Pulsatile Prolactin Release Research Articles

Characteristics of pulsatile and circadian prolactin release and its variability in men.

In order to investigate the intra- and interindividual variability of spontaneous prolactin (PRL) secretion, 24 h blood sampling at 10 min intervals was performed in ten healthy young men (age 19 to 25 yrs) on three occasions (intervals 2 weeks and 3 months). Plasma PRL concentrations were determined in duplicate by immunoradiometric assay. Peak detection was carried out with the PULSAR program. The circadian rhythm was analyzed by a complex cosinor method combining fundamental (24 h), 1st harmonic (12 h), and 2nd harmonic (6 h) frequencies. The original data was well represented by this calculation as shown by mean (+/- SD) correlation coefficients of 0.84 +/- 0.08. Mean and integrated PRL concentrations showed the lowest intraindividual variability (range 2.8 to 19.6%) of all parameters tested. For the number of peaks per 24 h, a median intraindividual variability of 24.2% (range 6.9 to 50%) was seen. In general, intraindividual variability of parameters of pulsatile PRL release was lower than the variability between subjects. The complex cosinor analysis revealed a bimodal pattern of PRL secretion in most profiles. Acrophases (times of highest PRL levels) were found between 0040 and 1000 h, nadirs between 0030 and 2300 h. The amplitude of the circadian rhythm (Max-Min) ranged from 3.8 to 16.9 ng/ml. The time lag between onset of sleep and acrophase was variable (1.75 to 7.38 hrs). Variability of nadir, minimal and maximal PRL, amplitude, and minimal PRL as percent of the mesor was significantly lower within individuals than between subjects (p < 0.02). During sleep, peak heights and peak amplitudes were significantly higher than during waking periods (p < 0.004). No statistically significant differences were found in the distribution of relative frequencies of peak number, peak amplitudes and peak heights between the three series of profiles. The distribution of peak heights was compatible with a normal distribution. In conclusion, it was shown that the circadian rhythm of PRL secretion in normal men can be analysed accurately and reliably with the complex cosinor method, which is relatively easy to perform and yields results comparable to those obtained by much more complicated programs.(ABSTRACT TRUNCATED AT 400 WORDS)

Cadmium does not inhibit pulsatile prolactin secretion through TRH.

This work was undertaken to analyse the effects of acute cadmium administration on the pulsatile pattern of prolactin release, in adult male rats. For this purpose, animals were cannulated 40 h before the experiment to allow a continuous blood withdrawal. Two hours after the administration of one dose of cadmium chloride (4.5 mg kg1), the pulsatile pattern of prolactin, during three hours, was studied. The effects of two pulses of thyrotropin-releasing hormone (TRH) (1 microgram per rat), given 60 and 120 min after starting the period of blood sampling, were studied. The mean values of prolactin during the bleeding period and the absolute pulse amplitude were decreased by acute cadmium chloride administration. However, no changes in any other parameters of prolactin pulsatility were observed. TRH administration to control rats increased mean prolactin levels, and absolute and relative pulse amplitudes, but decreased the mean half-life of the hormone. In animals pretreated with cadmium, TRH increased the mean levels of prolactin, and absolute and relative amplitudes of the hormone pulses. No other parameter studied was changed by TRH in cadmium pretreated rats. These data suggest that acute administration of cadmium did not inhibit the pulsatile prolactin release through TRH.

Prolactin-induced activation and binding of stat proteins to the IL-6RE of the alpha 2-macroglobulin (alpha 2M) promoter: relation to the expression of alpha 2M in the rat ovary.

Cellular signaling events by which prolactin (PRL) might regulate gene expression were analyzed in rat ovarian tissues. Whole cell extracts (WCE) were prepared from ovaries of pregnant rats (Days 4, 7, 9-11, 15, 17, and 21) and of hormonally primed (estradiol and FSH) hypophysectomized (H) immature rats before, or 15 min to 24 h after, acute administration of PRL (10 micrograms, i.v.). The DNA binding activity in the WCE was analyzed by electrophoretic mobility shift assays using the alpha 2-macroglobulin (alpha 2M) promoter interleukin (IL)-6 response element (IL-6RE) known to confer PRL and IL-6 inducibility to transgenes in target cells, including cultures of luteinized granulosa cells. Injections of PRL stimulated the appearance of a specific binding activity in ovarian extracts of H rats and in corpora lutea and interstitial extracts of pregnant rats from Days 4-9 of pregnancy. The presence of this protein/DNA complex was transient. The greater amount of binding was observed in luteinized tissue and interstitial tissue compared to follicles; and the binding activity contained specific tyrosine phosphorylated Stat (signal transduction and activators of transcription) factors identified by specific antibodies as acute phase response factor (APRF or Stat 3) and mammary gland factor (MGF, or Stat 5 [a and b]). In contrast to the transient activation and appearance of these factors in response to acute PRL treatment as administered to H rats or to pulsatile PRL release as occurs in early pregnancy, elevated levels of the same activated Stat factors were observed in WCE of CL and interstitial tissue prepared at mid-gestation (Days 10-17) when endogenous release of rat placental lactogen (rPL) is chronically elevated in serum. During this period, administration of additional exogenous PRL did not stimulate further activation (binding) of the Stat factors. During luteal regression (Day 21 of gestation) no binding was observed in the absence of PRL, and the response to PRL was markedly diminished despite the constitutive presence of Stat proteins and the Janus kinase that phosphorylates and activates these factors. Elevated binding of these factors to the IL-6RE of the alpha 2M promoter was associated with the expression of alpha 2M mRNA in luteinized granulosa cells and corpora lutea, indicating that activation of Stat factors is one mechanism by which PRL/rPL transactivates the alpha 2M gene in the tissue.

Gonadotropin-releasing hormone antagonists attenuate estrogen/progesterone-induced hyperprolactinemia in monkeys

Previous studies have documented that exogenous gonadotropin-releasing hormone (GnRH) stimulates prolactin (PRL) secretion and augments thyrotropin-releasing hormone-induced PRL release. Further, the concomitant pulsatile release of PRL and luteinizing hormone (LH) suggests that GnRH may be an important regulator of PRL release in certain physiologic states. The authors explored this possibility by evaluating the effect of a GnRH antagonist ([Ac-pClPhe1, pClPhe2, DTrp3, DAla10]-GnRH; GnRH-antagonist) on PRL secretion in monkeys with induced hyperprolactinemia. Monkeys were given estradiol (E2) benzoate 25 mg/kg intramuscularly (IM) on cycle days 1 to 28, and a 3-cm progesterone (P) silastic capsule was placed on cycle day 15 and removed on day 28. On cycle days 15 to 28, monkeys were given IM injections of 1 mg/kg GnRH-antagonist (n = 3), 2 mg/kg GnRH-antagonist (n = 3), or vehicle (n = 3). Daily blood samples were assayed for E2, P, and PRL. The degree of PRL elevation was calculated as percent increase in area under the curve for days 15 to 28 when compared with days 1 through 14 (baseline). Luteinizing hormone levels were calculated similarly. Results indicate a dose-dependent effect of GnRH-antagonist on PRL secretion, with the larger dose producing a significantly lower hyperprolactinemic response, as well as a decline in LH. Thus, GnRH-antagonist attenuates induced hyperprolactinemia in a dose similar to that which suppresses LH release. These findings suggest that GnRH is a physiologic regulator of pituitary PRL secretion. In addition, GnRH analogs may be of benefit in controlled ovarian hyperstimulation by attenuating gonadotropin-induced hyperprolactinemia, thereby reducing potential adverse effects on fertility.

Operating characteristics of the hypothalamo-pituitary-gonadal axis in men: circadian, ultradian, and pulsatile release of prolactin and its temporal coupling with luteinizing hormone.

To investigate the circadian, ultradian, and pulsatile nature of PRL release in the human, we sampled blood at 10-min intervals for 24 h in each of 12 normal young men. The subsequent serum PRL time series were subjected to contemporary techniques of rhythmic and episodic peak detection. Fourier analysis revealed a significant circadian rhythm in serum PRL concentrations in all 12 men. The mean circadian amplitude was 2.1 +/- 0.3 ng/mL (micrograms/L), which accounted for an average of 30 +/- 4% of the 24-h mean PRL concentration. In addition, multiple ultradian PRL rhythms were found with periodicities ranging from 22-242 min. Spectral analysis disclosed ultradian cycles with periodicities of 30-32, 51-59, 90-98, and 234 min. Assessment of episodic PRL pulsatility by Cluster analysis revealed 14 +/- 1 PRL peaks/24 h (P less than 0.01 vs. signal-free noise), which occurred at an interpulse interval of 95 +/- 6 min. The average duration of a serum PRL peak was 67 +/- 5 min, and its incremental amplitude was 4.0 +/- 0.3 ng/ml (micrograms/L), which represented a 58 +/- 6% increase above the preceding nadir. Discrete PRL peaks were separated by nonpulsatile valleys, with a mean duration of 27 +/- 1 min. Analysis of the temporal coupling between LH and PRL release by bivariate autoregressive modeling in six men revealed significant cross-correlations between LH and simultaneous PRL concentrations as well as between LH and PRL concentrations that lagged LH by 10 or 20 min. Cross-spectral analysis demonstrated significantly correlated PRL and LH cycles with periodicities of 33-37, 47-52, and 84-106 min. In summary, PRL release in normal young men is characterized by significant circadian and ultradian periodicities, by discrete episodic pulsations that occur approximately every 95 min, and by a close temporal coupling with LH (temporal lag between LH and PRL of 0-20 min).

Rostromedial septal area controls pulsatile growth hormone release in the golden hamster

Limbic forebrain inhibits growth and growth hormone (GH) secretion in mature golden hamsters as shown by acceleration of growth and increases in serum GH concentrations following the electrolytic lesions of septum, transection of the hippocampus and surgical separation of these two regions. The growth-inhibitory function of this circuit is most probably mediated by somatostatinergic (SRIF) neurons. Such lesions induce hypoactivity possibly due to damage to endogenous opiatergic (EOP) neurons. EOP neurons facilitate spontaneous running in hamsters and mediate exercise-induced acceleration of growth and GH pulses. The coincidence of hypoactivity and growth acceleration after such lesions suggested the coexistence of SRIF and EOP fibers within the growth-inhibitory limbic forebrain circuit which control the rate of growth in mature hamsters by the variable inhibition of SRIF neurons by the EOP neurons. This hypothesis posits that accelerated growth is due to increased GH pulse frequency, and hypoactivity due to damage to EOP neurons, and was tested in this study by measuring pulsatile GH release (and as a measure of specificity, pulsatile prolactin release) in the presence and in the absence of opiate-receptor blocker naloxone in 21 female hamsters which sustained electrocoagulative lesions of rostromedial septum and 30 hamsters subjected to control surgery. Lesions doubled GH but not PRL pulse frequency, neither of which was affected by naloxone. Results support the hypothesis that opiatergic neurons facilitate pulsatile GH release by inhibiting the action of somatostatin neurons.