Neuroendocrine control, puberty and seasonal breeding

The reproductive system is governed by a chain of command known as the hypothalamic–pituitary–gonadal axis. Neurons in the hypothalamus release gonadotrophin-releasing hormone (GnRH) into the blood vessels that feed the pituitary gland. The pituitary responds by secreting luteinising hormone (LH) and follicle-stimulating hormone (FSH), which act on the ovaries or testes. The gonads in turn produce sex steroids and other hormones that feed back on the brain and pituitary. Much of the research in this field asks how that loop is switched on at puberty, how it generates rhythms, and how it integrates signals about energy, stress and the environment.

Discovering the brain’s reproductive hormones

The idea that the brain controls the pituitary through chemical messengers was confirmed when hypothalamic hormones were isolated. The 1977 Nobel Prize in Physiology or Medicine recognised Roger Guillemin and Andrew Schally “for their discoveries concerning the peptide hormone production of the brain”. Working with extracts of sheep and pig hypothalami, their laboratories showed that the hypothalamus releases factors that make the pituitary secrete its hormones; around 1971 the factor releasing LH and FSH, now called GnRH (a small peptide of ten amino acids), was isolated, sequenced and synthesised, first by Schally and shortly afterwards by Guillemin. The other half of the same prize went to Rosalyn Yalow for developing radioimmunoassays of peptide hormones, a method described between 1956 and 1960 that allowed hormones to be measured in blood and tissues and so to chart the hormonal profile of the cycle, puberty and the breeding season in many species.

Rhythm matters: GnRH pulses

A landmark experiment published in 1978 showed that the pattern of GnRH delivery matters as much as the amount. In rhesus monkeys whose own GnRH production had been abolished by hypothalamic lesions, a constant infusion of GnRH failed to restore gonadotrophin secretion, whereas one pulse per hour, the natural frequency, restored it. Switching back to continuous GnRH then suppressed the pituitary again, a phenomenon described as desensitisation or down-regulation.

Because GnRH cannot be measured in peripheral blood, researchers use LH pulses as a proxy. The neurons that generate the rhythm were identified much later. In the arcuate (in humans, infundibular) region of the hypothalamus, a population known as KNDy neurons produces three signals: kisspeptin, neurokinin B, which is stimulatory, and dynorphin, which is inhibitory. Their interplay is thought to drive the pulsatile release of GnRH and LH, and these neurons also appear to mediate the negative feedback of oestrogen. Whether kisspeptin also drives the positive feedback that causes the mid-cycle LH surge in women is less certain.

Kisspeptin and the switch to puberty

Kisspeptin has an unusual history. The KISS1 gene was first described in 1996 as a suppressor of metastasis in melanoma, and its peptide product was identified in 2001 as the natural ligand of an orphan receptor, GPR54 (now KISS1R). Its reproductive role emerged in 2003, when two research groups independently linked inactivating mutations in this receptor to a failure of puberty. In one large consanguineous family, five of eight children had hypogonadotropic hypogonadism, with absent or delayed puberty and low gonadotrophin levels, caused by a deletion in the GPR54 gene. An activating mutation was later linked to precocious puberty. Kisspeptin is now regarded as a principal regulator of gonadotrophin secretion.

In humans, puberty can begin at any time between about 8 and 14 years of age, according to the NHS, which defines early puberty as signs appearing before 8 and delayed puberty as no signs by 15. Recognised causes of disordered timing range from problems with the ovaries, testicles or hormones to long-term illness, brain injury and malnutrition. The link with nutrition points to a broader question: how the brain senses whether the body has enough energy to reproduce. In mice, kisspeptin neurons carry receptors for leptin, a hormone made by fat tissue, and fasting reduces kisspeptin expression, but how these signals are integrated in humans is still being worked out. Clinical research has explored kisspeptin itself, for example to trigger egg maturation in IVF, and drugs that block neurokinin B signalling.

Seasonal breeding: reading the length of the day

Many wild and domestic animals breed only at certain times of year, so that their young are born when food is plentiful. Day length is the most reliable cue for anticipating the seasons. Long-day breeders, such as many birds, become reproductively active as days lengthen in spring. Short-day breeders, such as sheep, mate in autumn as days shorten; with a pregnancy of about six months, their lambs are also born in spring.

In mammals, day length is translated into a hormonal signal by the pineal gland, which secretes melatonin at night: the longer the night, the longer the melatonin signal. Work over the past two decades has traced the next steps:

• melatonin acts on the pars tuberalis, a part of the pituitary, to regulate a local form of thyroid-stimulating hormone (TSH);
• this TSH acts on ependymal cells (tanycytes) of the hypothalamus, switching on the enzyme DIO2, which converts the thyroid hormone T4 into its active form T3, and switching off DIO3, which inactivates it;
• the resulting local change in thyroid hormone in the hypothalamus alters the reproductive axis.

A key step was the 2003 finding in Japanese quail that light-induced conversion of T4 to T3 regulates the seasonal growth of the gonads. Birds also detect light directly through photoreceptors deep in the brain. The archive behind this page reflects the breadth of comparative work, with studies of seasonal hormone cycles in marsupials, marine mammals and other wild species.

Established and still debated

It is firmly established that GnRH must be secreted in pulses to sustain reproduction, that kisspeptin signalling is required for normal puberty, and that mammals use melatonin and local thyroid hormone signalling to time seasonal breeding. Open questions include what ultimately triggers the activation of the GnRH system at puberty, how kisspeptin neurons integrate metabolic and stress signals, how the mid-cycle LH surge is generated in women, and how far mechanisms described in rodents, sheep and birds apply to other species.