Persistence of LH Pulses in the Absence of Neurokinin B

Presentation Number: SUN 484
Date of Presentation: April 2nd, 2017

Margaret Flynn Lippincott*1, I Sadaf Farooqi2, Christopher Jones3, Yee-Ming Chan1, Wiebke Arlt4, Susan Stewart5, Trevor Cole6, Natalie D Shaw1 and Stephanie Beth Seminara1
1Massachusetts General Hospital, Boston, MA, 2Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom, 3University of Leeds, 4University of Birmingham, Birmingham, United Kingdom, 5Birmingham Women’s Hospital Foundation Trust and University Hospital Birmingham, 6Medical Genetics, University of Birmingham



Five percent of cases of hypogonadotropic hypogonadism (HH) are due to loss of function mutations in the genes encoding neurokinin B (encoded by TAC3) or its receptor (TACR3). Neurokinin B (NKB) is co-expressed with other proteins including kisspeptin and dynorphin; this ensemble of neuropeptides and their receptors are thought to play a role in the timing of puberty onset and the maintenance of a normal sex steroid milieu, in part, by contributing to the pulsatile release of GnRH. Notably, mutations in the NKB signaling pathway have been associated with a particular subphenotype of HH known as reversal, in which patients undergo spontaneous activation of the hypothalamic-pituitary-gonadal cascade. We sought to characterize the neuroendocrine profile of 4 HH sisters carrying homozygous, frameshift TAC3 mutations, 3 of whom underwent reversal. 

Experimental Design & Results

Four sisters presented at 13-15 y with primary amenorrhea and all received estrogen therapy to induce secondary sexual characteristics. Because of the lack of spontaneous sexual maturation by age 18, normal brain imaging, and low sex steroids in the setting of low gonadotropins, all received a diagnosis of HH. Three of the 4 sisters underwent reversal of their hypogonadotropism between 22-28 y as evidenced by pregnancy without fertility medications (n=2) and spontaneous menstrual cycles (n=1). All 4 sisters were found to carry mutations in TAC3 resulting in complete absence of neurokinin B (c.61_61delG p.A21LfsX44 hom). All underwent q 10 min blood sampling x 8 h (between ages 30 and 36 y). No subject was taking any hormonal medications and all were amenorrheic at the time of the study. Samples were assayed for LH and estradiol; analysis of pulsatile secretion was performed using a modification of the Santen and Bardin method.

Estradiol levels were low in all 4 sisters (16-41 pg/mL). Over the course of the blood sampling, three women each experienced one LH pulse (mean LH pulse amplitude of 1.5±0.8 mIU/mL). In the other subject, an LH pulse could not be identified by formal pulse analysis; however, the continuously declining LH values over the 8 hours suggested that an LH secretory event occurred before the initiation of blood sampling.


Patients with HH are typically conceptualized as having absent or abnormal GnRH-induced LH secretion. These 4 sisters, all with a biallelic loss of function mutation in TAC3, demonstrate that patients with a complete absence of neurokinin B are capable of generating low amplitude, low frequency LH pulses while still in their hypogonadal state. Future studies will be required to determine the factors contributing to the pulsatile release of GnRH in these individuals at baseline and the potential contributions of those factors to the normalization of steroidogenesis/gametogenesis as occurs in reversal.


Disclosure: YMC: Advisory Group Member, AbbVie. Nothing to Disclose: MFL, ISF, CJ, WA, SS, TC, NDS, SBS