Does the hypothalamic tyrosine-hydroxylase inhibition mediate the positive feedback of progesterone on gonadotropin release in women?

Neuropharmacological studies suggest a common inhibitory role for the hypothalamic dopaminergic pathway on gonadotropin and prolactin pituitary release, in humans. As a consequence, it has been hypothesized that the inhibition of hypothalamic tyrosine-hydroxylase and the subsequent fall in dopamine synthesis is involved in the positive feedback of progesterone on LH and PRL pituitary release in estrogen-primed hypogonadal women. The aim of our study was to verify whether an inhibition of tyrosine-hydroxylase may really account for the progesterone action on gonadotropin and prolactin secretion. For this purpose, we compared the effect of a specific tyrosine-hydroxylase inhibitor (alpha-methyl-p-tyrosine, AMPT) with the effect of progesterone on gonadotropin and prolactin release in estrogen-primed postmenopausal women. Progesterone induced a marked release of LH (delta: 129.7 +/- 16.5 mlU/ml, mean +/- SE) and a slight increase in FSH (delta: 39.4 +/- 11.6 mlU/ml) and PRL (delta: 15.3 +/- 2.8 ng/ml) serum levels. Acute or two-day administration of AMPT was followed by a marked rise in PRL serum levels (delta: 82.9 +/- 13.8 and 88.3 +/- 8.2 ng/ml, respectively) while there were no significant increases in serum LH (delta: 5.4 +/- 2.6 and 3.3 +/- 4.6 mlU/ml) and FSH (delta: 3.4 +/- 0.9 and -0.4 +/- 2.9) concentrations. The ineffectiveness of a specific tyrosine-hydroxylase inhibitor in simulating the progesterone effect on gonadotropin secretion seems to negate the hypothesis that a reduction in hypothalamic dopaminergic activity mediates the positive feedback of progesterone on gonadotropin release.     

Does a nonclassical signaling mechanism underlie an increase of estradiol-mediated gonadotropin-releasing hormone receptor binding in ovine pituitary cells?

Estradiol-17beta (E2) is the major regulator of GnRH receptor (GnRHR) gene expression and number during the periovulatory period; however, the mechanisms underlying E2 regulation of the GNRHR gene remain undefined. Herein, we find that E2 conjugated to BSA (E2-BSA) mimics the stimulatory effect of E2 on GnRH binding in primary cultures of ovine pituitary cells. The time course for maximal GnRH analog binding was similar for both E2 and E2-BSA. The ability of E2 and E2-BSA to increase GnRH analog binding was blocked by the estrogen receptor (ER) antagonist ICI 182,780. Also, increased GnRH analog binding in response to E2 and the selective ESR1 agonist propylpyrazole triol was blocked by expression of a dominant-negative form of ESR1 (L540Q). Thus, membrane-associated ESR1 is the likely candidate for mediating E2 activation of the GNRHR gene. As cAMP response element binding protein (CREB) is an established target for E2 activation in gonadotrophs, we next explored a potential role for this protein as an intracellular mediator of the E2 signal. Consistent with this possibility, adenoviral-mediated expression of a dominant-negative form of CREB (A-CREB) completely abolished the ability of E2 to increase GnRH analog binding in primary cultures of ovine pituitary cells. Finally, the presence of membrane-associated E2 binding sites on ovine pituitary cells was demonstrated using a fluorescein isothiocyanate conjugate of E2-BSA. We suggest that E2 regulation of GnRHR number during the preovulatory period reflects a membrane site of action and may proceed through a nonclassical signaling mechanism, specifically a CREB-dependent pathway.     

Do endogenous opioid peptides mediate the effects of photoperiod on release of luteinizing hormone and prolactin in ovariectomized ewes?

Three experiments were done to determine if endogenous opioid peptides (EOPs) mediate the effects of photoperiod on release of luteinizing hormone (LH) and prolactin (Prl) in ovariectomized (OVX) ewes. Intravenous infusions of 0.5 naloxone X h-1 X kg body weight-1 for 3.5 h increased (P less than 0.01) mean plasma concentrations of LH and decreased (P less than 0.025) mean interpulse interval (period) of LH pulses in OVX ewes exposed to long day lengths (16L:8D). Infusions of either 1.0 or 2.5 mg morphine-SO4 X h-1 X kg-1 for 3 h increased (P less than 0.005) the period of LH pulses and increased (P less than 0.005) concentrations of Prl in OVX ewes during the breeding season. In OVX ewes exposed to long (16L:8D) or short (8L:16D) day lengths infusions of naloxone increased (P less than 0.05) mean concentrations of LH, whereas morphine decreased (P less than 0.01) mean concentrations of LH. These effects were attributed to changes in period of LH pulses (P less than 0.001). The drug X photoperiod interactions were not significant for LH parameters. Naloxone did not affect Prl release in either long- or short-day groups, but morphine increased (P less than 0.001) Prl release during long and short day lengths. The effect of morphine on Prl release was more pronounced in ewes exposed to long day lengths than in those exposed to short day lengths. In conclusion, EOPs inhibit the LH pulse generator in OVX ewes. However, it is doubtful that the EOPs mediate the steroid-independent effects of photoperiod on LH release. The results also suggest that photoperiod may influence Prl release via opiate neurons.     

Ignoring the challenge? Male black redstarts (Phoenicurus ochruros) do not increase testosterone levels during territorial conflicts but they do so in response to gonadotropin-releasing hormone

Competition elevates plasma testosterone in a wide variety of vertebrates, including humans. The ‘challenge hypothesis’ proposes that seasonal peaks in testosterone during breeding are caused by social challenges from other males. However, during experimentally induced male–male conflicts, testosterone increases only in a minority of songbird species tested so far. Why is this so? Comparative evidence suggests that species with a short breeding season may not elevate testosterone levels during territory defence. These species may even be limited in their physiological capability to increase testosterone levels, which can be tested by injecting birds with gonadotropin-releasing hormone (GnRH). We studied two populations of black redstarts that differ in breeding altitude, morphology and the length of their breeding season. Unexpectedly, males of neither population increased testosterone in response to a simulated territorial intrusion, but injections with GnRH resulted in a major elevation of testosterone. Thus, black redstarts would have been capable of mounting a testosterone response during the male–male challenge. Our data show, for the first time, that the absence of an androgen response to male–male challenges is not owing to physiological limitations to increase testosterone. Furthermore, in contrast to comparative evidence between species, populations of black redstarts with a long breeding season do not show the expected elevation in testosterone during male–male challenges.