Table 2. Leptin-deficient states.
| Syndrome | Estimated prevalence | Associated features |
|---|---|---|
| I. Congenital leptin-deficient states | ||
| A. Leptin gene mutations | ||
| Homozygous congenital leptin deficiency | Rare | Early onset morbid obesity, hyperphagia, hypogonadotropic hypogonadism, advanced bone age, hyperinsulinemia, and immune dysfunction. These manifestations are normalized by leptin treatment in replacement doses. |
| Heterozygous congenital leptin deficiency | Rare | Less severe obesity that may respond to exogenous recombinant human leptin though this remains to be studied in interventional studies (59). |
| B. Mutations leading to lipoatrophy | ||
| Congenital lipoatrophy | Rare | Lipoatrophy, diabetes, and metabolic syndrome. Metabolic abnormalities improve in response to leptin administration but no randomized, controlled trials have been performed. |
| II. Acquired leptin-deficient states | ||
| A. Generalized decrease in adipose tissue mass | ||
| Anorexia nervosa | Up to 2.2% lifetime prevalence for women (60) | Profoundly decreased body weight and fat mass, amenorrhea/infertility, osteoporosis with stress fractures, decreased thyroid hormone levels, increased growth hormone levels, and decreased IGF-1 levels. |
| Exercise-induced hypothalamic amenorrhea and/or ovulatory dysfunction | Amenorrhea has been reported in 60-69% in trained female athletes and ovulatory dysfunction in up to 78% of recreational female athletes (61) | Lower percentage of body fat with or without decreased body weight, amenorrhea/infertility, osteoporosis, and neuroendocrine abnormalities listed above. Abnormalities improved in response to leptin treatment in a proof-of-concept, controlled trial (46). Larger, randomized, placebo-controlled trials are underway. |
| Non-athletic forms of hypothalamic amenorrhea | 7.6% in women aged 15-24, 3.0% in women aged 25-34, and 3.7% in women aged 35-44 years (62) | Relatively normal or slightly decreased body weight but lower percentage of body fat, amenorrhea/infertility, and neuroendocrine abnormalities listed above. |
| B. Selective decrease in adipose tissue mass | ||
| Acquired severe lipoatrophy and insulin resistance | Rare | Lipoatrophy, insulin resistance, hypercholesterolemia, and hypertriglyceridemia. These metabolic abnormalities improved with leptin replacement in both open-label (56) and randomized, placebo-controlled, cross-over (55) clinical trials. |
| HIV lipoatrophy | 15% - 36% of all HIV-infected patients (63) | |
Abbreviations: IGF-1, insulin-like growth factor-1; HIV, Human Immunodeficiency Virus; HAART, highly-active antiretroviral therapy.