Functional Medicine Jupiter, a kisspeptin almanac

Resetting the hormone clock

In thirteen healthy adult men, a single intravenous bolus of kisspeptin-10 brought on an immediate luteinizing hormone pulse regardless of when the preceding pulse had occurred. The investigators described a reset of the hypothalamic GnRH pulse generator. That is a more interesting verb than ‘increase’. It asks whether an intervention changes the system doing the timekeeping.

At first I rated a reproductive peptide by the height of the hormone rise. This experiment put the interval beside the peak in my estimation. An isolated result gives the clock no room to show itself. A succession of observations can reveal a rhythm, and a deliberate disturbance can test how that rhythm responds.

GnRH is the hormone signal upstream of the pituitary's release of LH, or luteinizing hormone. The biological connection has experimental substance: kisspeptin stimulated GnRH release in sheep, while mice lacking its receptor failed to produce the usual LH and FSH response. Those animal experiments help explain why a human LH pulse can be used to investigate the timing machinery further upstream.

A responsive system

The word ‘functional’ earns its place here when it means a system doing something over time. In five women with hypothalamic amenorrhea, an infusion of kisspeptin-54 restored pulsatile LH secretion. The highest infusion dose also produced a fading response during the experiment. A system can answer and then become less responsive while the signal continues.

That complication suits an almanac. The first appearance, the next return and the eventual disappearance each deserve an entry. I favor an experiment that follows the return of a signal. Driving a hormone signal permanently upward seems a much less interesting ambition. The longer exposure experiment gives that distinction a particularly uncomfortable pair of measurements.

Other scales of biological time

There is also the slower timing of reproductive maturation. Loss of function in the kisspeptin receptor was associated with absent or incomplete puberty in humans; a receptor mutation with prolonged responsiveness appeared in a girl with early puberty. Those contrasting observations make the signal's importance unusually tangible. Their implications for treatment require separate experiments.

The essays can be entered at different points:

• Pulse reset follows the experiment that gives this almanac its starting point.
• Fading response watches the first hormone rise lose its force.
• Puberty timing compares the genetic findings at the beginning of reproductive life.
• Egg maturation examines a deliberately timed task during IVF.

The reading list includes the original reports and a review of their clinical setting. The clock experiment leaves me fascinated and still doubtful about intervention.