Kisspeptin and Clinical Disorders - Kisspeptin Signaling in Reproductive Biology - page 187

(NKB) and dynorphin, giving rise to the term KNDY neurons ( K isspeptin - N eurokinin
B- Dy norphin); this co-localization has been observed in several mammalian species,
including humans [ 43 - 45 ]. About 5 years after the discovery of mutations in the
kisspeptin pathway, loss-of-function mutations in the genes encoding neurokinin B
( TAC3 ) and its receptor ( TACR3 ) in patients with normosmic isolated hypogonado-
tropic hypogonadism (IHH) and pubertal failure were discovered [ 46 ]. Patients with
mutations in KISS1R have a relatively straightforward phenotype without syndromic
features, although there can be evidence of residual GnRH activity [ 3 , 4 , 37 ]. Patients
bearing mutations in the neurokinin B signaling pathway also lack anosmia, renal
agenesis, and bony abnormalities, but their neuroendocrine phenotype is more
complex. A large proportion of patients with mutations in either TAC3 or TACR3
have undergone reversal of their hypogonadotropism [ 47 ], a phenomenon in which
patients undergo spontaneous recovery of their hypothalamic-pituitary-gonadal cas-
cade. Tacr3 −/− mice have numerous reproductive defects (including abnormal estrous
cycles, reduced corpora lutea, decreased uterine weights), but mutant female mice
are able to achieve fertility when mated, demonstrating that these mice are more
similar to the patients with TAC3 / TACR3 mutations than previously appreciated [ 48 ].
While reversible GnRH defi ciency is not exclusively associated with TAC3 / TACR3
[ 49 - 54 ], none of the patients bearing biallelic mutations in the kisspeptin signaling
pathway have yet to be reported with this clinical sub-phenotype. While the triggers
to reversal remain poorly understood, these clinical observations appear to be pro-
viding important clues as to the physiologic hierarchy and relative infl uence of neu-
rokinin B and kisspeptin in modulating GnRH release. In fact, the possibility that
the actions of neurokinin B are proximal to those of kisspeptin is supported by the
observation of increased LH pulse frequency during kisspeptin infusion to patients
with neurokinin B signaling defi ciencies [ 55 ].
Fertility Phenotypes
Although fertility data is available for only a subset of patients, mutations in KISS1R
do not appear to impact fertility potential. Despite bilateral cryptorchidism and mild
hypospadius, a male patient carrying a homozygous KISS1R c.1001_1002insC
mutation responded to exogenous pulsatile GnRH, normalizing testosterone levels
and inducing spermatogenesis [ 35 ]. Because his semen analysis showed oligoasthe-
nozoospermia, pregnancy, albeit achieved with assisted reproduction, was possible.
The male proband harboring p.R331X/p.X399R also received pulsatile GnRH and
experienced steady increases in testicular volume and the appearance of normal
spermatogenesis, resulting in fertility [ 39 ]. A homozygous p.L148S female had (1)
intact responses to exogenous GnRH and gonadotropins, (2) multiple conceptions
using the aforementioned therapies as well as IVF, and (3) two uncomplicated preg-
nancies [ 39 ]. While details are not available regarding the quality of her follicular
response, mutations in KISS1R do not appear to preclude steroidogenesis and
gametogenesis.