Response to kisspeptin reveals recovery of hypothalamic dysfunction in a woman with reversal of congenital hypogonadotrophic hypogonadism (CHH) with a heterozygous GnRHR inactivating variant

Nyunt Sandhi W; Maria Phylactou; Kanyada Koysombat; Jovanna Tsoutsouki; Yeung Arthur C; Megan Young; Anastasia Newman; Yaasir Mamoojee; Nelly Pitteloud; Richard Quinton; Dhillo Waljit S; Ali Abbara

doi:10.1530/endoabs.109.P218

P218

Prev Next

Section Contents Cite

Endocrine Abstracts (2025) 109 P218 | DOI: 10.1530/endoabs.109.P218

SFEBES2025 Poster Presentations Reproductive Endocrinology (22 abstracts)

Response to kisspeptin reveals recovery of hypothalamic dysfunction in a woman with reversal of congenital hypogonadotrophic hypogonadism (CHH) with a heterozygous GnRHR inactivating variant

Sandhi W Nyunt ^1,2 , Maria Phylactou ^1,2 , Kanyada Koysombat ^1,2 , Jovanna Tsoutsouki ¹ , Arthur C Yeung ^1,2 , Megan Young ¹ , Anastasia Newman ^1,2 , Yaasir Mamoojee ³ , Nelly Pitteloud ⁴ , Richard Quinton ^3,1 , Waljit S Dhillo ^1,2 & Ali Abbara ^1,2

Author affiliations

¹Imperial College London, London, United Kingdom; ²Imperial College Healthcare NHS Trust, London, United Kingdom; ³Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; ⁴Lausanne University Hospital (CHUV), Lausanne, Switzerland

Congenital hypogonadotrophic hypogonadism (CHH) is a rare genetic disorder with central hypogonadism and pubertal failure. While CHH reversal is rarely reported in women, we present a case of CHH reversal in a woman with a heterozygous GnRHR mutation highlighting kisspeptin’s role in assessing hypothalamic function. A 15-year-old girl presented with primary amenorrhoea and incomplete puberty. Due to high BMI, clinical hyperandrogenism and insulin resistance, she was initially diagnosed with polycystic ovary syndrome (PCOS) and treated with combined oral contraceptives (COC) resulting in breast development. A aged 21, she remained amenorrhoeic off COC. Her blood tests indicated hypogonadotrophic hypogonadism (HH): LH 0.2 IU/l, FSH 0.3 IU/l, oestradiol <92 pmol/l. She had a normal sense of smell and a normal MRI, leading to a revised diagnosis of CHH. A heterozygous pathogenic variant in the GnRHR gene was identified. COC was changed to hormone replacement therapy (HRT) due to hypertension. At 32, off HRT, she remained amenorrhoeic, but her hormonal profiles improved: LH 5.0 IU/l, FSH 8.3 U/l, oestradiol 162 pmol/l. Ultrasound showed normal ovarian morphology with an endometrial thickness 5.8mm. Following a 20 kg weight loss on a GLP-1 agonist, GnRH and kisspeptin challenge tests demonstrated increased LH and FSH responses. She subsequently resumed regular menstrual cycles (oestradiol 800 pmol/l). CHH was diagnosed based on primary amenorrhoea, HH and a GnRHR variant. A single heterozygous mutation is typically insufficient to cause CHH suggesting possible oligogenicity. Her robust response to kisspeptin indicated hypothalamic responsiveness, which is inconsistent with CHH suggesting CHH reversal, reported in 20% of cases with GnRHR variants. The elevated kisspeptin response compared to healthy women is consistent with decreased hypothalamic function, which could indicate Female Obesity-Related Hypogonadism. This case highlights kisspeptin’s utility in assessing hypothalamic function, diagnosing CHH and identifying reproductive recovery.