Kisspeptin: the peptide that lets puberty, and every pulse after it, happen

Kisspeptin is the peptide product of KISS1. It binds KISS1R, a receptor that used to be called GPR54, on GnRH neurons. When those neurons fire, GnRH reaches the pituitary and the pituitary releases LH and FSH. That is the entire sex-hormone axis in one step. Before 2003 the peptide was a curiosity that suppressed melanoma metastasis, which is how it got the name metastin. Then Seminara, in the New England Journal of Medicine, and de Roux, in PNAS, found families with mutations in the receptor who never went through puberty. The axis was intact below the missing signal and silent without it. A ligand people had filed under cancer biology turned out to be the permit for fertility.

In short. Kisspeptin is the hormone that lets GnRH fire. Without its receptor, puberty does not start. That was found in families in 2003, not in a gym.

The neurons that matter for the ongoing pulse sit in the arcuate nucleus and co-release two other peptides: neurokinin B, which speeds them up, and dynorphin, which slows them down. KNDy is the acronym, and it is the pulse generator. Oestradiol and testosterone feed back onto these cells, not by a vague 'the brain notices', but by sex-steroid receptors on this population. Negative feedback is kisspeptin output falling, GnRH pulses spacing out, LH falling. The mid-cycle surge is a different kisspeptin population, in the preoptic area, that oestradiol can excite once a threshold is crossed. Women have both the brake and the accelerator. Men mostly live on the brake. Enclomiphene, tamoxifen at the hypothalamus, and an aromatase inhibitor all change LH by changing what these neurons think oestradiol is doing. They do not invent a new pathway. They edit this one.

In short. A small set of neurons makes kisspeptin, speeds up with one peptide and slows with another. Oestrogen and testosterone tell those neurons whether to keep the GnRH pulse going. Fertility drugs that raise LH are editing this step.

Energy is a required input. The same neurons listen to leptin and to metabolic stress. When energy availability is too low for long enough, kisspeptin output falls, GnRH quiets, LH and FSH fall, and a menstrual cycle stops. That is hypothalamic amenorrhoea, and in men it is the same axis going quiet: lower testosterone, lower sperm, a pituitary that is not broken and is not being asked. The coming-off page describes the pharmacological version, where an androgen occupies the receptor and imposes the quiet. Under-eating imposes it without a drug. Both end at a silent GnRH neuron. Restoring pulses means restoring the permit, which means the steroid feedback has to ease and the energy signal has to return. A SERM can push the feedback lever. It cannot replace calories.

In short. If you under-eat for long enough, kisspeptin goes quiet and periods or testosterone stop. Anabolic steroids do the same job from the other direction. Food and a lifted feedback brake are different repairs.

Dhillo, Jayasena and colleagues in London have spent a decade giving kisspeptin-54 to people and watching LH move within minutes. It can mature eggs. It stimulates gonadotrophins in men and in women. It does it from above the pituitary, which is why a pituitary that still works will answer, and a pituitary that does not will not. The peptide is short-lived. A native pulse is a pattern, not a permanent bath. That is the same lesson as GHRH: the information is in the timing. Flood the receptor and you learn that the receptor exists. You do not automatically copy the pattern a fertile cycle was using. The research is real, and it is an endocrine tool, not a pre-workout.

In short. Infusions of kisspeptin make LH rise within minutes, and they have been used to mature eggs. The natural signal is a pulse. A constant bath is a different message.