12413 Reversal Of Congenital Hypogonadotropic Hypogonadism (CHH) In A Woman With A Heterozygous Inactivating Variant In GnRHR Gene
Authors: Nyunt S W , Phylactou M , Koysombat K , Tsoutsouki J , Yeung A C , Young M , Newman A , Comninos A N , Mamoojee Y , Pitteloud N , Quinton R , Dhillo W S , Abbara A 
Published: October 2024

Disclosure: S.W. Nyunt: None. M. Phylactou: None. K. Koysombat: None. J. Tsoutsouki: None. A.C. Yeung: None. M. Young: None. A. Newman: None. A.N. Comninos: None. Y. Mamoojee: None. N. Pitteloud: None. R. Quinton: None. W.S. Dhillo: None. A. Abbara: None.

Introduction: Congenital Hypogonadotropic Hypogonadism (CHH) is a rare genetic condition with central hypogonadism and pubertal failure affecting both sexes. Reversal of CHH is far less commonly reported in women in the literature. We presented a case of reversal of CHH in a woman with heterozygous GnRHR mutation and the use of kisspeptin in interrogating hypothalamic function. Case history: Our patient presented with primary amenorrhea and incomplete puberty aged 15 yrs. Based on high BMI from early adolescence, clinical hyperandrogenism, family history of polycystic ovary syndrome (PCOS) and insulin resistance, she was diagnosed with PCOS and commenced on a combined oral contraceptive (COC), achieving breast development.Aged 21yrs, she was reassessed for amenorrhea off COC. Biochemical assessment revealed hypogonadotropic hypogonadism (HH): LH 0.2 IU/L, FSH 0.3 IU/L, estradiol &lt;92 pmol/L. She had a normal sense of smell and Tanner 4 breasts; MRI demonstrated normal olfactory bulbs and pituitary. The diagnosis was therefore revised to CHH and COC was restarted, later changed to HRT due to hypertension. A 22-gene CHH panel (R148) identified a heterozygous pathogenic variant c.3171&gt;Gp in GNRHR.At reassessment off HRT aged 32yrs, she remained amenorrheic. Ultrasound showed normal ovarian morphology, antral follicle counts 17 and endometrial thickness 5.8mm; hormonal assays: LH 5.0 IU/L, FSH 8.3 U/L, estradiol 162 pmol/L, AMH 12.2 pmol/L, testosterone 1.6 nmol/L (RR &lt;2.0), SHBG 35 nmol/L (RR 30-100 nmol/L).She then achieved 20kg weight loss (BMI 41.8 to 35.2 kg/m2) on GLP-1 agonist. GnRH test (Gonadorelin 100mcg) incremented LH from 5.16 to 44.46 IU/L and FSH from 6.47 to 15.27 IU/L at 60 mins. After an intravenous kisspeptin (9.6nmol/kg) bolus, LH rose from 5.05 to 29.99 IU/L, FSH from 6.68 to 13.91 IU/L. Off HRT, she began having regular cycles (estradiol 800 pmol/L). Discussion: CHH was diagnosed based on primary amenorrhea, HH and pathogenic GnRHR variant that would not, however, be expected to result in a productive phenotype in the absence of a second deleterious allele (oligogenicity occurs in 20% of CHH), so whole exome sequencing is awaited. Kisspeptin is a potent stimulator of hypothalamic GnRH neurons and can be used to interrogate hypothalamic function. Typically, gonadotrophin responses to kisspeptin are minimal in CHH. Thus, her kisspeptin response was not consistent with CHH at time of assessment, indicating reversal of CHH (seen in 20% of CHH, particularly with GnRHR variants). Notably, her kisspeptin response was higher than in healthy women, consistent with decreased hypothalamic function and potentially a ‘Female Obesity-Related Hypogonadism’. Our case highlights the value of interrogating hypothalamic function using kisspeptin, both for the diagnosis of CHH, and to identify alternate pathology, as well as to identify recovery of reproductive function in CHH reversal.

Presentation: 6/1/2024