free pFF (group II; n = 3), or 5.0 ml steroid-free pFF (group III; n = 3). Blood was drawn daily for 32 days, beginning the day before castration. One day before and on days 6 and 20 after castration, monkeys were placed in a restraining chair, and blood samples were drawn every 15 min for 6 h via an indwelling venous catheter. All samples were radioimmunoassayed for FSH and LH. In group I, a significant increase in serum FSH and LH occurred on days 3 and 6 postcastration, respectively. A significant increase in serum FSH did not occur until day 13 postcastration in groups II and III. Serum LH was significantly increased on days 10 and 9 postcastration in groups II and III, respectively. The LH pulse frequency ranged from 60-105 min and did not change after castration in control or pFF-treated animals. The LH pulse increment was significantly increased on day 6 postcastration in group I, but not until day 20 postcastration in groups II and III. Only minor oscillations in FSH were found until day 20 postcastration, at which time there was no significant difference in FSH pulse frequency or increment among groups. These findings demonstrate that a nonsteroidal factor(s) in pFF suppresses basal FSH and LH concentrations and LH pulse increment in monkeys after surgical castration. Further, because LH, but not FSH, concentrations began to increase during pFF treatments, these data suggest a temporal disparity in the effects of pFF on FSH and LH secretory profiles.

Animals↗
PubMed1984

Inhibition of serum luteinizing hormone and testosterone with an inhibitory analog of luteinizing hormone-releasing hormone in adult male rhesus monkeys.

The effects of single and repeated administration of a potent LHRH inhibitory analog (antagonist) [( N-acetyl-D-p-chloro-Phe1,2,D-Trp3,D-Arg6,D-Ala10]LHRH) on serum concentrations of LH and testosterone (T) in adult rhesus monkeys were studied. In Exp 1, single sc injections of the LHRH antagonist (400 micrograms and 50 micrograms) or vehicle were administered and the temporal changes in serum LH and T were determined (n = 4 per group). Both LH and T declined markedly in all animals as soon as 30 min after the LHRH antagonist injection, reaching the nadir (80%) approximately 8 h later and remaining significantly lower than baseline levels for up to 24 h. Control animals had no marked variations in either LH or T serum levels. In Exp 2, daily sc injections of different doses of LHRH antagonist (400 micrograms, 50 micrograms, and 10 micrograms) or vehicle were administered for 7 days to four animals in each group. The animals in the control group had no significant changes in LH or T levels, whereas those treated with the lowest dose of LHRH antagonist (10 micrograms) had decreased T levels in the absence of changes in LH. The other two doses of LHRH antagonist (400 micrograms and 50 micrograms) induced, as early as 8 h after the initial injection, dramatic decreases in serum levels of both LH and T and these values remained significantly lower than control for up to 3 and 4 days after discontinuation of drug administration, respectively. We conclude from this study that LHRH inhibitory analogs are potent inhibitors of LH and T in adult rhesus monkeys. They have potential use in clinical trials for male contraception as well as in patients in whom inhibition of gonadotropin and steroid secretion is desired.

Animals↗
PubMed1984

Acute, short-term, and chronic effects of marijuana on the female primate reproductive function.

Studies with laboratory animals clearly show that the crude drug marijuana and delta-9-THC, the principal psychoactive ingredient, inhibit secretion of the pituitary hormones LH and FSH as well as prolactin. These changes in pituitary hormone levels produce decreases in sex steroid hormones and cause disruption of ovulation and spermatogenesis. With chronic drug use, disruption of sex accessory organs has also been observed. A principal site of THC action is the hypothalamus, because THC effects on pituitary hormone production can be reversed with hypothalamic releasing factors. It is now known that drug effects in sexually mature animals are reversible when drug treatment stops. In adults, tolerance develops to hormone changes brought on by the use of marijuana. Clinical studies on human subjects generally agree with the animal findings, although conflicting results have been reported as well. It is likely that the differences in results obtained in experiments with laboratory animals and with humans are caused, at least in part, by differences in experimental design. Further, it is not known how much disruption of reproductive hormone levels is necessary for changes in human fertility and sexual function to occur. The use of marijuana by pregnant women or by women who are attempting to become pregnant is cause for special concern. Studies with laboratory animals and retrospective studies on women who have used marijuana during pregnancy show that the risks of pregnancy loss and other adverse effects on the fetus are increased by marijuana use. THC crosses the placental barrier and while the potent teratogenic and mutagenic effects suggested for marijuana some years ago have not been confirmed, significant changes consistent with retardation of fetal growth and development have been observed. Effects of THC on the proper functioning of the placenta may be responsible for these effects on pregnancy. Pregnancy that occurs after the development of tolerance with chronic marijuana use may involve an ovum that has been damaged by exposure to the drug during critical developmental stages. More studies need to be done before the mechanisms of toxic effects on pregnancy and fetal development can be described. While there have been no clinical studies relating marijuana use to adolescent development, studies in laboratory animals show that the developing reproductive system during adolescence is particularly vulnerable.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Peptide and steroid hormone concentrations in human seminal plasma.

Concentrations of peptide (alpha fraction of human chorionic gonadotropin [alpha-hCG], beta fraction of human chorionic gonadotropin [beta-hCG], luteinizing hormone [LH], follicle-stimulating hormone [FSH], and prolactin [PRL] ) and steroid hormones (testosterone [T], dihydrotestosterone [DHT], estrone [E1], estradiol [E2] and delta 4-androstenedione [A] ) were measured in the seminal plasma of 193 men. They were divided into three groups: group 1--patients attending an infertility clinic; group 2--normal volunteers of proven fertility; and group 3--men vasectomized at least 1 year prior to the study. Correlations among concentrations of hormones in seminal plasma and characteristics of the spermogram were studied. Seminal concentrations of alpha-hCG, beta-hCG, LH, T, and DHT were significantly higher in subjects with sperm in their ejaculate than in vasectomized men. No differences were observed among the groups in seminal concentrations of FSH, PRL, A, E1, and E2. Concentrations of beta-hCG and LH were highly correlated with the numbers and motility of sperm in the ejaculates. Testosterone concentrations were significantly correlated with motility of sperm.

Chorionic Gonadotropin↗