Abstract
Kisspeptin and neurokinin B (NKB) are hypothalamic neuropeptides that are vital for
reproductive health. An absence of either kisspeptin or NKB signaling results in hypogonadotrophic
hypogonadism and a failure to proceed through puberty. In recent years, several studies
have demonstrated potential avenues for the clinical utility of medications that act
through these pathways in the assessment and treatment of reproductive disorders.
Kisspeptin acts to stimulate hypothalamic gonadotrophic-releasing hormone (GnRH) secretion
from the hypothalamus. Kisspeptin induces gonadotrophin secretion in both healthy
men and women, and in women with reproductive disorders such as hypothalamic amenorrhea
(HA). Kisspeptin-based treatments hold promise for use during in vitro fertilization
(IVF) treatment; a bolus of kisspeptin-54 induces an LH surge of 12 to 14 hours of
duration sufficient to induce oocyte maturation, but with markedly reduced rates of
the most significant complication of IVF treatment, ovarian hyperstimulation syndrome
(OHSS). Kisspeptin could also be used chronically to restore reproductive health in
patients with functional hypogonadism, such as those with HA. Furthermore, kisspeptin
has potential as a diagnostic test of hypothalamic function; a “kisspeptin test” could
be used in children with delayed puberty to identify the subset with genetically determined
deficits in hypothalamic pathways (congenital hypogonadotrophic hypogonadism [CHH]).
In addition to its role in hypothalamic GnRH pulse generation, NKB plays a critical
role in the occurrence of one of the most troubling symptoms of the menopause, the
“hot flush.” Neurokinin-3 receptor (NK3R) antagonists are highly effective as treatments
for hot flushes in postmenopausal women, with several compounds now in late-phase
development. Furthermore, NK3R antagonism leads to a reduction in LH secretion by
reducing GnRH pulsatility in the hypothalamus and has been shown to reduce androgen
levels in women with polycystic ovary syndrome (PCOS) (in whom GnRH pulsatility is
often increased). In summary, although further detailed evaluation in several clinical
settings is ongoing, medications based on kisspeptin and NKB pathways have prodigious
potential in the assessment and treatment of reproductive disorders.
Keywords
Kisspeptin - neurokinin B - reproductive disorders
