Involvement of the Y-1 receptor subtype in the regulation of luteinizing hormone secretion by neuropeptide Y in rats.

The present experiments were designed to investigate structure-function relationships, and identify the receptor subtype and postreceptor cellular mechanisms that mediate the ovarian hormone-dependent, excitatory, and inhibitory effects of neuropeptide Y (NPY) on LH release in female rats. Intracerebroventricular administration of NPY decreased plasma concentrations of LH in ovariectomized, hormonally untreated rats but stimulated LH release in ovariectomized rats pretreated with estradiol benzoate and progesterone. A similar dual response was also obtained after administration of NPY2-36.

Afferent stimulation regulates oxytocin messenger ribonucleic Acid during early lactation in rats.

The physiological factors that regulate the levels of oxytocin (OT) mRNA in the rat hypothalamo-neurohypophyseal system during lactation are unknown. The major objective of the present studies was to test whether afferent stimuli provided by the offspring influence the level of OT mRNA in the magnocellular nuclei of the hypothalamus, i.e.

Hypothalamic gonadotropin-releasing hormone secretion and follicle-stimulating hormone dynamics during the luteal-follicular transition.

To define the precise neuroendocrine characteristics of the luteal-follicular transition, 11 normal women underwent 12 frequent sampling studies at 10-min intervals for 48 h at various points during the transition from one cycle to the next. Daily blood samples captured both the preceding and subsequent LH surges, so that studies could be characterized in relation to the preceding LH peak (LH+), the subsequent LH peak (LH-), and menses (M). In the frequent sampling study, LH and FSH were measured in all samples, and estradiol (E2) and progesterone (P) were measured in 2-h pools.

A selective sexually dimorphic response in the median eminence neuropeptide Y.

Recent studies show that neuropeptide Y (NPY) is widely distributed in the hypothalamus and that it stimulates luteinizing hormone-releasing hormone (LHRH) release from the medial basal hypothalamus (MBH) of male and female rats. The neuroendocrine factors that regulate NPY neurosecretion in two sexes are not well understood. We have previously observed that orchidectomy (orch) in male rats decreased and testosterone (T) replacement increased NPY levels selectively in the median eminence (ME), arcuate nucleus (ARC) and ventromedial nucleus (VMN) and the KCl-evoked in vitro release of NPY from the MBH was likewise decreased after orch and restored by testosterone replacement.

Pulsatile gonadotropin-releasing hormone modifies polyadenylation of gonadotropin subunit messenger ribonucleic acids.

Gonadotropin subunit mRNA levels rise after castration, coincident with a period of increased GnRH input to the pituitary. In addition to increased levels of gonadotropin mRNAs, we observed that the sizes of the alpha and LH beta mRNAs were increased after ovariectomy (OVX) of rats. To determine whether these changes occurred in the 5' (alternate transcriptional start site or splicing)- or 3' (altered polyadenylation)-end of the molecules, mRNAs were cleaved using oligonucleotide-directed RNase-H digestion, and the fragments were analyzed by Northern blot, using probes specific to the 5'- and 3'-segments of each transcript.

Neuropeptide Y: a novel neuroendocrine peptide in the control of pituitary hormone secretion, and its relation to luteinizing hormone.

Evidence that establishes neuropeptide Y (NPY) as an important neuromessenger in the regulation of anterior pituitary hormone secretion is reviewed. In particular, NPY plays a critical role in stimulating the episodic, basal pattern of luteinizing hormone (LH) release, as well as the preovulatory surge of LH release in several species. The stimulatory effect of NPY on LH secretion is dependent upon the presence of gonadal hormones and involves amplification of the response of other interacting stimulatory signals.

Normal sequence of the gonadotropin-releasing hormone gene in patients with idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) results from absent or greatly diminished secretion of GnRH. Defects in the GnRH gene have been identified in an animal model of IHH and have been hypothesized as a possible basis for GnRH deficiency in humans. In this study, we used the polymerase chain reaction to clone and sequence the coding regions, promoter, and 3' untranslated tract of the GnRH genes from both alleles of four unrelated patients with IHH.

Precursors of alpha-inhibin modulate follicle-stimulating hormone receptor binding and biological activity.

Although several forms of monomeric alpha-inhibin have been isolated from follicular fluid, no biological function has yet been ascribed to these posttranslationally processed forms of the alpha-subunit precursor protein. Moreover, previous studies of a FSH receptor binding competitor (FRBC) isolated and characterized from porcine follicular fluid (pFF) suggested certain biochemical similarities between this protein and alpha-inhibin precursors. We, therefore, investigated the hypothesis that alpha-inhibin and/or its precursors might represent autocrine and/or paracrine modulators of FSH action in the ovary, accounting for some of this FRBC activity and thereby exerting some degree of regulation over follicular maturation.

Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children.

In children a progressive decrease in nocturnal serum melatonin (MT) has been shown with advancing age, suggesting a reduction in the amplitude of the circadian MT curve with maturation. Whether this alteration of MT levels is related to human sexual maturation or occurs independently remains to be elucidated. Also, the impact of gonadal steroids on the MT rhythm remains an open question.

Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men.

Although prior studies have suggested that estrogens exert their negative feedback effect at the pituitary level in men, these conclusions have been based on models that evaluate changes in LH pulse amplitude and frequency and, therefore, only provide indirect information concerning the site of action of estrogens. To assess whether estradiol (E2) inhibits gonadotropin secretion directly and solely at the pituitary level in men, we determined the pituitary responses to physiological doses of GnRH in six men with complete GnRH deficiency, whose pituitary-gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous E2 infusion (90 micrograms/day). To deduce whether E2 has an additional inhibitory effect on hypothalamic GnRH secretion, their responses were compared with the effects of identical E2 infusions on spontaneous gonadotropin secretion and the responses to a 100-micrograms GnRH bolus in six normal men.

Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men.

The precise sites of action of the negative feed-back effects of gonadal steroids in men remain unclear. To determine whether testosterone (T) administration can suppress gonadotropin secretion directly at the level of the pituitary, the pituitary responses to physiological doses of GnRH were assessed in six men with complete GnRH deficiency, whose pituitary-gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous T infusion (15 mg/day). Their responses were compared with the effects of identical T infusions on spontaneous gonadotropin secretion and the response to a 100-micrograms GnRH bolus in six normal men.

Variable tolerance of the developing follicle and corpus luteum to gonadotropin-releasing hormone antagonist-induced gonadotropin withdrawal in the human.

To examine the differential sensitivity of the ovary to temporary withdrawal of gonadotropin support at different stages of folliculogenesis and corpus luteum function, GnRH antagonist blockade of gonadotropin secretion was examined in 17 studies using the Nal-Glu GnRH antagonist. A vehicle control, antagonist treatment, and follow-up cycle format was used in each study. A previously determined ED100 dose of the Nal-Glu GnRH antagonist (150 micrograms/kg) or vehicle was administered sc every 24 h for 3 consecutive days in the midfollicular phase (MFP), late follicular phase (LFP), and midluteal phase (MLP).

Priapism in hypogonadal men receiving gonadotropin releasing hormone.

To our knowledge we report the first 2 cases of priapism occurring in hypogonadal men receiving gonadotropin releasing hormone therapy. Hypogonadal patients receiving hormonal therapy should be informed about the possibility of priapism and the importance of early urological consultation.

Prolactin stimulates the release of oxytocin in lactating rats: evidence for a physiological role via an action at the neural lobe.

The present studies were designed to investigate whether prolactin (PRL) influences the secretion of oxytocin (OT) in lactating rats, and to test whether the previously reported inhibitory and stimulatory effects of dopamine-2 (D-2) agonists and antagonists, respectively, on OT release might be secondary to their respective inhibitory and stimulatory effects on the release of PRL. Intravenous administration of either rat (r) or ovine (o) PRL to lactating, nonsuckled rats increased basal plasma concentrations of OT. rGH was ineffective, but administration of oGH did produce some stimulation of OT release.

Neuropeptide Y modulates the binding of a gonadotropin-releasing hormone (GnRH) analog to anterior pituitary GnRH receptor sites.

Neuropeptide Y (NPY) increases LH secretion in part by enhancing the release of LH in response to GnRH. The present studies examined whether NPY influences the binding of GnRH to its receptors and also assessed whether specific binding sites for NPY exist in rat anterior pituitary membranes. In concentrations from 66-200 nM, NPY dose-dependently enhanced the binding of a 125I-labeled GnRH agonist, [D-Ala6, des-Gly10]GnRH ethylamide (GnRHa; 30 pM) to anterior pituitary membranes of chronically ovariectomized rats; higher concentrations of NPY were ineffective.

Excitatory and inhibitory dopaminergic regulation of oxytocin secretion in the lactating rat: evidence for respective mediation by D-1 and D-2 dopamine receptor subtypes.

The present experiments were designed to test whether the previously reported excitatory and inhibitory effects of dopamine (DA) on the secretion of oxytocin (OT) in lactating rats are exerted at different DA receptor subtypes, and to examine whether one or both of these effects might occur at the level of the posterior pituitary. The basal release of OT in nonsuckled, lactating rats was increased after intravenous administration of the D-1 DA agonist SKF 38393, and this effect, as well as the suckling-induced release of OT, was prevented by treatment with the D-1 DA antagonist SCH 23390, suggesting that DA may exert an important stimulatory influence over OT secretion through an action at the D-1 DA receptor subtype. A small stimulation of basal PRL release was also produced by SKF 38393, but blockade of the D-1 DA receptor did not prevent the suckling-induced release of this hormone.

Development of a radioligand receptor assay for measuring follitropin in serum: application to premature ovarian failure.

We have developed a radioligand receptor assay (RRA) with sufficient sensitivity and specificity for quantifying follitropin (FSH) in unextracted serum samples. Standard curves prepared by adding pituitary FSH to either buffer or gonadotropin-free serum were parallel and statistically indistinguishable in this assay, whereas gonadotropin-free serum alone had no activity. Cross-reactivity with related pituitary hormones was negligible.

Altered patterns of pituitary secretion and renal excretion of free alpha-subunit during gonadotropin-releasing hormone agonist-induced pituitary desensitization.

Intact LH and free alpha-subunit (FAS) are differentially regulated during GnRH agonist (GnRHa)-induced pituitary desensitization; circulating levels of FAS rise, while LH levels decline. Increased steady state alpha and decreased LH beta mRNA levels in desensitized rat pituitaries suggest that differential regulation occurs at the level of subunit transcription. We assessed a renal contribution to these changes in serum hormone concentrations by studying LH and FAS levels in serum and urine in 15 pubertal children before and during long term GnRHa administration.

Gonadotrophin-releasing hormone analogues as therapeutic probes in human growth and development: evidence from children with central precocious puberty.

Statural growth and skeletal development were assessed in 87 girls with idiopathic central precocious puberty (CPP) during gonadotrophin-releasing hormone analogue (GnRHa)-induced suppression of gonadarche. Before the start of therapy, mean chronological age (CA) was 6.3 years and mean bone age (BA) was 10.

Neuroendocrine control of human reproduction in the male.

The traditional difficulty in studying the neuroendocrine control of reproduction in the human male has been the inability to tease out the hypothalamic from the pituitary component of this neuroendocrine system. The use of multiple models, each with its own strength and weakness, represents an overlapping approach that has permitted further insights to be gained into the hypothalamic control of the neuroendocrine regulation of gonadotropin secretion in the human. Such an insight is an important prerequisite to the understanding of the pathophysiology of various disease states, the unraveling of a control of FSH secretion by GnRH vs other modulators, and the subsequent design of rational therapies for male reproductive disorders.

Localization of neuropeptide-Y immunoreactivity in estradiol-concentrating cells in the hypothalamus.

Considerable evidence shows that gonadal steroids exert a facilitatory influence on levels and release of neuropeptide-Y (NPY) from the hypothalamus. However, it is not known whether gonadal steroids act directly on NPY-producing cells in the arcuate nucleus (ARC) of the hypothalamus to produce these facilitatory effects on NPY or whether they act on other cells that have a modulatory influence via synapses on ARC NPY cells. We applied the combined method of steroid autoradiography and immunocytochemistry to assess the localization of [3H]estradiol in relation to NPY-producing cells in the hypothalamus.

Clinical review 15: Management of ovulatory disorders with pulsatile gonadotropin-releasing hormone.

Pulsatile GnRH therapy has yet to achieve widespread acceptance as an alternative to exogenous gonadotropin therapy in women with hypothalamic amenorrhea and complete GnRH deficiency. However, when a physiologically based replacement regimen of pulsatile GnRH is used, a high rate of ovulation and conception can be anticipated in patients with complete GnRH deficiency and hypothalamic amenorrhea. Women with polycystic ovarian syndrome may also benefit from pulsatile GnRH, although rates of ovulation are lower.