Elsevier

Peptides

Volume 30, Issue 1, January 2009, Pages 111-122
Peptides

Menopause and the human hypothalamus: Evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback

https://doi.org/10.1016/j.peptides.2008.05.016Get rights and content

Abstract

Menopause is characterized by depletion of ovarian follicles, a reduction of ovarian hormones to castrate levels and elevated levels of serum gonadotropins. Rather than degenerating, the reproductive neuroendocrine axis in postmenopausal women is intact and responds robustly to the removal of ovarian hormones. Studies in both human and non-human primates provide evidence that the gonadotropin hypersecretion in postmenopausal women is secondary to increased gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. In addition, menopause is accompanied by hypertrophy of neurons in the infundibular (arcuate) nucleus expressing KiSS-1, neurokinin B (NKB), substance P, dynorphin and estrogen receptor α (ERα) mRNA. Ovariectomy in experimental animals induces nearly identical findings, providing evidence that these changes are a compensatory response to ovarian failure. The anatomical site of the hypertrophied neurons, as well as the extensive data implicating kisspeptin, NKB and dynorphin in the regulation of GnRH secretion, provide compelling evidence that these neurons are part of the neural network responsible for the increased levels of serum gonadotropins in postmenopausal women. We propose that neurons expressing KiSS-1, NKB, substance P, dynorphin and ERα mRNA in the infundibular nucleus play an important role in sex-steroid feedback on gonadotropin secretion in the human.

Introduction

Menopause marks the cessation in reproductive cycles of middle-aged women. It is heralded by depletion of ovarian follicles leading to the loss of ovarian hormones with repercussions throughout the body. The removal of sex-steroid negative feedback results in a marked increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH). This open-loop condition is accompanied by increased GnRH gene expression and cellular hypertrophy of a subpopulation of neurons within the human infundibular nucleus, the homologue of the arcuate nucleus in other species [80], [81]. Although postmenopausal neuronal hypertrophy was first described in 1966 [96], a major breakthrough in our understanding of this phenomenon occurred in 2007, when KiSS-1 mRNA was identified within the hypertrophied neurons [86]. To place this discovery in perspective, this article will review aging of the reproductive axis in women and the marked changes in hypothalamic morphology and gene expression in the postmenopausal human hypothalamus. As it will become apparent, the studies of kisspeptin and neurokinin B (NKB) gene expression in the human hypothalamus provide considerable insight into reproductive neuroendocrine regulation in postmenopausal women.

Section snippets

Ovarian aging and the menopausal transition

Ovarian failure is the critical determinant of menopause in women. At birth, there are approximately 500,000 to 1,000,000 primordial ovarian follicles. Recent stereological studies have shown that degeneration of non-growing ovarian follicles continually accelerates from the time of birth to menopause [43]. Although it has been argued that the loss of follicles accelerates after the age of 37 [25], [82], this conclusion has not been supported by mathematical modeling studies [60]. Regardless of

The reproductive neuroendocrine axis in postmenopausal women

By the time of the postmenopausal period, the degeneration of ovarian follicles is complete and circulating estrogen and progesterone are reduced to castrate levels [4], [9], [66], [105]. The profound deficiency in ovarian hormones results in elevated levels of serum gonadotropins due to the removal of steroid negative feedback and loss of the restraining action of inhibin on FSH secretion. In addition, ovarian failure results in a shift in the composition of the gonadotropins to acidic

Changes in morphology and NKB gene expression in the infundibular nucleus of postmenopausal women

More than four decades ago, Sheehan and Kovács described pronounced differences in hypothalamic neuronal morphology between pre- and post-menopausal women [96]. The neurons were larger in postmenopausal women, in a subregion of the infundibular (arcuate) nucleus which they named the subventricular nucleus [68], [96]. The enlarged neurons exhibited other signs of hypertrophy, including increased nuclear size, larger nucleoli and prominent Nissl substance. There was no evidence of increased

Evidence in animal models that NKB neurons in the infundibular/arcuate nucleus play a role in the sex-steroid feedback on gonadotropin secretion

In postmenopausal women and ovariectomized monkeys, the hypertrophy and increased gene expression of NKB/ERα neurons occurs in association with removal of ovarian steroids. These changes are accompanied by increased hypothalamic GnRH gene expression and elevated levels of serum gonadotropins consistent with removal of steroid negative feedback (see Sections 3 The reproductive neuroendocrine axis in postmenopausal women, 4 Changes in morphology and NKB gene expression in the infundibular nucleus

Kisspeptin neurons in the human hypothalamus and changes in KiSS-1 gene expression in postmenopausal women

Numerous studies have recently documented the importance of kisspeptin, the endogenous ligand of the G protein-coupled receptor 54 (GPR54), in the regulation of reproduction and the initiation of puberty [16], [74], [76], [83], [93]. Inactivating mutations of GPR54 in the human results in a failure of pubertal development with low levels of circulating gonadotropins and low serum sex hormones [16], [93]. Moreover, a GPR54-activating mutation has been shown to be associated with central

Summary and conclusions

The hormonal milieu of postmenopausal women is characterized by the depletion of ovarian follicles, loss of ovarian steroid secretion and secondary gonadotropin hypersecretion from the anterior pituitary gland. Rather than showing signs of degeneration, the reproductive neuroendocrine axis in postmenopausal women responds robustly to the removal of ovarian hormones. Throughout the postmenopausal period, administration of exogenous sex steroids is still effective in reducing GnRH and LH

Acknowledgements

This research was supported by a grant from the NIH (AG-09214). The author gratefully acknowledges the comments and support from Dr. Nathaniel McMullen, Adonna Rometo, Penny Dacks and Sally Krajewski.

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