20 YEARS OF LEPTIN: Role of leptin in human reproductive disorders

Abstract

Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin.

The role of leptin in regulating bone metabolism

“…Delayed puberty is often seen in leptin deficient states. Indeed, both congenital and acquired leptin deficiencies have been associated with hypothalamic amenorrhea or the cessation of the menstrual cycle and infertility [25]. Decrease leptin levels and increase soluble leptin receptor protein (sLep-R) were also seen in healthy volunteers after a four-week reduced calorie diet of 1000-1200 kcal/day intake [26].…”

“…Much of the evidence comes from women with hypothalamic amenorrhea, a state of infertility which can be caused by energy deficiency-through excess exercise and/or inadequate food intake [25]. Women with hypothalamic amenorrhea have markedly low leptin levels in addition to decreased estrogen and other hypothalamic output hormones, including thyroid hormones and growth hormones [12, 25]. They also have poor bone mass density, which can lead to low-energy bone fractures despite young age [25].…”

“…Women with hypothalamic amenorrhea have markedly low leptin levels in addition to decreased estrogen and other hypothalamic output hormones, including thyroid hormones and growth hormones [12, 25]. They also have poor bone mass density, which can lead to low-energy bone fractures despite young age [25]. Remarkably, all hormonal abnormalities and inappropriate bone density can be reversed by metreleptin therapy [12, 25, 28, 98].…”

The Impact of Bariatric Surgery on Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis

“…Other mechanisms proposed involve hyperleptinemia, leptin resistance, and other adipokines. The effect of PCOS on leptin serum levels is less clear [37]; however, studies have shown that PCOS is independently associated with increased serum leptin levels [38] and leptin resistance [37]. A review by Mitchell et al found that in the context of obesity, adipokines contribute to hyperinsulinemia and also act directly in the ovary to inhibit oocyte maturation ultimately contributing to infertility [39].…”

20 YEARS OF LEPTIN: What we know and what the future holds

“…Among these are its profound effects on the reproductive system. Farid Chehab and Christos Mantzoros, who have made seminal contributions to this aspect of the field, in rodent models and humans respectively, provide thoughtful and insightful summaries of the current state-of-the-art of leptin and reproduction (Chebab 2014, Chou & Mantzoros 2014.…”