**5. Leptin in puberty and infertility**

Robust data reveal that obesity is associated with precocious puberty and cachexic women often experience delayed puberty [34]. The association of obesity with puberty as well as infertility led the researchers to investigate the mediator and connecting factor linking obesity with reproduction.

Rat models with deficiency of leptin or leptin receptors failed to attain puberty, elaborating the significance of leptin for reproductive function. The serum levels of leptin rise continuously throughout the entire period of pubertal development. Leptin regulates female pubertal development more closely as compared to males where minimal leptin levels are sufficient to sustain reproductive function [1].

The actions of leptin on various levels of the HPO axis are detailed (**Figure 4**):

### **Figure 4.**

*Figure representing the actions of leptin on the hypothalamic–pituitary–gonadal axis. Both stimulatory and inhibitory effects are depicted. GnRH, gonadotropin releasing hormone; LH, luteinising hormone; FSH, follicle stimulating hormone; WAT, white adipose tissue [1].*

### **5.1 Effects on the central nervous system**

The primary site where leptin acts to control the reproductive function is the hypothalamus. Leptin receptors are present on the GnRH producing cells in the hypothalamus [1]. Leptin through its central action on the hypothalamus stimulates the production of GnRH and therefore may be a crucial determinant of the integrity of the HPO axis [35]. In mammals the effect of melatonin is also mediated by leptin, as observed by reduced litter size in leptin deficient mice [36]. The administration of daily dose of leptin to normal female mice resulted in advancement in the timing of opening of the vagina by some days [37].

Kisspeptin, a neuronal substance produced by the kiss1 neurons in the hypothalamus stimulates the release of GnRH. Physical stress conditions result in the inhibition of kiss1 neurons thereby resulting in the suppression of HPO axis. Studies have shown that leptin directly acts on the kiss1 neurons to release kisspeptin hence causing GnRH release [1].

The release of follicle stimulating hormone (FSH) and luteinising hormone (LH) from the pituitary gland is also governed by central pathways involving leptin [38]. Although increased leptin levels are seen in women with excessive body weight, obesity per se is associated with leptin resistance at the level of the hypothalamus. This leptin resistance further aggravates the hyperleptinemia via feedback mechanisms. Although leptin resistance is observed at the centre, the peripheral tissues, for example, the ovaries not only remain sensitive to leptin, but are also subjected to higher levels seen in obesity [35, 39].

### **5.2 Effects on the ovary**

Normal leptin levels (10–20 ng/ml) are required for the synthesis of oestrogen and progesterone from the theca and granulosa cells of the ovary. Leptin is also

essential for the normal growth and maturation of the oocyte. The follicular fluid of the maturing Graafian follicle contains leptin, the concentration of which is dependent on the serum leptin concentrations. Higher serum levels of leptin (50–200 ng/ml) were associated with suppression of oocyte maturation and reduced follicular count. Leptin may also play a role in ovulation as can be speculated by a surge in leptin levels occurring at the same time as the LH surge prior to ovulation. Therefore, hyperleptinemia also contributes to infertility by inhibition of ovulation. The role of leptin also extends to the maintenance of corpus luteum after ovulation [3, 38–40].

Hence it can be summarised that decreased leptin levels seen in energy deficient states may be a threat to fertility due to the suppression of HPO axis. However, hyperleptinemia in obese females also causes infertility due to the direct inhibitory action on the gonads.

### **5.3 Effects on the endometrium**

The receptivity of the endometrial epithelium is blunted under the effect of leptin. Studies in mice have revealed that the normal decidualisation of the endometrium is also diminished in obese women. Leptin controls the remodelling of the endometrial epithelium by mediating its proliferation as well as apoptosis [35].

### **5.4 Effects on the embryo**

The effects of leptin on fertility are not confined to the pre-conceptional phase. It also affects the implantation and development of the growing embryo as can be interpreted from lower success rates of IVF in women with hyperleptinemia [39]. Although in vitro studies have demonstrated the positive effects of leptin on growth and proliferation of trophoblastic stem cells, higher levels seen in obese women are a deterrent to the embryonal development [39, 41].
