Reversible Idiopathic Hypogonadotropic Hypogonadism: Clinical and Genetic Characteristics

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 134-163-GnRH & Gonadotroph Biology & Signaling
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-163
Valerie F Sidhoum*1, Yee-Ming Chan1, William F Crowley Jr.1, Ravikumar Balasubramanian1, Richard Quinton2, Lacey C Plummer1, Nelly Pitteloud1, Frances J Hayes1, Kathryn Ann Martin1, Paul A Boepple1 and Stephanie Beth Seminara*1
1Massachusetts General Hospital, Boston, MA, 2Newcastle-upon-Tyne Hospitals, Newcastle Upon Tyne, United Kingdom
Idiopathic hypogonadotropic hypogonadism (IHH) is caused by defective synthesis, secretion, or action of GnRH. Patients with IHH have low sex steroids and low or inappropriately normal gonadotropins in adulthood and are traditionally thought to require lifelong therapy. However, some individuals undergo spontaneous improvement of their reproductive function in the absence of therapy, a phenomenon termed “reversal”.

Charts of 389 IHH patients with detailed medical follow-up and documentation were reviewed. Reversal was defined as ≥1 of the following: 1) fertility without GnRH/gonadotropins, 2) LH pulse frequency and amplitude within the normal range, 3) serum testosterone ≥250 ng/dL off therapy, 4) testicular volume ≥4 ml and >2 ml of growth without use of GnRH/gonadotropins, and 5) spontaneous menstrual cycling. Relapse was defined as once again developing hypogonadal sex steroid levels off therapy (testosterone <100 ng/dl in men, estradiol <20 pg/ml in women).

Of 389 patients with IHH, 13% (45 men, 5 women) met criteria for reversal. Reversal was first noted at a mean age of 27 y (range 19-55 y) and in individuals with both no pubertal development (testes <4 ml, microphallus, cryptorchidism, apulsatile LH secretion) and partial pubertal development. Surprisingly, 30% (n=15) had Kallmann syndrome (IHH + anosmia). One anosmic patient demonstrated absent olfactory bulbs on MRI (structures important for proper GnRH neuronal migration). Among reversal probands, 16% (6/38) carried deleterious mutations in the neurokinin B signaling pathway (TAC3 and TACR3) compared to 5% (43/826) of IHH patients in general (p=0.02). Four men did not sustain their reversal and reverted back to their hypogonadotropic state.

Four key findings emerged from our examination of patients with reversal of IHH: 1) reversal can occur across a broad range of ages and disease severity, 2) GnRH neurons are not strictly dependent on an intact olfactory system to reach their target destinations in the hypothalamus, challenging the prevailing dogma of over 20 years, 3) mutations that disrupt the neurokinin B signaling pathway continue to emerge as a genetic signature for reversal, suggesting that they may display reduced pathogenicity over time, and 4) reversal is not always sustained. All individuals with IHH should periodically undergo brief therapy discontinuation to be screened for reversal and should be counseled about the possibility of reversal and relapse.

Disclosure: KAM: Editor, Up To Date. Nothing to Disclose: VFS, YMC, WFC Jr., RB, RQ, LCP, NP, FJH, PAB, SBS

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: NIH HD028138-22
<< Previous Abstract | Next Abstract