Melatonin and the human gonadotrophin-releasing hormone pulse generator

Abstract

The physiological role of melatonin in controlling the GnRH (hypothalamic gonadotrophin-releasing hormone) pulse generator in humans development is explained from recent research findings, and its application to the development of a non-steroidal contraceptive is introduced. Melatonin, identified as N-acetyl-5-methoxy tryptamine, is secreted by the pineal gland at night in a diurnal rhythm at a steady rate after maturation of the gland at the age of about 3 months. Meanwhile the GnRH pulse generator was functioning since birth, but is inhibited when melatonin levels increase beyond about 500 pmol/1 for several hours nightly, at age 3 months. Throughout childhood the GnRH axis remains inhibited. At puberty, body mass increases to the point where melatonin falls below the threshold concentrations so the GnRH pulse generator is re-activated, and menstrual cycling or male potency begins. Individuals with hypogonadotrophic hypogonadal infertility have been shown to have melatonin levels around 700 pmol/1, similar to levels found in pre-pubertal children. After several trials of melatonin injections for contraception that failed, presumably because the high levels were not maintained long enough, a melatonin-based contraceptive that blocks luteinizing hormone and follicle-stimulating hormone is now in Phase III clinical trials.