Naloxone-Induced Luteinizing Hormone Secretion in Normal, Precocious, and Delayed Puberty*

Abstract

The aim of the present study was to evaluate the activity of opiate receptors involved in the control of LH secretion during pubertal development, as determined by the LH response to naloxone. Normal children (n = 28) of both sexes, subdivided according to breast (girls) or testicular (boys) development, and patients with idiopathic precocious puberty (n = 7), delayed puberty (n = 8), or hypergonadotropic hypogonadism (n = 4) were studied. Plasma LH levels were measured after the administration of naloxone (NLX; 0.08 mg/kg BW, iv), GnRH (50 micrograms, iv) or placebo. In healthy subjects, NLX significantly increased plasma LH levels only in girls and boys at the most advanced stage of gonadal maturation. NLX was ineffective in prepubertal and early pubertal children, and it did not significantly alter LH levels in children with delayed puberty or hypogonadism or in most of the children with precocious puberty. GnRH injection consistently increased plasma LH levels in healthy subjects as well as in the children with pubertal disturbances. These results indicate that the LH response to NLX occurs only at the most advanced stages of pubertal maturation when normal or precocious and is absent in early puberty or in children with pubertal disturbances. Furthermore, the results suggest that opioid regulation of LH secretion in humans changes during puberty, reaching an adult-like functional state with maturation of the hypothalamus-pituitary-gonadal axis.

Neuromodulatory Role of Opioidergic System on Hypothalamus—Pituitary—Gonadal Axis during Puberty

“…In prepubertal and early pubertal children of both sexes the administration of naloxone does not change plasma LH levels 22 . On the contrary, naloxone only induces an LH response in children at the most advanced stages of pubertal maturation (Tanner PH 4–5) 19 . This demonstrates a close relationship between the activity of the opioid system and gonadal maturation occurring during pubertal development.…”

“…Inhibition of the activity of the hypothalamic GnRH‐producing neurons by opioids has been proposed to represent the neurochemical substrate of the hypothalamic gonadostat 1 ; however, the release of GnRH is modulated by LH (short‐loop feedback), GnRH (ultrashort‐loop feedback), and many other peptides and neurotransmitters such as dopamine, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), neurotensin, substance P, and α‐melanocyte‐stimulating hormone (α‐MSH). Hypothalamic βEP contents change during pubertal maturation, unmasking an age‐related opioid modulation of LH secretion in rats 1 as well as in prepubertal children 19 . Moreover, the lack of circadian changes of hypothalamic βEP before puberty in rats has been reported, thus supporting the specific modulatory role of gonadal steroids on opioidergic pathway development and activity 20 …”

“…It is difficult to specify whether the primary change is central or peripheral, since the inability of the opioid antagonist to raise LH plasma levels in prepuberty might depend on the absence of any activity of the central opioid pathways on gonadotropin secretion during this period of life. Moreover, the evidence that naloxone injection is ineffective in children with gonadal dysgenesis or with idiopathic delayed puberty suggests that the increase in gonadal steroid production is the triggering event for the inhibition of gonadotropin secretion by opioids at puberty 19 . In fact, patients with Turner's or Klinefelter's syndrome do not show any change in plasma LH after naloxone administration, even following chronic replacement therapies 23,24 .…”

“…Therefore, it may be suggested that the activity of the opioid system reflects the maturation of the HPG axis, and it is not simply related to the gonadal steroids: Girls with Turner's syndrome with spontaneous menarche are responsive to naloxone infusion. Age is not a critical factor in modulating the opioid control of LH because children with idiopathic delayed puberty or with precocious puberty do not show a significant increase in plasma LH after naloxone 19 . Moreover, Mauras et al 25 demonstrated that naltrexone administration to prepubertal boys determined a reduction of LH plasma levels, suggesting that this paradoxical inhibitory response represented an agonist‐like effect of chronic naltrexone administration.…”

Neuroendocrinology of the Menstrual Cycle

“…Endogenous opioid peptides (EOPs) play an important role in the control of LH secretion by inhibiting the activity of the hypothalamic neurons releasing GnRH. Naloxone administration increases plasma LH levels in men and women 15,16 . This suggests that in humans EOPs tonically inhibit LH secretion, and their effect is dependent on the steroid hormone milieu.…”