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M Ferin

Publications and source records attributed to M Ferin.

At least 55 records · Page 3Linked to original sources
PubMed1991

Effects of gonadal steroids on the ultrastructure of GnRH neurons in the rhesus monkey: synaptic input and glial apposition.

The secretion of the gonadotropins is modulated by the gonadal steroids, but the means by which these effects are mediated are not well understood. The present anatomical study was undertaken to investigate the possibility that the GnRH system responds to alterations in the gonadal steroid environment with reversible changes in synaptic input and glial wrapping such as have been observed in other neuroendocrine systems. The ultrastructure of GnRH neurons was studied in the preoptic area and medial basal hypothalamus of rhesus monkeys in various steroid conditions including five intact cycling, four long-term ovariectomized animals, two long-term ovariectomized animals with steroid replacement (LtOVX+), and two animals replaced with steroid at the time of ovariectomy (StOVX+). Electron micrographic montages of GnRH neuronal profiles were analyzed using computerized morphometrics, and the percentages of the length of perikaryal membrane immediately apposed by glial processes and that with postsynaptic modification were calculated. Ovariectomy resulted in a significant increase in the apposition of glial processes to GnRH perikaryal membranes and a significant decrease in their innervation in both brain regions. There was also a higher incidence of GnRH neurons with immunostaining confined to secretory granules and a decrease in the volume of nucleoli, both of which could be interpreted as indications that GnRH peptide synthesis was reduced in ovariectomized animals. After an ovarian steroid replacement regimen which mimicked two menstrual cycles, the innervation of GnRH neurons was increased and the glial ensheathment was partially reduced. This was true for both the LtOVX+ and StOVX+ steroid-replacement groups. GnRH neurons in the medial basal hypothalamus received more synaptic input than did those in the preoptic area, regardless of the steroid condition of the animal. The degree of glial ensheathment of GnRH neurons in the preoptic area became significantly greater than that in the medial basal hypothalamus after ovariectomy. These observations suggest there may be differences in the role of GnRH neurons in these two brain regions. These immunocytochemical ultrastructural studies provide strong evidence that alterations in the gonadal steroid milieu can produce morphological changes in the GnRH neuron and its immediate environment in the primate.

Animals↗
PubMed1990

Interaction between beta-endorphin and alpha-melanocyte-stimulating hormone in the control of prolactin and luteinizing hormone secretion in the primate.

The ability of alpha MSH, a POMC-derived peptide, to antagonize the effects of beta-endorphin (beta EP) on PRL and LH secretion was studied in the primate. Seven ovariectomized rhesus monkeys bearing chronic indwelling third ventricular catheters for peptide infusion were used for these studies. Peripheral blood samples for PRL and LH RIA were obtained every 15 min during a 3-h control period when saline was infused into the ventricle, followed by a 5-h period of peptide infusion at a rate of 25 microliters/h. When beta EP was infused at a dose of 5 micrograms/h, plasma PRL rose from a mean baseline of 3.5 +/- 0.7 ng/ml to a peak of 21.3 +/- 2.2 ng/ml. When the same animals were infused with 20 micrograms alpha MSH together with 5 micrograms beta EP, the peak concentration of PRL was reduced to 8.2 +/- 1.7 ng/ml (P less than 0.001). When a higher dose of beta EP (20 micrograms/h) was infused, PRL rose to a peak of 38.2 +/- 1.8 ng/ml. This response was again markedly blunted, and the peak PRL response was reduced to 7.3 +/- 2.2 ng/ml when 20 micrograms beta EP were infused together with 80 micrograms alpha MSH (P less than 0.001). Analysis of the area under the plasma PRL concentration curves demonstrated a significant reduction in area during the 5-h infusion with beta EP plus alpha MSH compared to that during infusion of beta EP alone. The mean area was reduced from 3480 +/- 570 ng min/ml after 5 micrograms beta EP alone to 1030 +/- 200 after 5 micrograms beta EP plus 20 micrograms alpha MSH and from 6230 +/- 990 after 20 micrograms beta EP to 1020 +/- 320 ng min/ml after 20 micrograms beta EP plus 80 micrograms alpha MSH (P less than 0.01). Des-acetyl alpha MSH (80 micrograms) was also effective in reducing the PRL response to 830 +/- 380 ng min/ml (P less than 0.05). The suppression of pulsatile LH release by beta EP was also attenuated by alpha MSH. During the 5-h infusion of beta EP, total LH secretion was reduced to 65.9 +/- 3.8% of that measured during the 3-h saline infusion compared to 87.2 +/- 2.7% after infusion of beta EP plus alpha MSH (P less than 0.001) or 91.7 +/- 4.1% after beta EP plus des-acetyl alpha MSH (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Unexpected inhibitory action of N-methyl-D,L-aspartate or luteinizing hormone release in adult ovariectomized rhesus monkeys: a role of the hypothalamic-adrenal axis.

N-methyl-D,L,-aspartate (NMA), an analog of the excitatory neurotransmitter aspartate, has been previously shown to acutely stimulate LH release in the rodent and primate. In this study, we examine the effect of NMA on LH secretion in the long term ovariectomized adult rhesus monkey. After a 3-h control period, three successive iv bolus injections of NMA (10 or 45 mg) were administered at hourly intervals, and LH and cortisol responses were compared with those after iv administration of physiological saline. LH concentrations remained unchanged throughout the saline infusion (n = 6) and during the 10-mg NMA injection regimen (n = 5). Unexpectedly, LH decreased during NMA injections at a dose of 45 mg (n = 10): areas under the LH curve, expressed as percentage of baseline control, were: hour 1, -16.0% (+/- 2.7 SE); hour 2, -28.4 (+/- 3.2 SE); hour 3; -30.9 (+/- 3.2 SE), P less than 0.005 vs. saline or 10 mg NMA. This inhibitory effect of NMA was prevented by the coadministration of GnRH (3 micrograms) (n = 5), suggesting that NMA acts at a suprapituitary level. Cortisol secretion was significantly increased by 45 mg of NMA; Total areas under the cortisol curve, expressed as percentage of baseline control, were: saline, -24.2% (+/- 4.2 SE); NMA (10 mg), -24.2 (+/- 2.0); NMA (45 mg), +22.2 (+/- 6.2); P less than 0.001 vs. NMA (10 mg) and saline, suggesting that NMA at the higher dose may activate the adrenal axis. To examine a possible role of the adrenal axis on NMA-induced LH inhibition, we next examined the effects of intraventricular administration of antiserum to CRF. Pretreatment with CRF antiserum prevented the decrease in LH levels seen during NMA (45 mg) in 4 of 8 monkeys (hour 2, -8.5% (+/- 6.5); hour 3, -10.3% (+/- 4.3); P less than 0.01 vs. NMA). The NMA-induced cortisol increase was prevented in the antiserum responsive but not in the nonresponsive animals. A similar preventive action on LH was seen after administration of the endogenous opiate receptor antagonist naloxone (2 or 5 mg/h), most notably in caged animals (n = 4: hour 1, 6.2% (+/- 3.8); hour 2, -2.8 (+/- 4.0); hour 3, -9.9 (+/- 5.0); P less than 0.005 vs. NMA, 45 mg, for hour 1 and hour 2). We conclude that the unexpected inhibitory effects of NMA on LH secretion in the adult ovariectomized monkey are the result of the activation of the hypothalamic-pituitary-adrenal axis by NMA and specifically of the release of CRF and endogenous opioid peptides.

Animals↗
PubMed1989

Dexamethasone treatment prevents the inhibitory effect of corticotropin-releasing hormone on gonadotropin release in the primate.

Corticotropin-releasing hormone (CRH) has been shown to inhibit gonadotropin secretion and this effect is mediated by endogenous opioid peptides, presumably stimulated by CRH. Since glucocorticoids are known to block the CRH-induced ACTH response, it can be hypothesized that by concurrently preventing endogenous opioid peptide release, they would also prevent the inhibitory action of CRH on gonadotropin secretion. We tested this hypothesis in 4 ovariectomized rhesus monkeys, pretreated with dexamethasone (DEX; 1.5 mg b.i.d. for 5 days). In experiment 1, the effects of a 5 h i.v. hCRH infusion with or without DEX pretreatment and of physiological saline were compared. Blood samples were taken at 15-min intervals during a 3 hour preinfusion control and throughout the infusion. Sera were assayed for luteinizing hormone (LH), follicle-stimulating hormone (FSH) and cortisol by RIA. In the absence of DEX pretreatment, LH and FSH levels were progressively decreased during the CRH infusion: by hour 5, LH and FSH areas under the curve were 34.1 ( +/- 7.6) and 65.3% ( +/- 2.5) (mean % of preinfusion control values; + SE), respectively (p less than 0.01 vs. saline). In contrast, DEX pretreatment prevented the CRH-induced gonadotropin decrease: by hour 5, LH and FSH areas under the curve were 91.9 ( +/- 9.0) and 99.0% ( +/- 5.7) (n.s. vs. saline). In experiment 2, we tested whether DEX-treated monkeys would remain responsive to the gonadotropin inhibitory action of an opiate agonist. After a 3 hour preinfusion control baseline, morphine (9 mg i.v.) was given as a bolus injection to the same 4 animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Acute inhibition of gonadotropin secretion by corticotropin-releasing hormone in the primate: are the adrenal glands involved?

To investigate the role of the adrenal glands in the acute inhibition of gonadotropins induced by CRH in the primate, we have compared the effects of CRH infusion on LH and FSH before and after adrenalectomy and under variable glucocorticoid backgrounds. The studies were performed in four ovariectomized rhesus monkeys. Confirming previous observations, a 5-h iv CRH (rat/human CRH, 100-150 micrograms/h), but not saline, infusion inhibited both LH and FSH secretion. Saline and CRH infusions were repeated at random intervals after adrenalectomy under each of three different glucocorticoid backgrounds, achieved by varying the glucocorticoid replacement therapy (groups 1-3). At the time of the saline or CRH tests, mean cortisol concentrations were 38.5 +/- 6.3 (+/- SE) micrograms/dl before adrenalectomy, and 21.9 +/- 1.4, 14.3 +/- 1.1, and less than 1.0 micrograms/dl in groups 1, 2, and 3 of adrenalectomized (ADX) monkeys. In response to CRH infusion, gonadotropin concentrations significantly decreased in groups 2 and 3, but not in group 1 ADX monkeys which had the highest cortisol background. By hour 5 of CRH infusion, the percentages of the preinfusion baseline area under the curves for LH were 96.8 +/- 6.2%, 44.6 +/- 3.7%, and 53.5 +/- 6.1%, for groups 1, 2, and 3; by hour 4 the values for FSH were 95.7 +/- 3.5%, 76.2 +/- 4.7%, and 74.7 +/- 4.0% for groups 1-3, respectively. The absence of a response to CRH in group 1 animals occurred even though mean cortisol concentrations were lower than those in the same monkeys before ADX. Morphine (9 mg, iv), which had previously been shown to decrease LH and FSH concentrations in ovariectomized monkeys, also significantly decreased LH and FSH concentrations in ADX monkeys of group 1, which did not respond to CRH. The maximal decline occurred by hour 3 after morphine injection, when LH and FSH areas under the curve were 51.5 +/- 11.4% and 61.0 +/- 3.2% of the preinfusion baseline. Our results clearly indicate that in the primate the adrenal glands are not required for the acute CRH inhibitory effect on LH and FSH, and consequently, the decrease in gonadotropins that follows CRH is not mediated by the resultant increase in cortisol release, but, rather, by central mechanisms. The results also show that the effectiveness of CRH in inhibiting gonadotropins in the ADX monkey is affected by the amount of glucocorticoids present at the time of the test; unexpectedly, the ADX monkey is more sensitive to this protective effect of glucocorticoids than the non-ADX animal.

Adrenal Glands↗
PubMed1988

Glucolimnanthin, a plant glucosinolate, increases the metabolism and DNA binding of benzo[a]pyrene in hamster embryo cell cultures.

Glucosinolates are common components of cruciferous vegetables that can be hydrolyzed during food processing to yield isothiocyanates, some of which have been shown to inhibit the induction of mammary tumors in rats by 7,12-dimethyl-benz[a]anthracene. To determine how intact glucosinolates affect the metabolism of benzo[a]pyrene (B[a]P) in mammalian cells in culture, the effects of a series of glucosinolates on the metabolism and DNA binding of B[a]P were investigated in early passage Syrian hamster embryo cell cultures. Glucolimnanthin, a glucosinolate from Limnanthes douglasii increased the amount of B[a]P metabolized by the hamster embryo cell cultures during a 24 h exposure. The glucolimnanthin-treated cultures contained a higher proportion of B[a]P-phenol glucuronides and other water-soluble metabolites than control cultures. Cotreatment with glucolimnanthan and [3H]B[a]P for 24 h resulted in a greater than 2-fold increase in the amount of B[a]P bound to DNA and a 3-fold increase in the amount of deoxyguanosine adduct formed by reaction of 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydroB[a]P [(+)-anti-B[a]PDE]. The glucolimnanthin was metabolized essentially completely within 24 h. An increase in B[a]P metabolism similar to that caused by glucolimnanthin was induced by cotreatment of hamster embryo cell cultures with m-methoxybenzyl isothiocyanate, a metabolite that can be formed from glucolimnanthin by enzymatic hydrolysis. These results indicate that the glucosinolate glucolimnanthin can increase the metabolic activation of B[a]P in mammalian cells in culture.

Animals↗
PubMed1988

The inhibitory action of corticotropin-releasing hormone on gonadotropin secretion in the ovariectomized rhesus monkey is not mediated by adrenocorticotropic hormone.

Earlier observations in our laboratory indicated that i.v. infusion of human/rat corticotropin-releasing hormone (hCRH) suppresses pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in ovariectomized rhesus monkeys. Since cortisol secretion increased significantly as well, it was not possible to exclude the possibility that this inhibitory effect of hCRH on gonadotropins was related to the activation of the pituitary/adrenal axis. The purpose of the present study was to determine the role of pituitary/adrenal activation in the effect of hCRH on LH and FSH secretion. We compared the effects of 5-h i.v. infusions of hCRH (100 micrograms/h, n = 7) and of human adrenocorticotropic hormone (ACTH) (1-24) (5 micrograms/h, n = 3; 10 micrograms/h, n = 3, 20 micrograms/h, n = 3) to ovariectomized monkeys on LH, FSH, and cortisol secretion. As expected, during the 5-h ACTH infusions, cortisol levels increased by 176-215% of baseline control, an increase similar to that observed after CRH infusion (184%). However, in contrast to the inhibitory effect observed during the CRH infusion, LH and FSH continued to be released in a pulsatile fashion during the ACTH infusions, and no decreases in gonadotropin secretion were observed. The results indicated that increases in ACTH and cortisol did not affect LH and FSH secretion and allowed us to conclude that the rapid inhibitory effect of CRH on LH and FSH pulsatile release was not mediated by activation of the pituitary/adrenal axis.

Adrenocorticotropic Hormone↗
PubMed1988

Transplanted gonadotropin-releasing hormone neurons promote pulsatile luteinizing hormone secretion in congenitally hypogonadal (hpg) male mice.

Congenitally hypogonadal (hpg) male mice are unable to synthesize biologically active gonadotropin-releasing hormone (GnRH). Implantation of normal fetal preoptic area tissue containing GnRH neurons into the third ventricle of adult hpg males significantly elevates pituitary levels of luteinizing hormone (LH) and corrects their hypogonadism. In all responding animals, immunoreactive GnRH neurons within the transplant innervate the median eminence of the host. To assess whether gonadal recovery in hpg hosts results from pulsatile secretion of GnRH from grafted neurons, we compared the pattern of variation in plasma LH levels in 19 hpg graft recipients with testicular growth to that of 10 normal adult mice. All animals were castrated prior to receiving an indwelling catheter in the jugular vein. Sequential blood samples were collected (t = 10 min) and assayed for LH. Pulsatile LH secretion was seen in 11 of 19 hpg hosts and in all control mice. While there was great variability between individual animals, measures of baseline LH, LH pulse amplitude and duration, interpulse interval, and LH pulse frequency revealed no difference between hpg graft recipients and normal castrates in their LH pulse pattern. Immunocytochemical analysis of the brain in hpg hosts suggested no correlation between any parameter of pulse activity and individual differences in GnRH cell number or GnRH fiber outgrowth into the median eminence. Sources of variation in LH secretion among graft recipients, and between hpg hosts and normal mice, are discussed. We suggest that transplanted GnRH neurons are capable of integration into a GnRH 'pulse generator' which can support a near-normal pattern of pulsatile LH secretion, leading to testicular growth and steroid production.

Animals↗
PubMed1988

Sustained effects of opioid antagonism during the normal human luteal phase.

The luteal phase of the menstrual cycle is characterized by a progressive decrease in LH pulse frequency. Short term administration of opiate receptor antagonists during the luteal phase increases the release of both LH and PRL. However, the effects of prolonged opioid antagonism throughout the luteal phase are unknown and, hence, the precise role of endogenous opioid peptides in the reproductive cycle remains to be elucidated. In this study, we examine the ability of longer term opioid antagonism during the luteal phase to alter pulsatile LH and PRL release. Naltrexone (NTX), a long-acting oral opioid antagonist, at a dose of 50 mg, was administered daily for 7 days during the luteal phase in five women. Blood samples were obtained at intervals of 10 min starting at 0800 h for 11-12 h on matched days of the luteal phase of both a control and the experimental cycle. LH and PRL pulse frequencies were significantly increased at the end of the 7-day NTX administration period compared to those in the control cycle [LH, 0.22 +/- 0.04 (+/- SE) vs. 0.07 +/- 0.03 pulse/h (P less than 0.01); PRL, 0.20 +/- 0.02 vs. 0.13 +/- 0.02 pulse/h (P less than 0.05)]. The concordance between LH and PRL pulses increased from 50% in the control cycle to 70% in the NTX cycle, and there was a significant positive correlation between the amplitudes of the concomitant LH and PRL pulses (r = 0.72; P = 0.01). In conclusion, prolonged oral opioid antagonism increased pulsatile LH and PRL secretion during the luteal phase in normal women. The results underscore the important role of endogenous opioid peptides in controlling LH pulse frequency during the luteal phase of the cycle.

Adult↗
PubMed1987

Is the decrease in the hypophysiotropic signal frequency normally observed during the luteal phase important for menstrual cyclicity in the primate?

The two phases of the ovulatory menstrual cycle of the primate are characterized by divergent activities of the GnRH pulse generator. During the luteal phase, LH pulse frequency is significantly reduced below that observed during the follicular phase. In this report we investigate whether the decrease in pulse frequency during the luteal phase is of physiological relevance to normal menstrual cyclicity. We have tested the effect of a pulsatile GnRH infusion given iv at hourly intervals for a period of 8-10 days during the luteal phase on the subsequent three to five cycles in eight female rhesus monkeys. Three of the eight animals received two treatment courses. Amounts of GnRH infused were 1.5 micrograms/pulse (n = 2 trials); 3.0 micrograms/pulse (n = 7); and 4.0 micrograms/pulse (n = 2). LH response to GnRH pulses of 1.5 and 3.0 micrograms resembled spontaneous LH pulses observed during the luteal phase. During the GnRH infusion period, the monkeys were fitted with a primate vest and tethered. Eleven control experiments were performed in these monkeys under similar conditions. GnRH therapy during the luteal phase affected subsequent cycles significantly, while no differences were observed in the control experiments. Overall mean follicular phase length in the control cycle was 13.4 days; it was significantly increased (P less than 0.005) in all post-GnRH treatment cycles to reach 34.4 (+/- 10.9), 43.9 (+/- 12.7), 40.4 (+/- 13.0), and 23.1 (+/- 4.8) days (+/- SE) in the first to fourth post-GnRH cycles, respectively. Progesterone secretion was significantly lower (P less than 0.05) in the first two post-GnRH cycles than in the control cycles: progesterone, 46.4 (+/- 2.1) in all control cycles, decreased to 27.7 (+/- 3.7), 24.8 (+/- 4.3), 34.0 (+/- 5.4), and 32.0 (+/- 6.5) surface units (+/- SE) from the first to fourth post-GnRH cycles, respectively, while luteal phase length remained relatively unchanged. The data indicate that significant disturbances in the menstrual cycle of the rhesus monkey follow imposed changes in the normal frequency pattern of the GnRH hypophysiotropic signal during the luteal phase and suggest that the naturally occurring slowing of GnRH-LH pulse frequency during the luteal phase is a relevant phenomenon in the sequence of events which control menstrual cyclicity.

Animals↗
PubMed1987

Endogenous opioid peptides modulate the effect of corticotropin-releasing factor on gonadotropin release in the primate.

Stress can induce endocrine abnormalities and menstrual dysfunction in the primate. Here, we examine the effects that CRF, the principal neurohormone in control of the hypothalamic-pituitary-adrenal axis, exerts on pulsatile gonadotropin secretion and the role that the endogenous opioid peptides may play in this phenomenon. Ovariectomized rhesus monkeys were given a 5-h continuous iv infusion of physiological saline (2 ml/h), human CRF (100 micrograms/2 ml . h), or hCRF plus the opiate receptor antagonist naloxone (2 mg/2 ml/h; 5 mg in two experiments; n = 7 experiments/group). LH and FSH concentrations were measured at 15-min intervals for a 3-h preinfusion baseline control, during the 5-h infusion, and during a 2-h postinfusion observation period, while cortisol concentrations were measured at frequent intervals during the entire experiment. CRF infusion produced a progressive and significant decrease in both LH and FSH. Mean areas (+/- SE) under the LH and FSH curves during the 5-h CRF infusion, expressed as a percentage of preinfusion baseline, were 59.9 +/- 4.6% and 83.0 +/- 3.1% (+/- SE), respectively (P less than 0.001 and P less than 0.01 vs. saline controls). Large amplitude LH pulses were abolished during the CRF infusion. However, after cessation of CRF infusion, there was a rapid resumption of LH pulsatile release in four of the seven experiments. Addition of naloxone to CRF prevented the CRF-mediated suppression of LH and FSH release. Mean areas for LH and FSH during the 5-h combined infusion were 100.3 +/- 6.6% and 99.6 +/- 4.3% of the preinfusion baseline, respectively (P less than 0.001 and P less than 0.05 vs. CRH alone; NS vs. saline), and pulsatile LH secretion was maintained. Regardless of whether naloxone was administered, CRF increased cortisol levels significantly. Mean cortisol levels at the end of the CRF and CRF plus naloxone infusions were 48.2 +/- 10.4 and 52.9 +/- 7.4 micrograms/dl (+/- SE), respectively, compared to 21.0 +/- 3.0 with saline (P less than 0.05). These results demonstrate that in the ovariectomized rhesus monkey, CRF suppresses the secretion of both LH and FSH, and this effect can be sustained. They also indicate that the CRF inhibitory action on gonadotropin is primarily mediated by endogenous opioid peptides, independent of glucocorticoid levels.

Animals↗
PubMed1987

Corticotropin-releasing hormone inhibits gonadotropin secretion in the ovariectomized rhesus monkey.

To evaluate whether the compromised gonadotropin secretion frequently occurring during stressful conditions in the primate may be related to an inhibitory action of CRH, the effects of ovine (oCRH) or human (hCRH) CRH on gonadotropin and cortisol secretion were studied in ovariectomized rhesus monkeys. LH secretion (assessed as area under the curve) decreased 35% and 21%, and cortisol increased 37% and 90%, 1-3 h after single iv injections of 200 and 500 micrograms oCRH, respectively (P less than 0.05 vs. pre-CRH control period; n = 4-7/dose). Single injections of 200 and 500 micrograms hCRH, respectively, resulted in 35% and 24% decreases in LH and 40% and 79% increases in cortisol secretion (P less than 0.05). Injections of 100 micrograms oCRH and hCRH elicited significant (P less than 0.05) increases in cortisol release (37% and 31%, respectively), but did not affect LH secretion. A 5-h infusion of hCRH (100 micrograms/h) reduced LH levels (23%, 49%, 59%, 61%, and 62% during the first through the fifth hour, respectively; P less than 0.05 for hours 2-5). FSH secretion also decreased during the hCRH infusion (26%, 33%, 42%, 46%, and 49% during the first through the fifth hour, respectively; P less than 0.05 for hours 3-5), while cortisol increased 76%. These data demonstrate that exogenous CRH administration results in inhibition of LH and FSH secretion in ovariectomized rhesus monkeys. These results are consistent with the hypothesis that elevated CRH levels could contribute to decreased LH and FSH secretion and, thus, disruption of reproduction function under conditions of stress in primates.

Animals↗
PubMed1987

The treatment of luteal phase defects with pulsatile infusion of gonadotropin-releasing hormone.

Because pulsatile administration of gonadotropin-releasing hormone (GnRH) can initiate normal follicular maturation and corpus luteum function in women with hypothalamic amenorrhea, the authors attempted to treat five women with inadequate and one with short luteal phase with GnRH therapy. Pulsatile administration of GnRH (5 micrograms intravenously every 90 minutes) was begun on days 1 to 4 and continued throughout the cycle. Blood levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, and progesterone were monitored daily throughout the control and treatment cycles. There were 12 GnRH treatment cycles, all of them ovulatory. The length of the induced luteal phases varied from 11 to 17 days in all patients. Mean progesterone levels during GnRH treatment were significantly increased over those of the matched control cycles (control cycle 3.5 +/- 0.5 ng/ml; treatment cycle 8.2 +/- 1.45 ng/ml [mean +/- standard error]). Endometrial biopsies obtained during the luteal phase (days 25 to 27) in five women were in phase during the GnRH treatment cycle, in contrast to the control cycle in which they were two or more days out of phase. One patient achieved pregnancy during the treatment cycle, but aborted spontaneously at 8 1/2 weeks. The data demonstrate that pulsatile GnRH infusion, when initiated in the early follicular phase, can restore normal corpus luteum function in women with luteal phase defects.

Estrogens↗
PubMed1985

Gonadotropin-releasing hormone pulses in third ventricular cerebrospinal fluid of ovariectomized rhesus monkeys: correlation with luteinizing hormone pulses.

Morphological evidence suggests that GnRH may be released into cerebrospinal fluid (CSF) of the third ventricle. Therefore, a method of cannulating the third ventricle of monkey brains was developed for the purpose of examining GnRH secretion in primates. A stainless steel guide cannula was stereotaxically implanted into the third ventricle of 14 ovariectomized rhesus monkeys. A Silastic cannula for collecting CSF was inserted via the guide cannula into the ventral portion of the ventricle, permitting repeated CSF sampling for long time periods from the same animal. One week to 6 months after cannulation, CSF was collected continuously for periods of 5-10 h at 2 different rates (480 and 120 microliter/h) from conscious monkeys seated in chairs. Samples were divided into 15-min fractions, and the GnRH concentration in each was determined by RIA. In contrast to most previous studies, third ventricular CSF was found to contain significant concentrations of GnRH. GnRH was detected in 40 of 50 collections. Concentrations ranged from less than 8 to greater than 800 pg/ml, a range similar to that observed in hypophyseal portal blood. Furthermore, fluctuations within individual collections indicated that GnRH was released in pulses. The mean GnRH pulse frequency during the higher rate of CSF withdrawal was 0.43 +/- 0.06 pulses/h (n = 31), while the mean pulse amplitude was 91 +/- 7 pg/ml (n = 64). Neither parameter was influenced by the rate of CSF removal, as frequency was 0.52 +/- 0.08 pulses/h (n = 19) and amplitude was 94 +/- 11 pg/ml (n = 82) during the lower collection rate. However, the CSF withdrawal rate had a profound influence on LH secretion. In 12 of 17 collections at the higher rate, LH levels plummeted to undetectable concentrations during the first 2 h of CSF exfusion and remained low throughout the collection period. Pituitary responsiveness was not reduced, as a GnRH bolus (0.25 or 2.5 micrograms) after 6 h of CSF removal elicited a dose-dependent stimulation of LH secretion. In contrast, a higher incidence of normal pulsatile LH secretion (12 of 19 collections) was observed when the CSF withdrawal rate was reduced. During these 12 collections, LH and GnRH pulses occurred at regular intervals and exhibited similar pulse frequencies (mean +/- SE, 0.76 +/- 0.07 and 0.67 +/- 0.09 pulses/h for LH and GnRH, respectively). Most GnRH and LH pulses were synchronized, as 86% of all GnRH pulses (43 of 50) were accompanied by a LH pulse.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Effects of an antiprogesterone agent, RU-486, on the menstrual cycle of the rhesus monkey.

RU-486 (RU), a synthetic steroid with antiprogesterone receptor activity, was used to study the role of progesterone in the normal menstrual cycle of rhesus monkeys. The drug, at dosages of 2, 4, or 12 mg/kg, was administered as a single im injection during the luteal phase (days 5-8) in 16 experiments in 8 monkeys. RU had acute effects on the endometrium, as it induced menstruation within 3 days in spite of persistant progesterone elevations, thereby shortening the cycle length by about 5 days. Long term effects on menstrual cyclicity were also found with the higher RU doses. The intermenstrual interval after RU treatment increased from 31.8 +/- 2.4 (+/- SE) days after a 2 mg/kg dose of RU to 82.4 +/- 6.8 days after a 12 mg/kg dose of RU, with a control cycle length of 29.4 +/- 0.7 days. This prolonged interval was related to a delay in the completion of the follicular maturation process and, therefore, a delay in ovulation, as judged by estrogen and progesterone concentrations. Subsequent menstrual cycles were regular and ovulatory. Our results suggest that RU binds to the endometrial progesterone receptor, thereby inducing premature menstruation in the presence of elevated progesterone levels. RU also exerts long term effects on the hypothalamo-hypophyseal axis, since it significantly alters menstrual cyclicity.

Animals↗
PubMed1984

Pulsatile administration of gonadotropin-releasing hormone for induction of ovulation.

Chronic pulsatile administration of gonadotropin-releasing hormone (GnRH) was used to induce ovulation in 12 women with various ovulatory disorders. In the first group of eight patients with normal to low baseline levels of gonadotropin, seven responded favorably to the treatment. Follicular maturation was observed in 57% of the treated cycles, and normal ovulatory cycles were induced in 24% of the patients. Two patients became pregnant. The intravenous route of administration was more effective than the subcutaneous one, possibly in response to the GnRH profile after each pulse. (The amplitude of GnRH peaks after an intravenous pulse was four times that seen after a subcutaneous one.) In contrast, follicular maturation and ovulation could not be induced in four women of a second group of patients with normal baseline levels of follicle-stimulating hormone but with high and frequent pulses of luteinizing hormone. The conclusion reached was that pulsatile administration of GnRH can be a new therapeutic tool in the treatment of ovulatory disorders in women who have an insufficient endogenous release of GnRH.

Adult↗