How Much Kissing Is Required for Fertility?

Abstract

The mammalian reproductive axis is regulated by neuroendocrine signaling pathways within the hypothalamus that control pulsatile secretion of GnRH into the hypophyseal portal system. GnRH stimulates gonadotropic hormone secretion from the anterior pituitary to activate pubertal maturation of the gonads and regulate fertility. Thus, substancesandphysiological inputs thataffectGnRHrelease provide important control mechanisms for regulation of the reproductive axis. Within the past decade, kisspeptins have beenidentifiedasakeyregulatorofGnRHrelease(forreview see Ref. 1). Kisspeptins are a family of overlapping amidated neuropeptides encoded by the Kiss1 gene that act as potent agonists of GnRH release by binding to their membrane receptor (kisspeptin receptor, KISS1R, also known as G-protein coupled receptor 54, GPR54) expressed by GnRH neurons (2). Kiss1 neurons reside within 2 regions of the hypothalamus; the arcuate (ARC) and the anteroventral periventricular (AVPV) nuclei. The Kiss1 neurons in the ARC are thought to regulate GnRH pulse frequency, whereas the AVPV neurons, which are sexually dimorphic with greater numbers in females, are required for inducing the preovulatory LH surge. Thecriticalrolethatkisspeptinsplayinmaintainingmammalian fertility was highlighted by the effect of loss of expression of these neuropeptides in transgenic mice (for review see Ref. 3). Disruption of the Kiss1 gene in mice results in failure of sexual maturation at puberty and infertility. The mutantmicehavehypogonadotropichypogonadism,similar to that found in patients with inactivating mutations of the kisspeptin receptor (4, 5). Mutant female mice do not show normal estrous cycling but have times of persistent estrus, probably reflecting their failure to ovulate. Consistent with this phenotype, the mutant female mice were incapable of eliciting an estradiol-induced LH surge required for ovulation (6). In contrast, however, female mice in which Kiss1 neurons were chronically ablated during development by cell-restricted expression of a diphtheria toxin entered puberty at the normal time and were fertile (7). This was a completely unexpected finding given that loss of Kiss1 neurons produced a less severe phenotype than loss of the kisspeptin protein and led to the controversial suggestion that kisspeptin signaling is not essential for female fertility. To account for these differences, it was suggested that compensatory changes occur during brain development that overcome the loss of the Kiss1 neurons. In support of this, it was shown that temporal ablation of Kiss1 neurons in 20-weekold adult females caused infertility, possibly because neuronalcompensationcouldnotoccur.Female infertilitywasalso found when Kiss1 neurons were ablated at postnatal day 20, suggesting that compensation occurs before this time point. The paper published in this issue of Endocrinology by Popa and colleagues (8) is an important contribution to this field because it provides data regarding the minimum amount of kisspeptin protein that is required to maintain fertility in mice. The authors report the reproductive phenotype of a transgenic mouse line that carries a hypomorphic mutation in the Kiss1 gene. These mice contain a CRE-GFP transgene inserted between the transcriptional start site and the coding region of the Kiss1 gene (9), which reduces expression of Kiss1 transcripts and greatly diminishes kisspeptin protein levels. Male mice with only a 5% level of Kiss1 transcripts are fertile and give rise to normal-sized litters. Female mice are also fertile but show a more severe effect than in males with reduced fertility rates and smaller litter sizescomparedwithwild-typemice.This sexuallydimorphic difference in the severity of the reproductive defect may indicate that male mice can cope with lower kisspeptin levels than females. It is likely that the mutant males will have a reduced sperm count because they have smaller testes and lowerFSHlevels thannormalbut that the spermnumbersdo