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Biomedical subjects

R H Asch

Publications and source records attributed to R H Asch.

At least 109 records · Page 6Linked to original sources
PubMed1988

Tubal embryo transfer in cynomolgus monkeys: effects of hyperstimulation and synchrony.

To date the main limitation of in-vitro fertilization-embryo transfer (IVF-ET) programmes is that transcervical transfer of embryos results in a rate of low implantation. On the other hand, the technique of gamete intra-Fallopian transfer (GIFT) does not contribute to information on oocyte fertilization rates, and the time of oocyte exposure to sperm may be limited. The development of ultrasonically guided follicular aspiration will allow transfer of embryos generated in vitro to the Fallopian tubes performing only one surgical procedure in the process. We have performed 25 intra-tubal embryo transfers in the cynomolgus monkey (Macaca fascicularis). Ovarian stimulation, follicular aspiration and IVF procedures have been reported previously by Balmaceda. ETs were performed via laparotomy. Embryos at the 2-, 4- or 9-cell stage were loaded into a tom-cat catheter in 5 microliter of culture medium and delivered to the mid-ampullary portion of the tube. Seven ETs performed during stimulated cycles resulted in one pregnancy, and 18 ETs performed in synchronized recipients resulted in six pregnancies. Ten ETs were performed 0-24 h, eight performed 24-48 h and seven performed 72-110 h after follicular aspiration or ovulation, and resulted in 4, 3 and 0 pregnancies respectively. Our results demonstrate that intra-tubal embryo transfer can result in normal intra-uterine pregnancies and suggest that both ovarian stimulation and cycle synchronization affect the probability of embryo implantation.

Animals↗
PubMed1988

Prolactin and gonadotrophin dynamics in response to antagonists of LHRH and dopamine in ovariectomized rhesus monkeys: a dissection of their common secretion.

This experiment was designed to study the prolactin (PRL) and gonadotrophin response to an inhibitory analogue of luteinizing hormone releasing hormone (LHRH-A; ORG 30276) and a dopamine antagonist, metoclopramide (MCP), in castrated female rhesus monkeys. The LHRH-A given as an i.v. bolus followed by an infusion 2 h later induced a significant decline in circulating PRL levels reaching a maximum suppression 1 h after initiation of the LHRH-A infusion. Intravenous administration of MCP, performed 1 h after beginning the LHRH-A infusion, resulted in a prompt and abrupt rise in PRL levels in the LHRH-A group as well as in the controls. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels showed a progressive decline during LHRH-A treatment. Injection of MCP did not affect the levels of LH and FSH in either of the groups. The data obtained demonstrate in primates that the prolactin inhibitory effect of LHRH-A is easily overcome by the dopamine antagonist, MCP, whereas the LHRH-A-induced gonadotrophin suppression remains unaffected by MCP.

Animals↗
PubMed1988

Oocyte donation and gamete intrafallopian transfer in premature ovarian failure.

Gamete intrafallopian transfer (GIFT) was performed in eight patients with premature ovarian failure (POF), using donated oocytes. The steroid replacement protocol consisted of the administration of increasing dosages of 17 beta-estradiol (E2) and progesterone (P). Hormonal replacement was maintained until day 100 of gestation. All patients underwent an evaluation cycle in which serum levels of E2 and P were monitored and an endometrial biopsy was performed on day 21 or 22. All cases of GIFT were performed between days 12 and 15. Six clinical pregnancies were achieved in eight cycles (75% success rate). Three patients delivered and three are in their second or third trimester. No ectopics or miscarriages occurred. These results offer a promising approach for the establishment of fertility in agonadal patients.

Adult↗
PubMed1987

Disposition of homovanillic acid in the primate.

Prior studies have shown that homovanillic acid is the principal metabolite of dopamine in the primate central nervous system (CNS). In studies of primates given deuterated homovanillic acid systemically, however, only 50% of the administered amounts have been recovered in the urine over the next 4-48 hr. These findings have left it unclear whether there is a slowly turning-over compartment of homovanillic acid, conversion of homovanillic acid to another compound, or excretion of homovanillic acid from the body by a nonrenal route. We synthesized [3H]homovanillic acid and administered it intravenously to four rhesus monkeys. Over the subsequent 4 hr, 94.9 +/- 8.9% (SD) of the administered radioactivity was recovered in the urine, almost entirely as homovanillic acid. These results are consistent with the interpretation that, in primates, there is not a major body pool of homovanillic acid with slow turnover, nor is metabolism to other compounds significant, nor is there evidence for nonrenal excretion.

Animals↗
PubMed1987

Drug abuse and reproduction.

It is clear that a number of CNS agents, including drugs of abuse, can inhibit reproductive function. Figure 1 shows the chemical diversity of some of the drug groups that affect reproductive hormones. Their structural dissimilarity to the steroid hormones is also readily apparent in the figure. These chemically diverse drugs share an important pharmacologic property: they are highly potent neuroactive drugs, and they can disrupt hypothalamic-pituitary function. Although it is frequently difficult to distinguish between direct drug actions on the hypothalamic-pituitary axis and subsequent effects on gonadal hormones and sex accessory gland function, the distinction is an important one. Most neuroactive drugs produce only transient effects on the central nervous pathways necessary for normal gonadotropin secretion. The disruptive effects of these drugs are likely to be transient and completely reversible, and tolerance to the inhibitory drug effects may occur even with continued drug use. Under these circumstances, normal adults may experience only subtle changes in sexual function. However, individuals with compromised reproductive function may exhibit major problems. It is also likely that adolescents may be at substantial risk for reproductive damage from these neuroactive drugs since the endocrine events associated with puberty are dependent on the normal development of the hypothalamic-pituitary axis.

Adolescent↗
PubMed1986

Effects of a long-acting LHRH agonist preparation on plasma gonadotropin and prolactin levels in castrated male rats and on the release of prolactin from ectopic pituitaries.

We have examined the effects of a single subcutaneous injection of an LHRH agonist, D-Trp-6-LHRH, in biodegradable microcapsules of poly(DL-lactide-co-glycolide) on plasma gonadotropin and prolactin (PRL) levels in castrated and in castrated-hypophysectomized-pituitary grafted (CAST-APX-GRAFT) male rats. The results were compared to the effects of daily injections of the same LHRH agonist dissolved in saline. In castrated rats, there were no significant alterations in plasma LH or PRL levels during the 10 days following the injection of LHRH agonist microcapsules, while FSH levels were generally reduced. In castrated males given daily injections of 6 micrograms of LHRH agonist in saline, plasma LH levels were significantly reduced while plasma PRL levels were not changed. In CAST-APX-GRAFT rats, both D-Trp-6-LHRH microcapsules and daily LHRH agonist injections appeared to increase plasma PRL levels. The pattern of changes in PRL release in both groups was similar, with levels on day 6 being significantly higher than those measured on days 1, 3 and 10 after onset of treatment. As expected, LH and FSH levels in these animals were extremely low. Immunoreactive D-Trp-6-LHRH was consistently detectable in the plasma of CAST-APX-GRAFT animals after microcapsule administration, whereas in animals given daily injections of this agonist in saline, its plasma concentrations were often below the detectability limit of the employed assay. These findings suggest that the LHRH agonist, D-Trp-6-LHRH, is capable of causing a short term stimulation of PRL release from ectopic pituitaries. Elevation of plasma LH levels is apparently not required for this effect.

Animals↗
PubMed1986

Sperm washing and swim-up technique using antibiotics removes microbes from human semen.

Pelvic infections may follow intrauterine or intratubal insemination with washed semen. In this study, we determined whether sperm washing removes microorganisms from human semen. Before and after semen wash, we cultured 15 ejaculates for aerobic and anaerobic bacteria, genital mycoplasma, and chlamydia. All semen samples had from one to five organisms isolated (total, 40 isolates) before the semen wash preparation. The mean number (+/- standard deviation) of isolates per sample was 2.67 +/- 1.35. After the semen were prepared, none of the samples showed a positive culture. The decrease in the number of samples with positive cultures and the decrease in the number of isolates is significant (P less than 0.0001). After sperm washing, electronmicroscopic studies did not show any microbes attached to any portion of the spermatozoa. We conclude that the method of sperm wash preparation used is effective in removing microbes present in human semen.

Anti-Bacterial Agents↗
PubMed1986

Inhibition of luteinizing hormone/human chorionic gonadotropin-stimulable adenylyl cyclase activity in rat luteal membranes by nonsteroidal component(s) in human follicular fluid.

We examined the ability of nonsteroidal components of human follicular fluid (hFF) to alter gonadotropin responsiveness using the LH/hCG-sensitive adenylyl cyclase system of rat luteal membranes. Follicular aspirates were obtained from regularly ovulatory women (n = 10) whose follicles were stimulated by human menopausal gonadotropin and hCG as part of an in vitro fertilization program. hFF from large follicles was pooled and extracted with 10% (wt/vol) activated charcoal. Maximal hCG stimulation of adenylyl cyclase activity obtained with 10 micrograms/ml hCG and 100 microM of the hydrolysis-resistant GTP analog guanyl 5'-yl-imidodiphosphate was significantly inhibited by hFF in a dose-dependent manner. Addition of about 500 micrograms hFF protein caused inhibition of 70% compared to the control value. Fractionations of hFF by ultrafiltration using membranes of precalibrated pore size demonstrated that the inhibitory activity was associated with a less than 10,000 mol wt fraction; 3 micrograms protein/assay of this fraction resulted in 50% inhibition (IC50) of maximal hCG stimulation. The inhibitory activity also passed through an Amicon YM-2 membrane (mol wt retention, 1,000), but not through an Amicon YC-05 membrane (mol wt retention, 500). An IC50 of about 0.01 microgram protein/assay was found for both the 500-1,000 and the 1,000-5,000 mol wt fractions. NaF or forskolin-stimulated adenylyl cyclase activity was not altered by unfractionated hFF or by the 500-10,000 mol wt subfractions, suggesting that inhibition was limited to LH/hCG stimulation. Further analysis of the effects of low mol wt fraction on hCG stimulation of adenylyl cyclase indicated that enzyme inhibition was not accompanied by a shift in the hCG concentration required for half-maximal stimulation (the apparent activation constant) compared to dose-response curves obtained in the absence of added fraction. Equilibrium binding studies showed that [125I]hCG interaction with luteal membranes was significantly inhibited by hFF; 7 micrograms protein/assay of the less than 10,000 mol wt fraction reduced specific binding by 60%. Moreover, kinetic analysis carried out in the absence or presence of a fixed amount of low mol wt fractions revealed a competitive type of binding inhibition. Our data demonstrate that a nonsteroidal component(s) of hFF has a direct inhibitory effect on LH/hCG-responsive luteal adenylyl cyclase and that the inhibitor(s) exerts its actions through a mechanism involving competition with LH/hCG for the same binding sites.

Adenylyl Cyclase Inhibitors↗
PubMed1986

Pregnancy-specific beta 1-glycoprotein concentrations throughout pregnancy in the rhesus monkey.

Proteins that are immunologically related to human pregnancy-specific beta 1-glycoprotein (hSP1) have been detected in serum samples from pregnant subhuman primates. However, little information is available concerning the concentrations or secretory dynamics of SP1 in nonhuman primate pregnancy. To examine serum SP1 concentrations throughout rhesus monkey gestation, a heterologous RIA for rhesus SP1 (rSP1) was developed which used an antiserum against rSP1 and purified human SP1 as the standard and for iodination. No rSP1 was detected in serum samples from 8 normal male monkeys, 8 castrated females, or 10 regularly cycling females. Levels of rSP1 were measured in 260 serum samples from 43 pregnant monkeys. rSP1 was first detected on day 14 after mating, and all monkeys sampled 25 or more days after mating had detectable serum rSP1 levels. Serum rSP1 rose exponentially from day 14 to about day 50, followed by a more gradual rise until term. This pattern of secretion was in marked contrast to that found for macaque CG, which was already detectable 10 days after mating, peaked at 20 days, and returned to nonpregnant levels by day 40. The disappearance of rSP1 after delivery was best fit by a 2-component 4-parameter model with a mean residence time of 48 h. These data indicate that the pattern of rSP1 secretion throughout pregnancy is qualitatively similar to that found for hSP1, as is the long half-life of the protein in the circulation after delivery. rSP1 measurements may provide a useful index of placental function during rhesus pregnancy and serve as a model to study the biological role of SP1 in primates.

Animals↗
PubMed1986

Effects of delta 9-THC, the principal psychoactive component of marijuana, during pregnancy in the rhesus monkey.

The effect of delta 9-tetrahydrocannabinol (THC), the principal psychoactive component in marijuana, was studied in pregnant and lactating rhesus monkeys. THC (2.5 mg/kg/d) or vehicle was administered during different periods of gestation, and effects on pregnancy outcome and hormone concentrations during pregnancy were studied. The most obvious effects were observed with administration early in pregnancy; three of five pregnancies aborted within days after the drug injections began, and one pregnancy resulted in a stillbirth at term. The three abortions were associated with a rapid decrease in chorionic gonadotropin and a subsequent fall in progesterone concentrations to nondetectable levels. In the two pregnancies that continued until term, estradiol concentrations were significantly higher than in vehicle control pregnancies. Daily THC administration during the middle or third portion of gestation resulted in lesser pregnancy loss (one premature birth and four live births at term with THC treatment during the middle portion; two premature births and three live births at term with THC treatment during the third portion). All the premature infants died within two weeks of birth. The weights of the infants at birth and weaning were not significantly different for the infants from vehicle control pregnancies and for full-term infants exposed to THC during gestation. Also, no effects on intrauterine growth and development were detected with ultrasound in the drug-treated pregnancies. With acute administration, THC readily crossed the placenta at term in rhesus monkeys and was transferred into the milk of nursing mothers. Significant blood levels of THC and depressant effects were observed in both mothers and neonates when the drug was administered to the mothers one hour before birth or during lactation.

Abortion, Spontaneous↗
PubMed1986

Regulation of human prolactin secretion by gonadotropin-releasing hormone in vitro.

The regulation of human prolactin (PRL) secretion by gonadotropin-releasing hormone (GnRH) was evaluated with human pituitary monolayer cell cultures. Synthetic GnRH stimulated PRL secretion when exposed to cells in an estrogen-depleted environment. This response was inhibited by pretreatment of the cells with 17 beta-estradiol (E2). A 10(-5) M GnRH antagonist inhibited luteinizing hormone (LH) but not PRL secretion when cells were maintained in an estrogen-depleted environment. However, the GnRH antagonist inhibited basal PRL secretion when cells were maintained in medium containing 10(-8) M E2. The 10(-5) M GnRH antagonist, when coincubated with 10(-5) M GnRH inhibited the release of PRL in an estrogen-depleted environment. However, coincubation of the 10(-5) M GnRH antagonist with 10(-5) M thyrotropin-releasing hormone (TRH) failed to inhibit PRL secretion. Incubation of 10(-8) M TRH and 10(-8) M GnRH produced a synergistic release of PRL in an estrogen-depleted environment. These observations led us to conclude that GnRH stimulates PRL secretion by direct action on human pituitary cells and that GnRH acts either via the gonadotrope or through receptors on the galactotrope other than that acted upon by TRH to release PRL.

Adult↗
PubMed1986

Preliminary experiences with gamete intrafallopian transfer (GIFT).

This article describes the first series of patients to undergo gamete intrafallopian transfer (GIFT) as a treatment for infertility. Ten patients with the diagnosis of either unexplained infertility or male factor were treated with human menopausal gonadotropin and human chorionic gonadotropin before surgery by laparoscopy or minilaparotomy. Semen was collected 2.5 hours before oocyte pickup at surgery and treated by the technique of wash and swim-up. After gamete evaluation, one or two oocytes and 100,000 actively motile sperm were loaded into a catheter and introduced through the fimbria. The contents of the catheter were gently emptied at a site approximately 1.5 cm inside each fallopian tube. Patients received progesterone in oil, 12.5 mg/day, from day 4 after GIFT until up to 8 weeks of gestation. Four patients became pregnant: two pregnancies aborted; the other two pregnancies proceeded to the delivery of viable infants. GIFT may be considered as an alternative to in vitro fertilization in infertility cases in which at least one fallopian tube is patent.

Adult↗
PubMed1985

Effects of luteinizing hormone-releasing hormone agonist and calcium upon adenylyl cyclase activity of human corpus luteum membranes.

We have investigated the ability of the agonist analog of luteinizing hormone-releasing hormone (LH-RH), D-Trp6-LH-RH (LH-RHa), and of CaCl2 to inhibit directly gonadotropin stimulation of adenylyl cyclase in a cell-free system prepared from human corpus luteum. In the presence of a submaximally effective concentration of hCG, addition of 10(-5)M final concentration of LH-RHa did not alter the gonadotropin-stimulated enzyme activity, nor did LH-RHa alone show any effect upon basal levels of the enzyme. The failure to inhibit adenylyl cyclase would indicate that the LH-RHa does not affect gonadotropin receptor binding or cAMP synthesis and/or degradation in this membrane system, suggesting that the luteolytic effects of LH-RH are unlikely to involve a direct antigonadotropic activity at the level of the human corpus luteum. In great contrast to LH-RHa, addition of CaCl2 resulted in a dose-dependent inhibition of hCG-stimulable adenylyl cyclase. Thus, in the presence of either a maximally or submaximally effective concentration of hCG, inhibition was significant at 0.5 mM CaCl2 added in excess of ATP (2 mM) and EDTA (1 mM), being about 90% upon addition of 2.5 mM CaCl2. We also found that calcium reduced enzyme stimulation by forskolin and the GTP analog, guanyl 5'-yl imidodiphosphate [GMP-P(NH)P] in a dose-related manner and that activation by NaF was less sensitive to inhibition by calcium. Accordingly, at 2.5 mM CaCl2, guanyl nucleotide and forskolin stimulations were inhibited 96% and 86%, respectively, while NaF stimulation was reduced by 40%. Because previous studies have shown that calcium does not impair gonadotropin binding activity, the calcium-dependent inhibition of gonadotropin responsiveness reported here would imply an alteration in the functional coupling of the components of the luteal adenylyl cyclase system. These data suggest that calcium may play a role in the regulation of gonadotropin action in the human corpus luteum.

Adenylyl Cyclases↗
PubMed1985

Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LH-RH) in the rhesus monkey.

Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12 h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41% (0.2 mg dose) and 41 and 58% (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40% (1 mg) and 32 and 53% (5 mg), respectively. These decreases were dose-related and lasted for up to 12 h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26%. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1%) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms.

Administration, Intranasal↗