PRL Pulses Research Articles

Circadian influence on the preovulatory LH surge, ovulation, and prolactin concentrations in heifers

A novel circadian study of the effect of clock hours on the preovulatory LH surge, ovulation, and maximal PRL concentration was done in 13 nontreated Holstein heifers. Hourly blood sampling and hourly ultrasound examinations to detect the hour of ovulation began at 8 and 48 hours, respectively, after CL area (cm2) had decreased 15% from the area at 15 days postovulation. The resulting experimental period began at the beginning of postluteolysis (progesterone, <1 ng/mL) and encompassed a mean of 3.5 days until ovulation. The frequency of the peak of the preovulatory LH surge for the three 8-hour periods of a 24-hour day was different (P < 0.02) between 2:00 AM to 9:00 AM (N = 9), 10:00 AM to 5:00 PM (N = 3), and 6:00 PM to 1:00 AM (N = 1). The median was 6:00 AM. The frequency of ovulations for 8-hour periods was different (P < 0.02) between 3:00 AM to 10:00 AM (N = 9), 11:00 AM to 6:00 PM (N = 3), and 7:00 PM to 2:00 AM (N = 1). The median was 7:30 AM. Two or three clusters of PRL pulses occurred during the 3.5 days. Based on all available PRL pulse clusters (N = 36), the clock hours of the maximal concentration/cluster was greater (P < 0.0001) for 9:00 AM to 2:00 PM (N = 33 clusters) than for each of the three other 6-hour periods (N = 0, 1, or 2 per period). The median was 11:30 AM. The hypothesis was supported that the peak of the preovulatory LH surge, ovulation, and maximal PRL concentration during pulse clusters occur with greater frequency during certain clock hours in heifers.

Ovarian and PGF2α responses to stimulation of endogenous PRL pulses during the estrous cycle in mares

The effects of a PRL-stimulating substance (sulpiride) on PRL and PGF2α secretion and on luteal and ovarian follicular dynamics were studied during the estrous cycle in mares. A control group (n = 9) and a sulpiride group (Sp; n = 10) were used. Sulpiride (25 mg) was given every 8 h from Day 13 postovulation to the next ovulation. Repeated sulpiride treatment did not appear to maintain PRL concentrations at 12-h intervals beyond Day 14. Therefore, the hypothesis that a long-term increase in PRL altered luteal and follicular end points was not testable. Hourly samples were collected from the hour of a treatment (Hour 0) to Hour 8 on Day 14. Concentrations of PRL increased to maximum at Hour 4 in the Sp group. The PRL pulses were more prominent (P < 0.008) in the sulpiride group (peak, 19.4 ± 1.9 ng/mL; mean ± SEM) than in the controls (11.5 ± 1.8 ng/mL). Concentrations of a metabolite of PGF2α (PGFM), number, and characteristics of PGFM pulses, and concentrations of progesterone during Hours 0 to 8 were not affected by the increased PRL. A novel observation was that the peak of a PRL pulse occurred at the same hour or 1 h later than the peak of a PGFM pulse in 8 of 8 PGFM pulses in the controls and in 6 of 10 pulses in the Sp group (P < 0.04), indicating that sulpiride interfered with the synchrony between PGFM and PRL pulses. The hypothesis that sulpiride treatment during the equine estrous cycle increases concentrations of PRL and the prominence of PRL pulses was supported.

Stimulation of a pulse of LH and reduction in PRL concentration by a physiologic dose of GnRH before, during, and after luteolysis in heifers

A single physiologic dose (5.0μg) of GnRH was given to 9 heifers each day (Hour 0) beginning on Day 15 postovulation until regression of the corpus luteum. Blood samples were taken each day for Hours −3, −2, −1, 0, 0.25, 0.5, 0.75, 1, 1.25, 1.50, 1.75, 2, 3, 4, and 5. Based on daily progesterone concentrations, data were grouped into phases of before (n=4), during (n=8), and after (n=7) luteolysis. The number of LH pulses with a peak at pretreatment Hours −2 or −1 (0.35±0.12pulses/sampling session) was less (P<0.0001) than for a pulse peak at posttreatment Hours 1 or 2 (1.0±0.0pulses/session). The characteristics and effects of LH pulses on progesterone and estradiol were similar between natural (pretreatment) and primarily induced (posttreatment) LH pulses. The same dose of GnRH stimulated an LH pulse with greater (P<0.05) amplitude after luteolysis than during luteolysis. Concentrations of PRL and number and prominence of PRL pulses decreased (P<0.05) between Hours 0 and 2 within each of the phases of before, during, and after luteolysis. The hypothesis that a physiologic dose of GnRH increases the concentration of PRL was not supported; instead, GnRH reduced the concentration of PRL. Results supported the hypotheses that an appropriate dose of GnRH stimulates an LH pulse during luteolysis that is similar to a natural pulse in characteristics and in the effects on progesterone and estradiol.

Direct effect of PGF2α pulses on PRL pulses, based on inhibition of PRL or PGF2α secretion in heifers

The relationships between PRL and PGF2α and their effect on luteolysis were studied. Heifers were treated with a dopamine-receptor agonist (bromocriptine; Bc) and a Cox-1 and -2 inhibitor (flunixin meglumine [FM]) to inhibit PRL and PGF2α, respectively. The Bc was given (Hour 0) when ongoing luteolysis was indicated by a 12.5% reduction in CL area (cm2) from the area on Day 14 postovulation, and FM was given at Hours 0, 4, and 8. Blood samples were collected every 8-h beginning on Day 14 until Hour 48 and hourly for Hours 0 to 12. Three groups of heifers in ongoing luteolysis were used: control (n = 7), Bc (n = 7), and FM (n = 4). Treatment with Bc decreased (P < 0.003) the PRL concentrations averaged over Hours 1 to 12. During the greatest decrease in PRL (Hours 2–6), LH concentrations were increased. Progesterone concentrations averaged over hours were greater (P < 0.05) in the Bc group than in the controls. In the FM group, no PGFM pulses were detected, and PRL concentrations were reduced. Concentrations of PGFM were not reduced in the Bc group, despite the reduction in PRL. Results supported the hypothesis that a decrease (12.5%) in CL area (cm2) is more efficient in targeting ongoing luteolysis (63%) than using any day from Days 14 to ≥19 (efficiency/day, 10–24%). The hypothesis that PRL has a role in luteolysis was supported but was confounded by the known positive effect of LH on progesterone. The hypothesis was supported that the synchrony of PGFM and PRL pulses represents a positive effect of PGF2α on PRL, rather than an effect of PRL on PGF2α.

The influence of hyperthyroidism on the hypothalamic-pituitary-gonadal axis.

We have investigated the function of the hypothalamic-pituitary-gonadal (H-P-G)-axis in patients with severe, untreated Graves' disease. We studied 7 male and 6 female healthy volunteers, and 7 male and 7 female patients with Graves' disease. Hormone profiles were developed by blood sampling every 10 min for an 8 hour period. In women this was done in the early follicular phase of menstrual cycle. LH-, FSH-, and PRL levels were measured using immunoradiometric assays and testosterone (T), estradiol (E2), sex-hormone binding globulin (SHBG), and progesterone (P) were measured with standard assays. The pulsatility of LH, FSH and PRL was calculated using the programmes Pulsar, Cluster and Desade. The temporal relationship of plasma LH, FSH, and PRL pulses was also investigated using specific concordance analysis. Data were evaluated by means of non-parametric statistics. LH-secretion was increased in all hyperthyroid patients, while FSH-secretion was increased in hyperthyroid men only. Pulsatile characteristics of LH- and FSH-secretion (frequency, peak shape) in patients were not different from controls. No change in PRL-secretion was shown. Significant copulsatility occurred between LH and FSH, and LH and PRL. This was more pronounced in hyperthyroid than in healthy study subjects. Plasma levels of steroid hormones and sex-hormone-binding globulin were significantly (p<0.005) increased in hyperthyroid men. Free Androgen Index was significantly (p<0.005) decreased in hyperthyroid males. No other auto immune diseases were noticed. Our results indicate that the function of the H-P-G axis is not impaired in hyperthyroid patients, but gonadotropin levels are increased. Hyperthyroid men show relative primary gonadal insufficiency that may be due to exaggerated SHBG levels. The copulsatility of LH and FSH, and of LH and PRL was confirmed both in patients and controls.

Acute Effects of Nalmefene on LH, Prolactin, and Testosterone in Male Rhesus Monkeys

The effects of the long-acting opioid antagonist, nalmefene [17-N-cyclopropylmethyl-3,14-β-dihydroxy-4,5-α-epoxy-6-methylene morphinan hydrochloride] on LH, T, and prolactin release in rhesus monkeys are unknown. The acute effects of nalmefene (0.01 and 0.10 mg/kg, IV) or placebo on LH, PRL, and T were studied, and samples were collected at 10-min intervals for 360 min to permit cluster analysis of pulsatile release patterns. LH increased significantly within 30 min after nalmefene, and remained significantly above baseline levels for 50 to 60 min ( p < 0.05). Testosterone increased significantly within 70 to 80 min after nalmefene, and remained significantly above baseline for 60 min ( p < 0.05). Although nalmefene antagonizes opioid agonists for 6–8 h, inhibitory feedback by testosterone appeared to limit the duration of its antagonism of endogenous opioid inhibition of LHRH and stimulation of LH. Nalmefene did not change LH or PRL pulse frequency or amplitude significantly in comparison to placebo administration.

Leptin116–130 Stimulates Prolactin and Luteinizing Hormone Secretion in Fasted Adult Male Rats

Leptin is a hormone secreted by adipocytes with an important role in the control of feeding behavior and neuroendocrine function. Leptin stimulates in vivo LH secretion in fasted female rats and in vitro PRL secretion. Recent data indicate that leptin_116–130, an active fragment of the native molecule, exerts effects similar to those of the native peptide on body weight and food intake. The present study was carried out to determine whether this fragment is also able to stimulate LH and PRL secretion. Adult male rats fasted for 5 days were injected with saline or leptin_116–130 (15 µg i.c.v.) and LH and PRL concentrations were measured thereafter at 15-min intervals during a 150-min period. Administration of leptin_116–130 increased the frequency of LH pulses (2.0 ± 0.26 vs. 1.20 ± 0.37/150 min; p ≤ 0.05), mean LH levels (0.24 ± 0.06 vs. 0.07 ± 0.03 ng/ml; p ≤ 0.05), LH pulse amplitude (0.33 ± 0.10 vs. 0.10 ± 0.05 ng/ml; p ≤ 0.05) and the net LH secretion estimated by area under curve (AUC: 36 ± 8.5 vs. 9 ± 3.9 ng/ml/150 min; p ≤ 0.01). In addition leptin_116–130 increased the frequency of PRL pulses (2.83 ± 0.48 vs. 1.33 ± 0.21/150 min; p ≤ 0.05), trough PRL levels (5.71 ± 0.99 vs. 2.72 ± 0.32 ng/ml; p ≤ 0.01), mean PRL levels (13.02 ± 0.92 vs. 5.89 ± 0.51 ng/ml; p ≤ 0.01) and net PRL secretion (AUC: 1,625 ± 171 vs. 658 ± 46 ng/ml/150 min; p ≤ 0.05). In conclusion, these data show that leptin_116–130 stimulates LH and PRL secretion in fasted adult male rats.

Mechanisms subserving the physiological nocturnal relative hypoprolactinemia of healthy older men: dual decline in prolactin secretory burst mass and basal release with preservation of pulse duration, frequency, and interpulse interval--a General Clinical Research Center study.

Increasing age is accompanied by decrements in randomly obtained, fasting, or frequently sampled serum PRL concentrations. The precise neuroendocrine mechanisms underlying such relative hypoprolactinemia in aging are incompletely understood. In the present study, we sampled blood at 2.5-min intervals overnight in 11 young (aged 21-34 yr) and 8 older (aged 62-72 yr) healthy men for subsequent chemiluminescence-based assay of serum PRL concentrations. The mean (+/- SEM) serum PRL concentration was significantly reduced at 4.3 +/- 0.78 microg/L in older men compared with 9.5 +/- 1.2 microg/L in young volunteers (P = 0.0049). PRL concentrations correlated with serum testosterone (r = 0.473; P = 0.041), dehydroepiandrosteroen sulfate (r = +0.455, P = 0.05), and insulin-like growth factor I (r = 0.494; P = 0.032) levels. Deconvolution analysis was used to evaluate combined pulsatile and basal modes of PRL secretion. In older men, discrete PRL secretory bursts were marked by a significantly (2.4-fold) attenuated mass of hormone secreted per burst (amount of PRL secreted per unit distribution volume), viz. 1.6 +/- 0.23 (older) vs. 3.9 +/- 0.57 microg/L (young; P < 0.01). In contrast, PRL secretory burst frequency, interpulse interval, and pulse duration were invariant of age. Concomitantly, basal PRL secretion was reduced by 2-fold in older subjects, namely to 0.00030 +/- 0.00027 (older) vs. 0.00065 +/- 0.0002 microg/L/min (young; P < 0.01). The amount of total PRL secretion that was pulsatile averaged 82 +/- 5.3% in young and 99 +/- 0.13% in older men (P = 0.012), indicating preferential loss of the basal mode of PRL release in aging. Assuming that basal PRL secretion mirrors functional pituitary lactotroph cell secretory mass, whereas pulsatile PRL release reflects effective (net) intermittent hypothalamic drive to responsive lactotroph cells, then our results suggest both an attrition in lactotroph cell mass and an impoverishment of net positive hypothalamic (agonistic) input to lactotrophs in older men. Given the multiple roles of PRL reported in experimental animals (e.g. on the one hand to support immune function and adrenal androgen biosynthesis and on the other hand to activate intraprostatic growth factors), we suggest that the nocturnal relative hypoprolactinemia observed in healthy aging men may have both adaptive and maladaptive clinical implications to target tissues.

Prolactin pulsatile characteristics in postmenopausal women.

Pulsatile PRL secretion undergoes diurnal variation, with maximal PRL release in the evening during sleep in both women and men. However, the impact of the menopause on PRL pulsatile dynamics are largely unknown. To characterize diurnal PRL pulsatile secretion in postmenopausal women, we performed frequent venous sampling over 24 h every 10 min for serum PRL in 7 postmenopausal women (age, 56 +/- 4 yr) and in 2 control groups, 8 men (age, 25 +/- 8 yr) and 22 cycling women (age, 28 +/- 5 yr), at 3 phases of the menstrual cycle. Standard TRH tests (200 microg, i.v.) were administered at 0900 h after completion of the 24-h sampling, and PRL levels were then obtained at 0, 10, 20, 30, and 60 min in all subjects. PRL pulse characteristics were similar between the postmenopausal women and men. Mean serum PRL levels and PRL pulse frequency were significantly higher in the cycling women than in either postmenopausal women or men over 24 h and during either the day or night periods. Mean serum PRL levels and pulse frequency were significantly higher during the night compared to those during the day in all groups. Pulse amplitude was higher during the night vs. the day in all groups and was highest in the cycling women. PRL responses to TRH administration were greatest in cycling women. These data demonstrate that PRL pulse dynamics are significantly different between postmenopausal women and cycling women, and endogenous estrogen levels may have an important role in this difference. Pulsatile PRL secretion is similar between postmenopausal women and men, suggesting that estrogen levels modulate PRL dynamics across genders.

Evidence for an altered luteinizing hormone sensitivity to naloxone in pathological hyperprolactinaemia

The underlying mechanisms involved in the pathogenesis of amenorrhoea in hyperprolactinaemic states still remain unclear. Conflicting information exists on the role of endogenous opiates on gonadotrophin disturbances in this pathological condition. In this study we have undertaken a detailed investigation of LH and PRL secretion before and during administration of naloxone, an opioid receptor blocker, in hyperprolactinaemic women with or without ovarian function in order to assess the role of ovarian steroids upon naloxone induced LH and PRL release. Five anovulatory and six ovulatory subjects with hyperprolactinaemia were studied before and during naloxone infusion. Five normo-prolactinaemic ovulatory subjects were included as controls. All ovulatory subjects were studied during the luteal phase of a menstrual cycle. Blood was sampled every 10-20 minutes over a 16-hour period on two alternate days. On study day 1 (control day), subjects received two sets of saline infusion every 6 hours and one saline bolus at the beginning of the seventh hour; on study day 3 (naloxone day), they received a saline infusion during the first 6 hours, an intravenous bolus of naloxone (20 mg) at the beginning of the seventh hour and then a continuous naloxone infusion (1.6 mg/hour) during the ensuing 6 hours. Pituitary LH responsiveness and reserve were assessed on both study days by the subsequent administration of 5 and 95 micrograms of GnRH 4 hours before the completion of each sampling period. Serum concentrations of LH, PRL, oestradiol and progesterone were determined by radioimmunoassay. LH and PRL pulse detection and characteristics were analysed by the Cluster program. Serum PRL levels in hyperprolactinaemic anovulatory and ovulatory subjects were significantly elevated above the normal range. Oestradiol and progesterone serum levels during the luteal phase in women with hyperprolactinaemia and regular menses were similar to those in control ovulatory subjects. Mean LH concentrations increased during naloxone infusion (P < 0.05) in ovulatory hyperprolactinaemia and controls, whereas PRL increased (P < 0.05) only in the group of control subjects. LH pulse amplitude and pulse interval were increased by naloxone (P < 0.05) in all the ovulatory subjects, with no significant changes in anovulatory hyperprolactinaemic women. PRL pulse characteristics were modified significantly by naloxone only in the control group. On day 1, GnRH administration increased LH in all groups, whereas a consistently lower pituitary LH response was observed after naloxone (day 3). Serum PRL levels significantly increased after GnRH administration on day 1 only in normal women, whilst on day 3 this GnRH-dependent PRL releasing effect was significantly attenuated. The absence of stimulatory effects of naloxone on LH in anovulatory hyperprolactinaemia implies that endogenous opiates do not play a significant role in the mechanisms governing hypothalamic amenorrhoea in this syndrome. The results in subjects with ovulatory hyperprolactinaemia suggest the existence of an active role of ovarian steroids on naloxone induced LH release. These data, along with those previously reported in normal women throughout the menstrual cycle, are consistent with the concept that sex steroid hormones contribute to the underlying mechanisms involved in the opioidergic control of LH and PRL release. Whether PRL by itself or through other non-opioid neuroendocrine pathways alters the hypothalamic-gonadotroph unit still requires further investigation.

Serotoninergic control of gonadotrophin and prolactin secretion in women.

Due to conflicting observations from previous investigations, the role of serotonin (5-HT) in the regulation of the human menstrual cycle has not been clearly established. We have therefore investigated the possible participation of 5-HR in the control of gonadotrophin and PRL secretion in women, using the potent 5-HT3 receptor antagonist ondansetron as a pharmacological probe. Serum profiles of LH, FSH and PRL were obtained in 9 normally cycling women during a control and a treatment cycle, during which ondansetron (8 mg orally) was administered daily. On day 10 of both cycles, the serum pulsatility of LH, FSH and PRL was assessed by frequent blood sampling (at 10-minute intervals for 10 hours). Pituitary responsiveness was tested by administration of a GnRH bolus (25 micrograms i.v. after 8 hours). LH, FSH and PRL were serially determined in all blood samples by immunofluorescence assays. The resulting hormone data arrays were searched for significant fluctuations by the Cluster pulse algorithm. Compared with control cycles, the temporal organization and the endocrine characteristics of the treatment cycles remained virtually unaltered. Serotonin antagonism did not noticeably affect the LH pulse attributes (frequencies, interpulse intervals, amplitudes). Although FSH amplitudes declined markedly (P < 0.05), the remaining pulse attributes were unchanged. A clear increase (P < 0.05) in the PRL pulse frequency was noted, while PRL pulse amplitudes tended to increase (P = 0.1). Gonadotrophin and PRL release in response to GnRH administration was unaltered by ondansetron treatment. Serotoninergic blockade by a selective 5-HT3 receptor antagonist failed to modify pulsatile LH secretion, but induced distinct changes in episodic FSH and PRL secretion. Since the pituitary gonadotrophin and PRL responsiveness remained unaltered during 5-HT3 receptor blockade, the observed alterations in the FSH and PRL secretion presumably relate to altered hypothalamic regulation of these pituitary hormones. Thus, the central regulation of pulsatile FSH and PRL release in women appears to involve 5-HT3 receptor-mediated processes.

Hormone ontogeny in the ovine fetus. XXVII. Pulsatile and copulsatile secretion of luteinizing hormone, follicle-stimulating hormone, growth hormone, and prolactin in late gestation: a new method for the analysis of copulsatility.

To analyze the secretion patterns of LH, FSH, GH, and PRL in the late gestational sheep fetus in vivo, we measured simultaneous plasma levels of these hormones during a period of frequent sampling under basal conditions (samples every 15 min for 5 h) in 17 chronically catheterized sheep fetuses. To calculate mean plasma levels and areas under the curve, we analyzed hormone pulses and coincident pulse patterns to assess interactions between the release of these pituitary hormones. Mean plasma levels for all fetuses were: LH, 0.8 +/- 0.2 ng/ml (mean +/- SEM); FSH, 4.6 +/- 0.7 ng/ml; GH, 136.6 +/- 16.5 ng/ml; and PRL, 40.5 +/- 10.3 ng/ml. Pulse analysis detected 20 LH pulses during 5100 min of total sampling time, which gave a mean interpulse interval of 255.0 min. For GH, 37 pulses were detected; the mean interpulse interval was 129.7 min. Twenty PRL pulses yielded a mean interpulse interval of 225.0 min. FSH pulses could not be analyzed due to the long half-life of this hormone, but hormone level fluctuations were screened for maxima. A new method was developed to detect an interaction between hormone pulses. The probability of the simultaneous occurrence of hormone pulses was calculated and compared with the rate of coincidences found in the experiments. Analysis of copulsatile release of LH, GH, and PRL revealed 11 GH pulses coinciding with the LH pulses (P = 0.0020). An interaction between the pulsatile release of LH and GH can, therefore, be assumed. There was also a significant interaction between GH and PRL. Seven PRL pulses preceded the GH pulses by 15 min (P = 0.0014). In contrast, no significant copulsatile release could be observed between LH and PRL; 95.5% of LH pulses were accompanied by a maximum FSH level, suggesting an interaction between LH and FSH secretion. In summary, we show that LH, GH, and PRL (and possibly FSH) are secreted in a pulsatile fashion in the ovine fetus. Furthermore, the pulsatile releases of LH, FSH, and GH as well as GH and PRL are temporarily coupled, as demonstrated by a significant number of coincident pulses between LH/GH and GH/PRL and a high number of FSH hormone maxima concomitant with LH pulses.

Hormone ontogeny in the ovine fetus. XXVII. Pulsatile and copulsatile secretion of luteinizing hormone, follicle-stimulating hormone, growth hormone, and prolactin in late gestation: a new method for the analysis of copulsatility

To analyze the secretion patterns of LH, FSH, GH, and PRL in the late gestational sheep fetus in vivo, we measured simultaneous plasma levels of these hormones during a period of frequent sampling under basal conditions (samples every 15 min for 5 h) in 17 chronically catheterized sheep fetuses. To calculate mean plasma levels and areas under the curve, we analyzed hormone pulses and coincident pulse patterns to assess interactions between the release of these pituitary hormones. Mean plasma levels for all fetuses were: LH, 0.8 +/- 0.2 ng/ml (mean +/- SEM); FSH, 4.6 +/- 0.7 ng/ml; GH, 136.6 +/- 16.5 ng/ml; and PRL, 40.5 +/- 10.3 ng/ml. Pulse analysis detected 20 LH pulses during 5100 min of total sampling time, which gave a mean interpulse interval of 255.0 min. For GH, 37 pulses were detected; the mean interpulse interval was 129.7 min. Twenty PRL pulses yielded a mean interpulse interval of 225.0 min. FSH pulses could not be analyzed due to the long half-life of this hormone, but hormone level fluctuations were screened for maxima. A new method was developed to detect an interaction between hormone pulses. The probability of the simultaneous occurrence of hormone pulses was calculated and compared with the rate of coincidences found in the experiments. Analysis of copulsatile release of LH, GH, and PRL revealed 11 GH pulses coinciding with the LH pulses (P = 0.0020). An interaction between the pulsatile release of LH and GH can, therefore, be assumed. There was also a significant interaction between GH and PRL. Seven PRL pulses preceded the GH pulses by 15 min (P = 0.0014). In contrast, no significant copulsatile release could be observed between LH and PRL; 95.5% of LH pulses were accompanied by a maximum FSH level, suggesting an interaction between LH and FSH secretion. In summary, we show that LH, GH, and PRL (and possibly FSH) are secreted in a pulsatile fashion in the ovine fetus. Furthermore, the pulsatile releases of LH, FSH, and GH as well as GH and PRL are temporarily coupled, as demonstrated by a significant number of coincident pulses between LH/GH and GH/PRL and a high number of FSH hormone maxima concomitant with LH pulses.

GnRH antagonists suppress prolactin release in non-human primates

GnRH antagonists, such as Antide, are being evaluated for potential contraceptive applications. Although their contraceptive efficacy clearly results from their rapid inhibitory effects on gonadotropin release, there remains the possibility of other incidental effects. Under certain physiological conditions,the release of prolactin (Prl) appears to be temporally related to the secretion of luteinizing hormone (LH) and hence by inference to the secretion of GnRH. Here, we examined the effects of the GnRH antagonist Antide on the release of LH and Prl. Under agonadal conditions, a remarkable concordance was seen between LH and Prl pulses with up to 100% of pulses being coincident. Administration of Antide resulted in a rapid parallel decline in both LH and Prl with LH levels falling by 50% within 2 h and Prl levels falling by 30%–40%. At this dose of Antide (1.0 mg/kg, sc), pulsatile release of LH and Prl continued albeit at a much reduced amplitude. The administration of a bolus of exogenous GnRH in the face of GnRHant-induced suppression resulted in prompt release of LH and Prl in all 3 monkeys. Since Antide inhibits the release of LH and Prl in a parallel fashion, and GnRH re-stimulates the release of both hormones in a parallel fashion, we conclude that the synchronous pulsatile release of LH and Prl observed in the agonadal monkey is due to a direct action of GnRH. What this action is for Prl release, and how it relates to the control of dopamine or other neuroendocrine mechanisms normally controlling the release of Prl remains unclear. It also remains to be seen whether this GnRH antagonist-induced suppression of Prl will have physiologic significance.

Pulsatile Prolactin Secretion in Hyperprolactinemia due to Presumed Pituitary Stalk Interruption

PRL, like other anterior pituitary hormones, is normally secreted in a pulsatile fashion. However, it is not known whether such pulses depend on dopamine and/or other hypothalamic factors. This question can be addressed by investigating patients with large pituitary mass lesions, since such patients often have hyperprolactinemia due to disruption of normal hypothalamic input to the pituitary gland. Six such patients (5 with non-PRL-secreting tumors and 1 with a craniopharyngioma) and 11 healthy control subjects had PRL levels measured every 15 min over 24 h. PRL pulses were located by cluster analysis. All patients had PRL pulses of normal frequency, but increased amplitude. Circadian variation in PRL pulse amplitude, present in healthy women, was abolished in tumor patients. These results imply that normal pituitary levels of dopamine do not control the generation of PRL pulses. Instead, PRL pulses may arise from the pituitary gland, with pulse amplitude and circadian rhythm modulation by dopamine and other hypothalamic factors. Alternatively, the mild hyperprolactinemia associated with large hypothalamic-pituitary tumors may represent partial impairment of dopamine secretion, with sufficient pituitary dopamine levels to maintain normal PRL pulse frequency.

A Physiological Role for Sporadic Interruptions of the Dopaminergic Tone in the Genesis of Big Mass Prolactin Pulses

The present studies were designed to evaluate pulsatile PRL secretion after the establishment of either a continuous dopaminergic input or a complete blockade of the dopaminergic inhibitory tone. Adult female rats on estrus and male rats implanted with indwelling jugular cannulae were bled at 3-min intervals for a 3-h period. Bromocriptine (CB-154) and domperidone (DOM) were administered sc and iv, respectively. The administration protocol used for both treatments produced either a continuous dopaminergic input (CB-154 treatment) or a complete dopaminergic blockade (DOM treatment). Pulse analysis was performed on the data series using the algorithm Detect. In both estrous female and male rats, dopaminergic receptor activation by CB-154 reduced peak and trough values, pulse amplitude, area under the pulse, and mean PRL levels. In contrast, a complete dopamine (DA) receptor blockade by DOM increased these parameters. Domperidone treatment increased pulse frequency and reduced pulse interval and duration. Bromocriptine, however, differentially affected some pulsatility parameters depending on the sex of the rats. In females, CB-154 did not alter any of the qualitative parameters (frequency, pulse interval, and duration) of pulsatile PRL secretion. In contrast, in male rats the treatment reduced frequency and duration while increasing pulse interval. CB-154 reduced basal PRL levels in male rats, whereas in estrous females this parameter was not altered. PRL pulses were further evaluated by frequency distribution analysis, using the area under the pulses divided by the baseline to normalize the data due to treatment-induced differences in baselines. This calculation allows the estimation of the amount of hormone released per pulse over the baseline. In both estrous female and male rats, two classes of PRL pulses were identified. One class corresponded to pulses containing a small mass of hormone [small mass pulses (SM)], while the others were characterized by pulses containing a large mass of hormone [big mass pulses (BM)]. Interestingly, both the dopaminergic agonist CB-154 and the dopaminergic antagonist DOM dramatically diminished BM pulse incidence in both estrous female and male rats. In fact, BM pulses were practically absent in both experimental groups. To further substantiate this notion, animals of each experimental group were assigned to one of the following categories: animals depicting BM and SM pulses or rats presenting solely SM pulses.(ABSTRACT TRUNCATED AT 400 WORDS)

Prolactin Secretion and Corpus Luteum Function in Women with Luteal Phase Deficiency

Luteal phase deficiency (LPD) as a clinical infertility problem is considered to have a heterogeneous etiology. Hyperprolactinemia has long been considered a causative factor of LPD. In this context we investigated PRL secretion in 18 women with LPD. All of the subjects were infertile with 2 out of phase (greater than 2 days) endometrial biopsies; 10 of the women also had daily blood samples, this latter subgroup had significantly decreased integrated luteal phase progesterone (P) levels compared to normal women with in-phase biopsies. PRL secretion was investigated as follows: 1) daily blood levels; 2) pulsatile secretion patterns in 3 cycle phase [early follicular (12 h); late follicular (12 h); midluteal (24 h)], 3) LH-PRL coupling, and 4) nocturnal patterns. Results were compared to findings in 36 normal women. The mean daily levels of PRL over the menstrual cycle were not different between the two groups (LPD, 12.1 +/- 1.5; normal, 13.8 +/- 0.8 microgram/L; P = 0.3). There was no correlation between luteal phase integrated P and PRL levels for either group. There was a small difference in the PRL pulse amplitude in the early follicular phase between the LPD and normal women (2.6 +/- 0.3 vs. 5.5 +/- 1.3 micrograms/L; P less than 0.05). There were no significant differences between groups in PRL pulse frequency or mean level during the 12 or 24 h in any cycle phase. There was an equivalent amount of LH-PRL pulse coupling in both groups in all three cycle phases. Diurnal and nocturnal PRL secretion was studied by breaking the 24 h data (midluteal) into day (0700-2300 h) and night (2300-0700) segments. Mean PRL levels were higher at night in both groups (LPD, 15.9 vs. 12.6; normal, 15.4 vs. 9.3 micrograms/L; P less than 0.05), as expected. There were no differences in nocturnal PRL secretory patterns between the two groups. In summary, we have serious reservations whether abnormalities in PRL secretion are a common or integral part of the pathophysiology of LPD. From previous work we know these subtle abnormalities in PRL secretion in LPD are associated with definite abnormalities in gonadotropin secretion. We believe these gonadotropin abnormalities are probably more significant in terms of decreased P secretion.

Prolactin Secretion and Corpus Luteum Function in Women with Luteal Phase Deficiency*

Luteal phase deficiency (LPD) as a clinical infertility problem is considered to have a heterogeneous etiology. Hyperprolactinemia has long been considered a causative factor of LPD. In this context we investigated PRL secretion in 18 women with LPD. All of the subjects were infertile with 2 out of phase (greater than 2 days) endometrial biopsies; 10 of the women also had daily blood samples, this latter subgroup had significantly decreased integrated luteal phase progesterone (P) levels compared to normal women with in-phase biopsies. PRL secretion was investigated as follows: 1) daily blood levels; 2) pulsatile secretion patterns in 3 cycle phase [early follicular (12 h); late follicular (12 h); midluteal (24 h)], 3) LH-PRL coupling, and 4) nocturnal patterns. Results were compared to findings in 36 normal women. The mean daily levels of PRL over the menstrual cycle were not different between the two groups (LPD, 12.1 +/- 1.5; normal, 13.8 +/- 0.8 microgram/L; P = 0.3). There was no correlation between luteal phase integrated P and PRL levels for either group. There was a small difference in the PRL pulse amplitude in the early follicular phase between the LPD and normal women (2.6 +/- 0.3 vs. 5.5 +/- 1.3 micrograms/L; P less than 0.05). There were no significant differences between groups in PRL pulse frequency or mean level during the 12 or 24 h in any cycle phase. There was an equivalent amount of LH-PRL pulse coupling in both groups in all three cycle phases. Diurnal and nocturnal PRL secretion was studied by breaking the 24 h data (midluteal) into day (0700-2300 h) and night (2300-0700) segments. Mean PRL levels were higher at night in both groups (LPD, 15.9 vs. 12.6; normal, 15.4 vs. 9.3 micrograms/L; P less than 0.05), as expected. There were no differences in nocturnal PRL secretory patterns between the two groups. In summary, we have serious reservations whether abnormalities in PRL secretion are a common or integral part of the pathophysiology of LPD. From previous work we know these subtle abnormalities in PRL secretion in LPD are associated with definite abnormalities in gonadotropin secretion. We believe these gonadotropin abnormalities are probably more significant in terms of decreased P secretion.

Circadian, ultradian, and episodic gonadotropin and prolactin secretion in human pseudocyesis

Six women with pseudocyesis were studied by 15-min blood sampling for 12 to 24 h to determine their gonadotropin and PRL secretory profiles aiming to clarify the endocrine alterations in this form of hypothalamic amenorrhea. Clinical and biochemical evidence of hyperandrogenism was found in 4 patients. Persistent hyperprolactinemia was present only in one patient. Significant circadian and ultradian periodicities were identified by time series analysis in the 12-24 h profiles of FSH, LH and PRL secretion. Pulse analysis by the Van Cauter (UL-TRA.JN) method revealed a 24-h mean LH interpulse interval of 91 +/- 21 min with a mean LH amplitude of 5.4 +/- 0.8 IU/l. There was a significantly lower pulse frequency at night than during the daytime. The mean 24-h PRL interpulse interval and pulse amplitude were 134 +/- 22 min and 9.2 +/- 1.8 IU/l, respectively. Both FSH and LH mean levels were higher during the daytime than at night, while the reverse was true for PRL values. Decreased LH pulse frequency and amplitude emerged as the most distinctive findings. Antecedent hypothalamic-pituitary aberrations due to other endocrinopathies and the timing of the hormonal assessment (e.g. recovery phase) may explain, at least in part, the reported heterogeneity of neuroendocrinologic findings in pseudocyesis.

Attenuated Pulsatile Release of Prolactin in Men with Insulin-Dependent Diabetes Mellitus*

Pulsatile and circadian patterns of PRL release were studied in 11 insulin-dependent diabetic men by sampling blood every 10 min for 24 h and comparing the results to those obtained in 12 normal nondiabetic men. The diabetic men had a mean (+/- SE) 24-h serum PRL concentration of 5.5 +/- 0.42 micrograms/L, which was significantly lower than that in the nondiabetic men (9.3 +/- 0.86; P = 0.0008). Quantitative Cluster analysis of pulsatile PRL time series revealed a normal pulse frequency, but decreased maximal peak amplitude (6.6 +/- 0.5 vs. 11.8 +/- 1.1 micrograms/L; P = 0.0009), peak increment (2.6 +/- 0.24 vs. 4.0 +/- 0.3 micrograms/L; P = 0.009), peak area (126 +/- 15 vs. 192 +/- 19 micrograms/L.min; P = 0.03), and interpulse valley mean concentration (4.8 +/- 0.4 vs. 8.6 +/- 1.2 micrograms/L; P = 0.0007). PRL pulse incremental amplitude correlated significantly (r2 = 0.577; P = 0.007) and negatively with duration of disease. Fourier analysis disclosed a normal circadian rhythm of PRL release in diabetic men, with a mean circadian amplitude of 1.5 micrograms/L +/- 0.31, which peaked at 0201 h +/- 89 min (+/- SE). In summary, we have demonstrated significantly reduced mean 24-h serum PRL concentrations in men with poorly controlled insulin-dependent diabetes mellitus. The concomitant suppression of spontaneous PRL pulse amplitude, peak increment, and interpulse valley mean concentrations in the presence of normal pulse frequency is consistent with a reduced mass of PRL secreted per burst and/or accelerated metabolic clearance of PRL in men with type I diabetes mellitus.