M. E. Quigley

Neuroendocrinology of opioid peptides and their role in the control of gonadotropin and prolactin secretion

Substantial evidence now exists to indicate that the endogenous hypothalamic opioidergic mechanism(s) represents one of the important controlling systems for release of gonadotropin-releasing hormone. Modulations of frequency and amplitude of the secretory activity of gonadotropin-releasing hormone appears to be mediated through an inhibitory action of endogenous opioids, and the functional coupling of the opioidergic and gonadotropin-releasing hormone systems is an ovarian steroid-dependent event. There is also evidence to implicate suprahypothalamic mechanism(s) that enhance endogenous opioid inhibition of secretion of gonadotropin-releasing hormone. Although exogenous opioid peptides and their synthetic analogs consistently induce the secretion of prolactin, blockade of opioid receptors in humans by naloxone failed to elicit a decrement in the levels of prolactin under a variety of conditions. On the contrary, naloxone induced a remarkable increment in the secretion of prolactin via an increased frequency of pulsatile release which is synchronized with pulses of luteinizing hormone. These observations suggest that a common neuroendocrine mechanism is involved in the opioidergic control of the secretion of both luteinizing hormone and prolactin in women.

Evidence for decreased endogenous dopamine and opioid inhibitory influences on LH secretion in polycystic ovary syndrome.

The inhibitory role of the dopaminergic and opioidergic mechanisms in the control of LH secretion in patients with polycystic ovary syndrome (PCO) was evaluated. The administration of an opiate receptor antagonist, naloxone, of a dopamine receptor antagonist, metoclopramide, or of human synthetic βh‐endorphin, were unable to alter LH secretory activity in patients with PCO. Since identical doses of these antagonists and the opiate agonist have elicited respectively a rise and fall of LH levels in normal cycling women, these findings suggest that an underlying hypothalamic component of defect in endogenous dopamine and opioid control may be responsible for the inappropriate gonadotrophin secretion in this syndrome.

Effects of maternal smoking on circulating catecholamine levels and fetal heart rates

Eight pregnant chronic cigarette smokers were studied after 34 weeks of gestation to determine the effects of acute cigarette (two nonfilter cigarettes) inhalation on maternal neuroendocrine and cardiovascular changes and on the fetus. Cigarette smoking was found to induce rapid (within 2 1/2 minutes) elevations in maternal plasma norepinephrine and epinephrine levels and this was associated with a rise in maternal pulse and blood pressure. These changes are followed, with a 5 minute lag time, by a significant increase in fetal heart rate. A relatively slow but sustained increase in maternal carboxyhemoglobin (HbCO) concentration occurred. The time course of this increase in HbCO did not seem to be responsible for the acute changes in fetal heart rate. Maternal cortisol levels also showed a slow but sustained elevation. Our present findings, together with data obtained from animal models, suggest that cigarette smoking during pregnancy induces fetal hypoxia through two independent but additive pathways: (1) An acute effect is caused by nicotine activation of adrenergic discharge, resulting in vasoconstriction, a decreased uterine perfusion, and a consequent transient fetal tachycardia, and (2) a delayed but prolonged increase in HbCO may cause a sustained reduction of fetal oxygenation.

The dopaminergic inhibition of LH secretion during the menstrual cycle

To assess the potential inhibitory role of hypothalamic dopaminergic input on the LRF-LH system, the gonadotropin response to a dopamine receptor antagonist, metoclopramid (MCP, 10 mg iv bolus) was examined during different phases of the menstrual cycle in 12 women. In addition, the role of dopamine infusion on naloxone (opiate receptor antagonist) induced LH increments was examined. MCP induced an abrupt increase in circulating LH levels in the mid-luteal phases but not in the early and late follicular phase subjects. No significant changes in serum FSH levels were observed. Dopamine, when infused concomitantly with naloxone, completely suppressed the naloxone induced pulsatile increments of LH in mid-luteal subjects. These findings support the contention that an increased dopaminergic inhibition of LRF-LH system occurs during the high estrogen-progesterone phase of the menstrual cycle, and provide preliminary evidence that the inhibitory role of endogenous opioids on LRF release may involve the dopaminergic system.

Evidence for increased dopaminergic inhibition of secretion of thyroid-stimulating hormone in hyperprolactinemic patients with pituitary microadenoma

The administration of a dopamine-receptor antagonist, metoclopramide (10 mg, intravenous bolus), elicited a significant increase in the circulating concentration of thyroid-stimulating hormone (TSH) which was substantially greater for hyperprolactinemic patients with pituitary microadenoma than for normal women during the early follicular phase of the cycle. This study provides evidence of an inhibitory role of hypothalamic dopamine in the regulation of secretion of TSH and suggests an increased dopaminergic inhibition of secretion of TSH in these patients with prolactin-secreting tumors.

Postpartum hypogonadotrophinism: evidence for increased opioid inhibition.

To investigate a proposed role for endogenous opioids in the inhibition of LH: RH‐gonadotrophin release in the postpartum hypogonadotrophic state, LH and FSH responses to naloxone infusion (1·6 mg/h for 2 h) and to a pulse of LHRH (10 μg) were measured in five non breast‐feeding women. Sequential studies were made at four intervals during the first 25 d postpartum. LH and FSH responses to naloxone were absent on Day 10 postpartum, but significant increments were observed in all studies performed between Days 13–25 postpartum. The relative increments of FSH and LH during naloxone varied as the puerperium progressed; a 3‐fold greater release of FSH than LH was found on Day 13 to 15 while the reverse was observed on Day 25. The intermediate days (17–20) yield an equal response. There was a positive linear correlation between the LH and FSH responses to naloxone infusion and to LHRH. These data suggest that the hypogonadotrophinism of the puerperium is due at least in part to increased opioid inhibition of LHRH secretion.