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Biomedical subjects

I Khan

Publications and source records attributed to I Khan.

At least 163 records · Page 9Linked to original sources
PubMed1987

Decidual luteotropin secretion and action: its role in pregnancy maintenance in the rat.

Studies of rat decidual luteotropin production and action have revealed that decidual mRNA directs the synthesis of a 28,000 MW protein in a cell-free system which binds to prolactin receptors in luteal cells and appears to represent a prohormone for decidual luteotropin. Hybridization studies indicate that although rat decidual and prolactin-like placental hormones bind to prolactin receptors, they possess little homology to other members of the prolactin family. In addition, results of this investigation have revealed a possible physiological relationship between the mesometrial and the antimesometrial cells of the decidual tissue. The large antimesometrial cells produce decidual luteotropin in which secretion and/or synthesis is inhibited by the neighboring mesometrial cells. Since mesometrial cells possess binding sites for decidual luteotropin, it is possible that decidual luteotropin acts on the mesometrial cell to affect the formation of its own inhibitor. Mesometrial cells are rich in glycogen, whose synthesis is stimulated by prolactin-like hormones in other tissues. Therefore, decidual luteotropin may also act on these cells to enhance glycogen formation. In summary, decidual luteotropin appears to have at least two sites of action--the luteal cell, where it can substitute for prolactin in maintaining progesterone production, and the mesometrial cell, where its role remains to be investigated.

Animals↗
PubMed1987

Catecholamine content and adenylate cyclase activity in corpora lutea of different ages of the PMSG-treated immature rat.

The catecholamine content and adenylate cyclase response were studied in a well-characterized corpus luteum model, where ovulation was induced by treatment of prepubertal Sprague-Dawley rats with pregnant mare's serum gonadotropin. The luteal content of noradrenaline, determined with HPLC, was constant during the first 7 days of pseudopregnancy, followed by a 3-fold increase in older corpora lutea. No detectable amounts of dopamine were found, while trace amounts of adrenaline were found in a few cases. The increase in noradrenaline content was not associated with a changed sensitivity of luteal adenylate cyclase to catecholamines. The response to adrenaline was maximal in 3-day-old corpora lutea, whereafter a decrease was seen. The significance of the increased endogenous levels of noradrenaline at the end of pseudopregnancy is at present unknown. However, the fact that the increase in noradrenaline occurs a few days before spontaneous luteolysis is of special interest, since it has been suggested that an adrenergic innervation is a prerequisite for the antigonadotropic effect of prostaglandin F2 alpha in the human corpus luteum.

Adenylyl Cyclases↗
PubMed1987

Gamete intra-Fallopian transfer: evaluation of 100 consecutive attempts.

The results of 100 gamete intra-Fallopian transfer (GIFT) procedures to treat persistent infertility are reported. Twenty-four pregnancies were achieved, of these six aborted, two were extra-uterine, two stillbirths occurred and nine patients delivered 11 healthy children (two sets of twins) and five pregnancies are progressing well, including two sets of twins. Pregnancy rate in the different groups of patients was: 28% for idiopathic infertility (n = 39), 13% for male infertility (n = 16), 22% for endometriosis (n = 27), and 29% in the presence of antisperm antibodies (n = 7). In our GIFT procedure, we place three oocytes and 50,000 to 100,000 motile spermatozoa per patient into one healthy tube, the remaining oocytes being inseminated and cultured in vitro. Of 502 oocytes recovered, 252 fertilized normally and 178 early embryos were frozen. The replacement of 41 frozen-thawed embryos resulted in five additional, ongoing pregnancies. The combined treatment by gamete intra-Fallopian transfer, in-vitro fertilization and cryopreservation increases the chance of conception.

Adult↗
PubMed1987

Management of failed cycles in an IVF/GIFT programme with the combination of a GnRH analogue and HMG.

The addition of the gonadotropin releasing hormone (GnRH) agonist Buserelin to human menopausal gonadotrophin/human chorionic gonadotropin (HMG/HCG) during ovarian stimulation was evaluated in 23 cycles of 21 women who previously had unsuccessful IVF treatments when stimulated with clomiphene--HMG/HCG. No adverse effects of GnRH-agonist on folliculogenesis were seen. A mean number of 7.2 oocytes per retrieval was collected in 20 treatment cycles. Oocytes quality, fertilization and cleavage parameters were normal. Replacements by gamete intra-Fallopian transfer (GIFT) or IVF took place for 16 patients. Four patients became pregnant in their treatment cycle, one aborted. For 8 patients 18 embryos were cryopreserved, one transfer of a frozen--thawed embryo in a subsequent natural cycle led to a pregnancy. Inadequate luteal phases were constantly observed when supplementation was omitted. Further study is required to confirm that systematic luteal support improves the pregnancy rate.

Adult↗
PubMed1987

Cryopreservation of human embryos obtained after gamete intra-Fallopian transfer and/or in-vitro fertilization.

During a one-year period 636 excess embryos obtained after in-vitro fertilization and gamete intra-Fallopian transfer combined with in-vitro fertilization were cryopreserved using two different protocols. For early stage embryos including the pronucleate stage, 1,2-propanediol was used as cryoprotectant (procedure A, adapted from Renard) and for later stage embryos dimethylsulphoxide was used in protocol B, adapted from Trounson and Mohr. After thawing 288 embryos, half of them were of sufficient quality to be replaced. After cryopreservation, procedure A gave the best survival in embryos having less than or equal to 2 blastomeres; for later stage embryos best survival was obtained using the dimethylsulphoxide protocol. Survival after cryopreservation was also clearly related to the quality of the embryos prior to freezing. Embryos were replaced during endocrinologically monitored natural cycles and were transferred in synchrony between endometrial and embryonic age. After replacement of 126 embryos in 110 patients, 20 pregnancies occurred. So far six healthy children have been born, two patients aborted and 12 pregnancies are ongoing. In this series no statistical difference was observed between the implantation rate of embryos cryopreserved by procedure A or B. Six pregnancies occurred in patients from the oocyte and embryo donation programme. An adequate cryopreservation programme circumvents the difficult problem of synchronizing the ovarian cycles of donor and acceptor patients.

Embryo Transfer↗
PubMed1987

Reactivation of regressing corpora lutea by estradiol in the pregnant rat: dependence on placental lactogen.

Previous investigations have clearly demonstrated that estradiol maintains corpus luteum function. However, it is unknown whether estradiol can restimulate progesterone synthesis and/or growth of corpora lutea that have already undergone luteolysis. The present study was designed to determine 1) whether estradiol can reactivate the steroidogenic capacity and/or growth of corpora lutea that are deprived of luteotropic support, 2) whether estradiol affects progesterone metabolism, and 3) whether the action of estradiol is related to levels of rat placental lactogen in the peripheral circulation. Rats were hypophysectomized and hysterectomized on Day 12 of pregnancy and were treated between Days 12 and 15 with either estradiol (100 micrograms/day) or 1-cm testosterone implants. Both treatments are known to maintain luteal concentrations of estradiol at physiological levels. In vivo treatment with either estradiol or testosterone prevented the drop in progesterone production and maintained the concentration of serum progesterone at levels found in intact pregnant rats. This action was not due to an alteration in the rate of metabolism of progesterone to 20 alpha-hydroxyprogesterone, since peripheral serum levels and in vitro production of 20 alpha-hydroxyprogesterone were unaffected by estradiol. When testosterone treatment was started 24 and 48 h after hypophysectomy and hysterectomy, at a time when progesterone production had been markedly reduced and luteal growth had ceased, a restimulation of both progesterone synthesis and luteal growth was observed. However, in all cases the ability of estradiol to stimulate progesterone was finite, and corpora lutea ceased to respond by Day 17, coincident with the time that rat placental lactogen became undetectable in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Selective stimulation of luteal androgen biosynthesis by luteinizing hormone: comparison of hormonal regulation of P45017 alpha activity in corpora lutea and follicles.

Recent investigations have indicated that luteal cells of pregnant rats become capable of synthesizing androgen and estradiol when stimulated by sustained low levels of LH/hCG. In this investigation we sought 1) to determine whether hCG causes the induction/activation of the luteal enzymes responsible for the conversion of progesterone to estradiol, 2) to investigate the time course of hCG action, and 3) to compare the effect of hCG on luteal and follicular P45017 alpha activities. To determine first the minimum stimulatory dose of hCG, pregnant rats were treated with 0, 1.5, 3, 9, or 30 IU hCG twice on days 12 and 13 and once on day 14. Two hours after the last injection, rats were bled from the ovarian vein, and corpora lutea were isolated and incubated for the determination of in vitro steroid production. Exposure of rats to twice daily injections of 1.5 IU hCG caused a dramatic increase in the ovarian secretion and luteal production of both testosterone and estradiol. However, an inverse dose-related response was observed with higher doses of hCG. To determine the time course of hCG action, pregnant rats were injected with a single dose of 3 IU hCG, and steroid production was determined at different times thereafter. There was no increase in either in vivo or in vitro testosterone and estradiol production until 12 h after hCG administration, at which time a dramatic increase in the secretion of both steroids was observed. hCG administration did not affect the capacity of luteal cells to secrete progesterone, nor did it enhance aromatase activity. It did, however, increase P45017 alpha activities; lyase and hydroxylase activities were stimulated 5- and 1.7-fold, respectively. To compare the effects of hCG on luteal and follicular P45017 alpha, both corpora lutea and follicles were isolated from ovaries of pregnant rats treated with either 1.5 IU hCG or vehicle between days 12-14. In vivo hCG administration caused at least a 1000-fold increase in the specific activity of follicular 17 alpha-hydroxylase and 17,20-lyase. The hCG-induced increase in the specific activities of both hydroxylase and lyase in the follicle far exceeded that in the corpora lutea. However, total lyase and hydroxylase activities in each follicle were only 3- and 5.5-fold higher, respectively, than those in the corpus luteum. In summary, the results of the present investigation have revealed that hCG stimulation of luteal estradiol production is due to a selective effect of this gonadotropin on P45017 alpha.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgens↗
PubMed1987

Difference in luteal and placental P450(17) alpha: substrate preference and hormonal regulation in the rat.

The purpose of this study was to assess the substrate specificity of P450(17) alpha in both the corpus luteum and placenta of pregnant rats, and to analyse the site at which LH/human chorionic gonadotrophin (hCG) regulates the activities of this enzyme. To distinguish the substrate preference, placentas and corpora lutea were obtained from rats on day 15 of pregnancy. Tissues were homogenized and the 10,000 g supernatants incubated in the presence of equimolar concentrations of [14C]progesterone and [3H]17 alpha-hydroxyprogesterone as substrate with either NADH or NADPH as cofactors for 2, 8, 16 and 24 min. The labelling pattern of both 17 alpha-hydroxyprogesterone and testosterone indicated that the corpus luteum produced testosterone preferentially from progesterone, whereas the placenta principally used 17 alpha-hydroxyprogesterone and synthesized six times as much testosterone from 17 alpha-hydroxyprogesterone than from progesterone. Addition of either NADPH or NADH as cofactors had no effect on substrate preference. The products of the two enzymatic activities were identified by recrystallization to constant 14C/3H ratios. The ratio of 14C/3H in testosterone produced by the corpus luteum was 16-fold higher than in that produced by the placenta. To explore which of the two activities of P450(17) alpha is regulated by the gonadotrophin, rats were treated with either 1.5 IU hCG or vehicle between days 13 and 15 of pregnancy. Hydroxylase and lyase activities were determined on day 15 after incubation for 2, 8, 16 or 24 min in the presence of either NADH or NADPH. Administration of hCG significantly inhibited NADH-dependent 17 alpha-hydroxylase in the placenta at each time-point studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Corticotropin releasing hormone: relevance to normal physiology and to the pathophysiology and differential diagnosis of hypercortisolism and adrenal insufficiency.

CRH is a 41 amino acid peptide first isolated from ovine and subsequently from rat and human hypothalami. We have conducted a series of clinical studies with oCRH and hCRH in volunteers and patients with various disorders of hypothalamic-pituitary-adrenal function. In volunteers, it was demonstrated that hCRH administration produced ACTH and cortisol responses which closely mimic naturalistically occurring secretory episodes. This data, as well as the demonstration that pulsatile hCRH can reestablish normal ACTH and cortisol secretion in patients with hypothalamic CRH deficiency, strongly argue that CRH is of physiological relevance to the human pituitary-adrenal axis. However, since the ACTH response to an insulin tolerance test is greater than the maximal ACTH response to CRH, other factors such as vasopressin may be relevant to stress-induced ACTH secretion in man. Following the demonstration that CRH seems to be of physiological relevance to human subjects, a CRH stimulation test was developed based on pharmacokinetic and dose response studies with oCRH and hCRH. Based on these data, which revealed that oCRH functions as a long-acting analogue of hCRH, and the demonstration that hormonal responses to CRH are greatest in the evening, patient groups with abnormalities of the hypothalamic-pituitary-adrenal axis were tested with intravenous oCRH with a dose of 1 micrograms/kg given at 2000 hours. This CRH stimulation test has proved helpful in clarifying the pathophysiology of hypercortisolism in a variety of psychiatric disorders characterized by this endocrine abnormality. Thus, blunted ACTH responses in hypercortisolemic patients with depression, anorexia nervosa, and panic anxiety disorder indicate normality of the pituitary corticotroph in these patient subgroups. These data, along with the finding that a continuous infusion of CRH to normal volunteers, reproduces the pattern and magnitude of hypercortisolism in depression and anorexia nervosa, suggest that the hypercortisolism in these disorders represents a defect at or above the hypothalamus resulting in the hypersecretion of CRH. This hypothesis is particularly intriguing in light of the demonstration that CRH administration to experimental animals produces many of the physiological and behavioral responses classically associated with depression and anorexia nervosa, including hypercortisolism, hypothalamic hypogonadism, and decreases in libido and appetite. The CRH stimulation test has also helped to resolve one of the oldest endocrinological dilemmas, namely whether the hypercortisolism of depression and Cushing's disease share a common or dissimilar pathophysiological basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Insufficiency↗
PubMed1986

Abnormal ACTH and cortisol responses to ovine corticotropin releasing factor in patients with primary affective disorder.

To further explore hypothalamic pituitary adrenal regulation in patients with affective illness, we administered 1 microgram/kg of synthetic ovine corticotropin releasing factor at 2000h to 26 drug-free patients with this disorder and to 15 healthy controls. Compared to controls, depressed patients (N = 12) showed a significant elevation in baseline cortisol and significant reductions in the net ACTH and cortisol responses to corticotropin releasing factor. These findings were normal in manic (N = 6) and improved (N = 8) subjects. An additional finding was that baseline cortisol and net ACTH and cortisol responses to CRF were negatively correlated in the entire group of patients and controls as well as in the patients alone. These data indicate that the reduced ACTH and cortisol responses to CRF in depression reflect normal functioning of the pituitary corticotroph cell (i.e., that the negative feedback effect of cortisol on ACTH secretion in depression is physiologically intact, effectively serving as a brake on the ACTH response to exogenous CRF. Thus, the hypercortisolism of depression may be due to a hypothalamic defect, possibly involving hypersecretion of endogenous CRF. This possibility may be of particular interest in light of clinical observations that depression can often be precipitated by stress and by data in experimental animals that CRF may influence several processes known to be altered in the overall symptom complex of depression.

Adrenocorticotropic Hormone↗
PubMed1986

Evidence for the secretion of decidual luteotropin: a prolactin-like hormone produced by rat decidual cells.

Rat decidual tissue contains a PRL-like hormone named decidual luteotropin. We have recently revealed some of its physiological and biochemical characteristics. However, because rat decidual tissue contains specific binding sites for PRL, it was important to demonstrate that the hormone found in the tissue is not locally stored and structurally transformed PRL but a hormone actively synthesized by the rat decidual tissue. Decidual explants or decidual cells obtained from day 9 pseudopregnant rats were incubated for different times under either static conditions or continuously perifused with medium at a rate of 1 ml/h. Levels of decidual luteotropin were measured by a specific radioreceptor assay using luteal membranes as source of receptors and [125I]iodo-ovine(o)PRL as a tracer. In the static incubation, no proof of hormone production was obtained; levels of decidual luteotropin in medium and tissue or cells at the end of the incubation were similar to levels found in either cells or tissue before incubation. In sharp contrast, decidual cells perifused with media secreted large amounts of hormone. This may suggest that an inhibitor of decidual luteotropin production was being removed from the culture by the perifusion. For the first 4 h of perifusion, no hormone was produced. However by the fifth hour, cells began to actively release decidual luteotropin. Secretion of the hormone increased with time and reached maximal values between 7-15 h of perifusion. During the 15 h of perifusion, decidual cells released approximately 1000 times more decidual luteotropin than the amount they originally contained. A dose-response increase in hormone secretion was obtained with increased concentrations of decidual cells. The net amount of decidual luteotropin released into the medium over an 18-h period was approximately 6.5 micrograms/30 X 10(6) cells, 3.5 micrograms/10 X 10(6) cells, and 0.5 micrograms/2 X 10(6) cells. A similar profile of decidual luteotropin release was obtained when decidual explants were perifused. However, in contrast to decidual cells which secreted no hormone for the first 4 h of culture, decidual explants immediately began to release decidual luteotropin in the medium. The secretion of decidual luteotropin in vitro was inhibited 75% by the protein synthesis inhibitor, cycloheximide. In summary, results of this investigation demonstrate for the first time that rat decidual cells secrete in vitro a PRL-like hormone, decidual luteotropin.

Animals↗
PubMed1986

Placental secretion of androgens in the rat.

In contrast to the human placenta, which does not secrete androgens, the rat placenta synthesizes significant amounts of these steroids. The purpose of this study was to determine why the rat placenta does not secrete androgens before day 12 of pregnancy, to ascertain whether the rat placenta secretes more androstenedione than testosterone, to compare the capacity of luteal and placental tissue to secrete androgen, and to determine whether the rat placental produces androstenedione via the delta 4- or delta 5-steroidogenic pathway. To determine whether the inability of the rat placenta to produce androstenedione before midpregnancy was due to the absence of active 17 alpha-hydroxylase and 17,20-lyase enzymes and also to investigate the ontogeny of both placental production of androstenedione and enzyme activities, placentas were isolated from rats between days 8-21 of pregnancy and either incubated or used to determine the activities of 17 alpha-hydroxylase and 17,20-lyase. Before day 11, enzyme activity was not detectable. From day 11, both enzyme activities and placental secretion of androstenedione steadily increased to peak values by day 18 and declined just before parturition. To investigate the principal aromatizable androgen secreted both in vivo and in vitro approaches were used. Levels of androstenedione and testosterone found in the uterine vein as well as those produced by placental tissue were determined. Rat placentas secreted markedly more androstenedione than testosterone, both in vivo and in vitro. When placental and luteal secretion of androstenedione and testosterone were compared, it was found that luteal tissue had a higher capacity for androgen synthesis than did the placenta. Yet, because of its greater mass, each placenta secreted 15 times more androstenedione and 4.5 times more testosterone than each corpus luteum. To determine the preferential usage of progesterone or pregnenolone as substrate by the placenta, [14C] progesterone and [3H]pregnenolone were added in equimolar concentrations. The resulting 14C to 3H ratio of the androgen produced indicates that the preferred substrate is progesterone. In summary, results of this investigation describe, for the first time, the development of 17 alpha-hydroxylase and 17,20-lyase activities in the rat placenta and demonstrate that the placenta does not produce androgen before day 11 due to the absence of active enzymes. The results further demonstrate that the rat placenta secretes significantly more androstenedione that testosterone both in vivo and in vitro, produces more androgen than the corpus luteum because of its greater mass, and forms its androgen primarily via the delta 4-st

Aldehyde-Lyases↗
PubMed1986

Adenylate cyclase activity in rat corpora lutea evidence for a rapid development of the regulatory Ns-protein.

Adenylate cyclase activity was studied in membranes from isolated corpora lutea of defined ages obtained from pregnant mare's serum gonadotropin treated rats and the effects of luteinizing hormone (LH), isoproterenol, guanylylimidodiphosphate (Gpp (NH)p), fluoride and forskolin were compared. The effect of LH on adenylate cyclase activity increased with the luteal age up to nine days of age, while the effect of isoproterenol increased dramatically during the first days, reaching a maximum at 2-3 days of age and then declined. Forskolin potentiated the effects of both LH and isoproterenol without affecting the patterns of age-dependency. The effect of forskolin itself was fairly constant during the luteal phase, indicating a relatively constant amount of the catalytic unit in the corpus luteum. The effects of fluoride and Gpp(NH)p on the other hand increased markedly during the first days and then remained constant for the rest of the period studied. These results suggest that the regulatory Ns-protein develops during the first days of luteal life. It is speculated that the close correlation between the development of beta-adrenergic response and the development of Ns-protein are causally related.

Adenylyl Cyclases↗