Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients. Here we present a promising approach to address these limitations by utilization of a macrochamber specially engineered for islet transplantation. The s.c. implantable device allows for controlled and adequate oxygen supply and provides immunological protection of donor islets against the host immune system. The minimally invasive implantable chamber normalized blood glucose in streptozotocin-induced diabetic rodents for up to 3 mo. Sufficient graft function depended on oxygen supply. Pretreatment with the growth hormone-releasing hormone (GHRH) agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing β-cell insulin reserve in rats thereby allowing for a reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Consequently, this system opens up a fundamental strategy for therapy of diabetes and may provide a promising avenue for future approaches to xenotransplantation.     

Effect of treatment with an agonist of luteinizing hormone releasing hormone on early maturational changes in pituitary and testicular function in the rat.

Male rats aged 30 days were injected once daily for between 1 and 7 days with 50 ng (D-serine t-butyl6, des-glycine-NH210) luteinizing hormone releasing hormone ethylamide (LH-RH agonist), and pituitary and testicular function were assessed. Treatment for 7 days significantly (P less than 0.02) inhibited maturational increases in the pituitary content and serum concentration of gonadotrophins, testicular luteinizing hormone (LH)-receptor concentration and the testicular capacity to secrete testosterone; the pituitary content and serum concentration of prolactin, the hypothalamic content of LH-RH and testicular weight were unaffected. In rats treated with LH-RH agonist, the initial (2 to 3 days) reduction in testicular LH-receptors and the capacity to secrete testosterone probably resulted from acutely raised levels of LH in the blood, whilst later effects may have resulted from the apparently chronic reduction in serum gonadotrophin levels. The latter may reflect a decrease in pituitary responsiveness to repeated stimulation with LH-RH agonist. Despite the extensive loss of testicular LH-receptors and diminished responsiveness, the concentration of HCG which significantly (P less than 0.05) increased testosterone secretion by the testis in vitro was the same (2 pmol/l) as that for testes from control rats.     

An implant of a gonadotropin releasing hormone agonist (buserelin) which suppresses ovarian function in the macaque for 3-5 months

Four adult female stumptailed macaque monkeys with regular menstrual cycles and one with irregular cycles and dysfunctional uterine bleeding were treated with a single implant containing 2.6 mg of the GnRH agonist buserelin in a matrix of polylactide/glycolide copolymer (75:25). The implant was used as a cylindrical rod of 0.8 X 0.12 cm and implanted sc in the abdominal wall. The insertion of the implant was followed by a modest rise in serum concentrations of LH and FSH lasting 3-4 days before falling to basal values. The release profile of buserelin from the implant was measured in urine by a radioimmunoassay detecting the intact molecule and its major metabolites. Immunoreactive buserelin in urine was high between days 1-3 after implant after which there was a rapid decline to form a plateau between days 15-70 followed by a further gradual decline. This prolonged release of buserelin suppressed ovulation for a mean of 148 days (range 105-182 days) as indicated by absence of serum progesterone rises. Serum FSH concentrations were low for at least 75 days and during this time serum oestradiol concentrations were uniformly suppressed in all monkeys. Once the buserelin release from the implant declined serum FSH concentrations began to rise. There was a variable delay of 7-60 days before this rise in FSH was associated with stimulation of ovarian oestradiol secretion followed by rises in serum progesterone concentrations indicative of ovulation. Apart from the first menses after insertion of implant, 4 of the monkeys became amenorrhoeic for the period of anovulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

A central action of alpha-melanocyte-stimulating hormone on serum levels of LH and prolactin in rats

We have investigated the effect of administration of alpha-MSH into the median eminence (ME) of rats on the release of LH and prolactin. Continuous infusion of alpha-MSH (0.5 micrograms/h) into the ME from the afternoon of the second day of dioestrus and over the 24 h of pro-oestrus inhibited the preovulatory LH and prolactin surge and the occurrence of ovulation. This inhibitory effect on LH and prolactin release was also observed in chronically ovariectomized rats given a single injection of alpha-MSH (1 micrograms/ml per rat) into the ME (blood samples were collected 0, 20, 60, 90, 105 and 120 min after injection). The intraperitoneal injection of the dopamine receptor blocker, haloperidol (2 mg/kg), 30 min before the injection of alpha-MSH into the ME prevented the inhibitory effect of alpha-MSH on the release of LH and prolactin. These results suggest that hypothalamic alpha-MSH might be involved in the regulation of LH and prolactin release via the tuberoinfundibular dopaminergic system and that this system also modifies the serum concentrations of alpha-MSH.     

Effects of chronic treatment with oestrogen, an oestrogen antagonist and a potent luteinizing hormone releasing hormone agonist analogue on pituitary responsiveness to luteinizing hormone releasing hormone in the rat

The rise in gonadotrophin release which occurs after ovariectomy is caused by steroid withdrawal resulting in an enhanced pituitary responsiveness to LH releasing hormone (LHRH) associated with increased LHRH release and pituitary LHRH binding. The effects of oestrogen replacement after ovariectomy and chronic treatment of intact rats with an oestrogen antagonist, tamoxifen, on LH release and in-vitro pituitary responses to LHRH have been investigated. Capsules containing crystalline oestradiol, implanted at the time of ovariectomy, completely inhibited the rise in LH release although pituitary responsiveness was greater after 10 days in the oestrogen-treated rats than in untreated ovariectomized controls. On day 4 after ovariectomy pituitary responses to LHRH were comparable in both treated and untreated groups although in both groups the responses were greater than those measured in intact dioestrous rats. Treatment with tamoxifen over a 4-day period also augmented pituitary responsiveness but only at the lowest dose (0.5 mg/kg); no effect on serum LH concentrations was observed. Higher doses of the antagonist (1 and 2 mg/kg) did not affect pituitary responses, although the highest dose did cause a significant rise in serum LH. Treatment with a daily dose of 50 ng [D-Ser(But)6]LHRH(1-9)nonapeptide-ethylamide, starting on the day of ovariectomy, markedly attenuated the LH responses to LHRH ex vivo at days 2, 4 and 10 after ovariectomy. In contrast, the analogue treatment did not abolish the rise in LH release but this was proportionately less than in controls.     

Effect of immunoneutralization of LH releasing hormone on LH, FSH and ovarian steroid secretion in the preovulatory phase of the oestrous cycle in the ewe

Immunoneutralization of LH releasing hormone (LHRH) by the i.v. administration of LHRH antiserum in the preovulatory period in the ewe resulted in a prompt abolition of the pulsatile secretion of LH without alteration of basal plasma levels of LH. This resulted in an immediate cessation of the pulsatile secretion of ovarian oestradiol, with no change in the secretion rate of androstenedione or plasma levels of FSH. The ovarian secretion rate of testosterone increased significantly. Twenty to 22h after the injection of LHRH antiserum, pulsatile secretion of LH and ovarian oestradiol and androgen secretion remained suppressed while plasma levels of FSH had increased significantly. The bolus injection of ovine LH (10 micrograms, i.v.) at this time caused a significant increase in oestradiol, androstenedione and testosterone, these responses being inversely related to the titre of LHRH antiserum in the plasma at this time. These results show that (1) the secretion of oestradiol from the preovulatory sheep follicle is entirely dependent on the pulsatile secretion of LH and (2) since the secretion of ovarian androgens was not inhibited, LH may exert a short-term control over the aromatase enzyme system controlling the conversion of androgen to oestrogen in the granulosa cell of the preovulatory sheep follicle.     

Effect of chronic thyroid hormone treatment on cycling, ovulation, serum reproductive hormones and ovarian LH and prolactin receptors in rats

We studied the effect on cycling, ovulation and hormone secretion of a chronic thyroxine treatment (HT, 1 mg/kg,S.C., daily, initiated at oestrus) on female rats. HT rats showed normal 4-day vaginal cycles on the first three cycles after initiation of the treatment, but on the fourth cycle had a prolonged oestrus and subsequently entered in constant di-oestrus. In spite of the normal vaginal cycles only 66%, 50%, 33% and 10% of the HT rats ovulated on cycles 1 to 4 respectively. In contrast, during cycles 2 and 3, ovulating HT rats shed a significantly greater number of ova than controls. Hormones were measured at 12.00 and 18.00 h (pre-ovulatory) on prooestrus and at 11.00 h on oestrus. HT ovulating rats had normal LH levels on the first two cycles, but low levels on the third one, while non-ovulating HT rats had low preovulatory LH levels. Serum FSH concentrations were elevated in all the HT rats on cycles 1 and 2 and on pro-oestrus morning in cycle 3 and may have been responsible for the increase in ovulation rate. On oestrus, ovulating HT rats had higher FSH values than nonovulating ones. Serum prolactin levels were similar to controls in all the HT rats on cycle 1, but on the subsequent cycles pre-ovulatory levels were lower than controls in all the HT rats, while values were increased in the non-ovulating HT rats on the third and fourth oestrus mornings. Pro-oestrous serum oestradiol concentrations in all the HT rats were not different from controls on cycles 1 and 2 and diminished on 3 and 4. Oestrous levels were significantly lower on the cycle 1 and only on the nonovulating HT rats on cycle 2. Serum progesterone levels had values similar to those of FSH, with increased values in the first two cycles. Serum corticosterone levels were increased in the mornings of cycles 2 and 3, but values were normal on the fourth one. Ovarian prolactin and LH receptor mRNAs, measured on HT rats on the third prooestrus by Northern blotting, showed significant increases in all the majoritary molecular forms (2.5 and 7 kb for LH receptor and 0.9, 2.9–3, 5 and 10 kb for the prolactin receptor) with respect to control pro-oestrous rats. These results show a progressive disruption of cycling, ovulation and hormonal secretion after the initiation of a chronic thyroid hormone treatment in rats, which eventually lead to an anovulatory state. These results may be of importance for the interpretation of the reproductive disfunctions provoked by hyperthyroidism in women.     

Clinical and hormonal effects of chronic gonadotropin-releasing hormone agonist treatment in polycystic ovarian disease

Previously, we reported that short term administration of a highly potent GnRH agonist (GnRHa) for 1 month to patients with polycystic ovarian disease (PCO) resulted in complete suppression of ovarian steroidogenesis without measurable effects on adrenal steroid production. This new study was designed to evaluate the effects of long term GnRHa administration in PCO patients with respect to their hormone secretion patterns and clinical responses. Eight PCO patients and 10 ovulatory women with endometriosis were treated daily with sc injections of [D-His6-(imBzl]),Pro9-NEt]GnRH (GnRHa; 100 micrograms) for 6 months. Their results were compared to hormone values in 8 women who had undergone bilateral oophorectomies. In response to GnRHa, PCO and ovulatory women had rises of serum LH at 1 month, after which it gradually declined to baseline. In both groups FSH secretion was suppressed throughout treatment. Serum estradiol, estrone, progesterone, 17-hydroxyprogesterone, androstenedione, and testosterone levels markedly decreased to values found in oophorectomized women by 1 month and remained low thereafter. In contrast, serum pregnenolone and 17-hydroxypregnenolone were partially suppressed, and dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol levels did not change. Clinically, hyperplastic endometrial histology in three PCO patients reverted to an inactive pattern, and proliferative endometrium in two other PCO patients became inactive in one and did not change in the other. Regression of proliferative endometrial histology occurred in all ovulatory women. Vaginal bleeding occurred in all women studied during the first month of GnRHa administration, after which all but one PCO patient became amenorrheic. Hot flashes were noted by all ovulatory women and by four of eight PCO patients. All PCO patients noted subjective reduction of skin oiliness, and five had decreased hair growth. We conclude that in premenopausal women: 1) chronic GnRHa administration results in apparently complete persistent suppression of ovarian steroid secretion; 2) adrenal steroid secretion is not influenced directly or indirectly; and 3) its use may be helpful in the treatment of endometrial hyperplasia and ovarian androgen excess in women with PCO.     

Concordant suppression of serum immunoreactive luteinizing hormone (LH), follicle-stimulating hormone, alpha subunit, bioactive LH, and testosterone in postmenopausal women by a potent gonadotropin releasing hormone antagonist (detirelix).

The purposes of the current study were 2-fold: 1) to assess the effects of a new antagonistic analog of GnRH [N-Ac-D-Nal(2)1, D-pC1-phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] GnRH, or detirelix (Syntex Research) on gonadotrope function as reflected by serum levels of immuno- and bioassayable LH, and immunoactive FSH and alpha-subunit concentrations in postmenopausal, hypergonadotropic women; and 2) to determine if androgen production in the postmenopausal ovary is gonadotropin dependent. Six normal postmenopausal women were studied. Each volunteer received doses of 1, 5, and 20 mg detirelix sc in a random order separated by at least a 1-week interval. Serum LH, FSH, and alpha-subunit were measured by RIA at frequent intervals for 72 h after each injection. Bioactive LH levels were measured at 0, 24, 48, and 72 h after injection by a mouse Leydig cell bioassay, to permit comparison of biological with immunological LH activity. The steroids testosterone (T) and dehydroepiandrosterone sulfate were measured before injection and 12 (T only), 24 and 48 h after injection of the 20 mg dose. Immunoactive levels of serum LH and FSH were both suppressed in a dose-dependent manner, but LH suppression was greater than that of FSH. Maximum LH suppression (mean +/- SEM) after the 1, 5, and 20 mg doses was 40.2 +/- 7.0%, 63.2 +/- 3.4%, and 75.8 +/- 2.2%, respectively. For the same doses, maximum FSH suppression was 18.0 +/- 6.0%, 25.6 +/- 4.6%, and 39.6 +/- 2.7%. LH levels remained suppressed below baseline for up to 72 h after the 20 mg dose. Bioactive LH changes closely paralleled those of immunoactive LH. Mean LH suppression (area under the serum concentration curve) during the first 24 h after injection was 23.5 +/- 6.2% for the 1-mg dose, 47.2 +/- 4.7% for the 5-mg dose, and 61.0 +/- 2.1% for the 20-mg dose. Mean percent FSH suppression during the first 24 h, calculated in the same manner, was 6.8 +/- 3.9% (1 mg), 14.5 +/- 2.9% (5 mg), and 18.2 +/- 2.6% (20 mg). Serum alpha-subunit concentrations were significantly suppressed by 1 h after dosing with the 5- and 20-mg doses (P less than 0.05), and remained suppressed throughout the 72-h sampling period. Gonadotropin dependence of steroidogenesis in the postmenopausal ovary was suggested by a significant suppression of serum T concentrations after the 20-mg dose of detirelix.(ABSTRACT TRUNCATED AT 400 WORDS)     

Regulation by oestradiol of serum levels of LH and FSH and pituitary levels of gonadotrophin-releasing hormone receptors after ovariectomy in the rat

We studied cyclic and ovariectomized, oestradiol treated rats to investigate whether oestradiol concentrations before ovariectomy determine the dynamics of the rises in serum levels of LH and FSH, and in pituitary gonadotrophin-releasing hormone (GnRH) receptors after ovariectomy. In cyclic rats, ovariectomy on metoestrus (oestradiol = 44 pmol/l), but not at midnight of dioestrus (oestradiol = 254 pmol/l) was followed by a rise in GnRH receptors 40 h later. Randomly cyclic females were ovariectomized under ether anaesthesia and treated with s.c. oestradiol implants for 2 days to provide serum levels spanning the physiological range. Exposure to lower oestradiol concentrations (48 or 74 pmol/l) resulted in significant rises in levels of LH and FSH, and in GnRH receptors earlier than exposure to higher (148 or 309 pmol/l) oestradiol levels (2 compared with 4 days). GnRH given for 24 h after removal of the implant was unable to induce a rise in GnRH receptors in any group, while LH and FSH responses to GnRH were proportional to the pretreatment levels of oestradiol. This suggests that the concentration of oestradiol before ovariectomy determines the subsequent dynamics of LH and FSH and of GnRH receptors through actions at the hypothalamic and pituitary level.     

Divergent effects of the antiestrogen tamoxifen and of estrogens on luteinizing hormone (LH) pulse frequency, but not on basal LH levels and LH pulse amplitude in men

We studied the role of estrogens on LH pulse modulation in men in two ways. Firstly, we compared LH pulse frequency and amplitude in 13 normal men before and after 6 weeks administration of the antiestrogen tamoxifen (10 mg twice daily). Secondly, we compared LH pulse frequency and amplitude between a group of 10 agonadal men not receiving sex steroid treatment and a group of 9 agonadal men (male to female transsexuals) continuously treated with 50 micrograms ethinyl estradiol/day. Tamoxifen administration to normal men resulted in a significant rise in the mean serum LH level from 5.7 +/- 1.3 (+/- SD) to 10.1 +/- 2.4 U/L, which was associated with significant increases in LH pulse frequency (from 4.2 +/- 1.5 to 5.8 +/- 1.7/7 h) and LH pulse amplitude (from 3.8 +/- 0.9 to 4.6 +/- 0.7 U/L). In the group of agonadal men the mean LH pulse frequency was 6.8 +/- 1.5/7 h, while it was 5.9 +/- 1.7/7 h in the estrogen-treated agonadal group (P = NS). The mean serum LH level and LH pulse amplitude were, however, significantly lower in the estrogen-treated agonadal men than in the agonadal men (14.7 +/- 7.0 vs. 34.3 +/- 8.6 and 4.1 +/- 1.8 vs. 7.4 +/- 1.8 U/L, respectively). We conclude that estrogens reduce basal LH levels and LH pulse amplitude. With regard to the modulation of LH pulse frequency our data provide contradictory results. While an antiestrogen increased LH pulse frequency in normal men, estrogen alone produced no change in LH pulse frequency in agonadal men. The study design in the agonadal men ignores the possible interaction of the two major testicular hormones (estradiol and testosterone) on gonadotropin secretion. Therefore, a possible explanation for this discrepancy in the effects of antiestrogen and estrogen could be an interaction between estrogens and androgens on gonadotropin secretion at the level of the LHRH pulse generator.     

Basal serum prolactin levels and prolactin responses to constant infusions of thyrotropin releasing hormone in healthy aging men

We measured serum prolactin (PRL) levels by RIA before and during a 240-min constant infusion of TRH (0.4 microgram/min iv) in three similarly sized groups of healthy aging men 30 to 49, 50 to 69, and 70 to 96 years. Basal data were evaluated by analysis of variance with Duncan's multiple range test and regression analysis. Mean basal serum PRL level was elevated (p less than .05) in the oldest group, attributable to PRL elevations (between 20 and 40 ng/ml) in 4 men over 75 years. Serum PRL levels decreased (p less than .001) from -30 min to 0 min before TRH infusion in all groups, but there was no age-dependent difference (p greater than .3) in the magnitude of the reduction. Repeated measures analysis of variance showed increased serum PRL levels (p less than .001) during TRH infusion in all age groups, and an age-dependent increase (p less than .05) in magnitude of peak PRL response. This significant difference was between the two oldest age groups early in the infusion. Chi-square analysis revealed an increased (p less than .05) frequency of early (less than 120 min) peak responses in the oldest age group. The present data suggest that basal and TRH-stimulated PRL secretion may be augmented in some healthy older men.     

Alcohol ingestion does not affect serum levels of peptide YY but decreases both total and octanoylated ghrelin levels in healthy subjects

Alcohol has been reported to have appetite-stimulating properties in humans. The underlying mechanism is unknown. Gastrointestinal hormones, such as ghrelin and peptide YY (PYY), could be involved as mediators of the alcohol effect because ghrelin stimulates the appetite and PYY appears to induce satiety. This investigation was undertaken with the intention to study that issue. Twelve young and healthy volunteers of both sexes participated in 2 experiments (experiments A and B), which were performed in random order 1 week apart. Alcohol (0.55 g ethanol per kilogram) was ingested in experiment A, drinking water in experiment B. Venous blood samples were collected before and repeatedly after the drinks. Serum concentrations of total ghrelin, octanoylated ghrelin (the bioactive form of the hormone), PYY, and ethanol were determined over a period of 5 hours. In experiment A, the ethanol level increased from 0 to 12.5 +/- 0.7 mmol/L in 1 hour (P < .001), and then began to decrease. In experiment B, the ethanol level remained at zero throughout the entire experiment. Alcohol induced significant declines in total and octanoylated ghrelin concentrations from 30 minutes on. The total ghrelin level reached its lowest point 5 hours after the alcohol intake (36% +/- 4% below the basal level; P < .001). The octanoylated ghrelin level fell 48% +/- 5% below the basal level in 2 hours (P < .001) and then tended to level out. Drinking water left both total and octanoylated ghrelin levels unaffected. The PYY level remained unchanged after both alcohol and water ingestion. Alcohol has a strong inhibitory influence on human ghrelin secretion, but has no effect on circulating PYY levels. This makes it unlikely that the orexigenic effect of alcohol is mediated by either of these 2 hormones.     

Effects of a sustained release formulation of the gonadotrophin-releasing hormone agonist histrelin on serum concentrations of gonadotrophins and oestradiol, and ovarian LH/human chorionic gonadotrophin receptor content in the rat.

Pituitary and ovarian function were studied during the loss and recovery of oestrous cyclical activity in rats following treatment with a sustained release formulation of the gonadotrophin-releasing hormone (GnRH) agonist [imidazole benzyl-D-His6,Pro9-ethylamide]-GnRH (histrelin). A single s.c. injection of microencapsulated histrelin (10-300 micrograms peptide/kg) induced a dose-dependent disruption of normal oestrous cyclical activity with a persistent dioestrous-like vaginal cytology. In preliminary studies, pituitary gland stimulation and desensitization were demonstrated when serum LH and FSH levels were greater 1 week after administration of 10 micrograms microencapsulated histrelin/kg compared with 300 micrograms microencapsulated histrelin/kg. Changes in pituitary and ovarian function were assessed over time following injection of microencapsulated histrelin (100 micrograms peptide/kg). LH secretion was maximal within 8 h and then gradually declined, remaining at dioestrous levels from days 7 to 28. Serum oestradiol concentrations remained low and rose above dioestrous levels only on day 28. In contrast, ovarian LH/human chorionic gonadotrophin (LH/hCG) receptor content fell within 8 h and, after a nadir on day 7, slowly returned to dioestrous levels by day 28. The increase in ovarian LH/hCG receptor content preceded any significant change in pituitary gonadotrophin secretion, indicating a differential pattern of recovery for pituitary and ovarian function. Subsequent studies tested the possibility that these temporal differences in pituitary and ovarian function may result from histrelin acting directly on these tissues. Treatment with histrelin microcapsules (300 micrograms peptide/kg) prevented any increase in LH secretion in response to a GnRH challenge 3 days later, indicating a direct action of histrelin on the pituitary gland.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of treatment of neonatal rats with highly purified FSH alone and in combination with LH on testicular function and endogenous hormone levels at various ages

Factors which play a role in the regulation of testicular size in rats were investigated using neonatal animals treated with exogenous gonadotrophins for 2 or 3 weeks, starting on the day after birth. Effects on testis weight and various aspects of the pituitary-testicular axis were evaluated up to the age of 9 weeks. Daily treatment with human FSH (Metrodin; 0.15 U/g body wt) for 2 or 3 weeks, starting on the first day or 1 week after birth, resulted in enlargement of the testes, increased testicular content of inhibin and a suppression of pituitary and plasma FSH. The relative increase of testis weight decreased after cessation of treatment. Injections of human FSH combined with administration of human LH (Pergonal) for 3 weeks, starting on the first day after birth, resulted in larger testes immediately after treatment. In addition, an increased amount of interstitial tissue was observed in these animals. Pituitary and plasma FSH and LH were suppressed after this treatment, while the growth of the accessory sex organs was significantly stimulated. In animals treated with human FSH during the first 2 or 3 weeks of life, levels of rat FSH in blood samples collected at weekly intervals were significantly suppressed until the animals were killed at the age of 9 weeks. In the animals treated with human FSH and human LH, both FSH and testosterone concentrations were significantly lower than those in control animals between the ages of 4 and 9 weeks. At the age of 9 weeks testicular weights were still higher than those in control animals after these treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of bromocriptine and naloxone on plasma levels of prolactin, LH and FSH during suckling in the female rat: responses to gonadotrophin releasing hormone

The roles of dopamine and the endogenous opiate peptides in the mediation of the inverse relationship between prolactin and gonadotrophin secretion during lactation were studied by comparing the effects of bromocriptine and naloxone on plasma levels of prolactin, LH and FSH during suckling in the female rat. The effects of exogenous gonadotrophin releasing hormone (GnRH) on the LH and FSH responses to bromocriptine and naloxone were also assessed. In control animals (saline), there was a marked fall in LH levels and a large increase in prolactin levels within 15 min of suckling. In response to GnRH (25 ng) there was a small progressive increase in LH levels reaching a maximum at 45 min. Both bromocriptine (500 micrograms) and naloxone (500 micrograms) markedly suppressed the suckling-induced prolactin surge when administered in two separate groups of animals. However, despite the bromocriptine-induced suppression of prolactin levels, there was no increase in LH levels which remained low throughout the suckling period. Naloxone (500 micrograms), however, induced a twofold increase in LH levels within 15 min suggesting that an enhanced opiate rather than dopaminergic activity may be responsible for the suppression of GnRH and hence gonadotrophin secretion during suckling. This is supported by the finding that whereas combined bromocriptine (500 micrograms) and GnRH (25 ng) treatment suppressed the suckling-induced prolactin rise and also induced only a small progressive increase in LH (similar to GnRH alone), combined naloxone (500 micrograms) and GnRH (25 ng) treatment induced a sharp sixfold increase in LH levels within 15 min while at the same time markedly suppressing prolactin levels. None of these drug treatments affected the levels of FSH.(ABSTRACT TRUNCATED AT 250 WORDS)