Effect of hypothalamic lesions that induce precocious puberty on the morphological and functional maturation of the luteinizing hormone-releasing hormone neuronal system

Marie Pierre Juniert, Axel Wolff, Gloria E. Hoffman, Ying Junma, Sergio R. Ojeda

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Recent evidence has implicated the transforming growth factor-a (TGFα)/epidermal growth factor receptor (EGFR) system in the mechanism by which hypothalamic lesions accelerate female sexual development. Since acquisition and maintenance of reproductive functions depend on the secretory activity of LHRH neurons, the present studies were undertaken to characterize some of the cellular and molecular events that underlie lesion-induced activation of the LHRH neuronal network. Bilateral electrolytic lesions of the posterior portion of the preoptic region and anterior hypothalamic area (POA-AHA) in 22.dayold rats resulted in vaginal opening and ovulation within 7 days. Morphological maturation of LHRH neurons was assessed by the relative frequency of irregular and smooth neurons (the former being the predominant type in adult animals). Within 20 h after the lesion, there was a significant decrease in the proportion of LHRH neurons with spiny irregular contours, indicating reversal to a more immature morphological type. This change was followed by accelerated spine reformation, so that at the time of precocious proestrus, the incidence of irregular LHRH neurons was similar in lesioned and age-matched control rats. A striking increase in c-fos mRNA levels occurred within 1 h after the lesion in the area neighboring the site of injury, reflecting the immediate cell response to trauma. Immunohistochemical localization of the c-jos protein, used to estimate changes in cellular activity at the single cell level, demonstrated c-fos induction in unidentified cells near the lesion and astrocytes, but not in LHRH neurons 20 h after injury. In contrast, a selective increase in c-fos expression was observed in LHRH neurons during the initiation of precocious puberty 5-7 days later at the time of the first proestrus. An increase in plasma LH associated with a drop in LHRH content in the median eminence and an increase in pro-LHRH precursor in the POA-AHA, with no changes in LHRH mRNA, was found to antedate the first preovulatory surge of gonadotropins in lesioned rats. Assessment of the changes in PC2 mRNA, which encodes a novel dibasic endoprotease presumptively involved in tissue-specific processing of a class of prohormones that includes pro-LHRH, showed that the content of PC2 mRNA in the AHA-POA increases during normal puberty, but not in lesioned animals, thus providing a potential explanation for the divergent changes in pro-LHRH and mature decapeptide found in lesioned rats. The results suggest that POA-AHA lesions induce sexual precocity via a mechanism that predominantly affects LHRH release, independently of changes in either LHRH gene expression or prohormone processing. The lack of c-fos expression in LHRH neurons during the initial tissue response to injury suggests that activation of LHRH release is not the immediate consequence of trauma, but, rather, is caused by events associated with the repair phase of injury. It has been previously postulated that an increased production of TGFα by reactive astrocytes represents one such stimulatory event. The present results indicate that this change is preceded by an acute loss of mature morphological features of LHRH neurons and coincides with the time of morphological recovery. The hormonal changes detected in animals undergoing sexual precocity and the transient increase in c-fos expression observed in LHRH neurons on the day of the precocious first proestrus suggest that the stimulatory process initiated by the lesion culminates when the ovary is driven by the rising gonadotropin levels to produce estradiol levels able to stimulate a preovulatory surge of LHRH secretion.

Original languageEnglish (US)
Pages (from-to)787-789
Number of pages3
Issue number2
StatePublished - Aug 1992
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology


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