SFEEU2024 Society for Endocrinology National Clinical Cases 2024 Poster Presentations (53 abstracts)
Reversal of congenital hypogonadotrophic hypogonadism (CHH) in a woman with a heterozygous inactivating variant in GnRHR gene
Sandhi W Nyunt 1,2 , Maria Phylactou 1,2 , Kanyada Koysombat 1,2 , Jovanna Tsoutsouki 1 , Arthur C Yeung 1,2 , Megan Young 1,2 , Anastasia Newman 1,2 , Alexander N Comninos 1,2 , Yaasir Mamoojee 3 , Nelly Pitteloud 4 , Richard Quinton 3,1 , Waljit S Dhillo 1,2 & Ali Abbara 1,2
1Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom; 2Department of Endocrinology, Imperial College Healthcare NHS Trust, London, United Kingdom; 3Department of Endocrinology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; 4Department of Endocrinology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Case history: Our patient presented with primary amenorrhoea and incomplete puberty aged 15 yrs. Based on BMI >40 kg/m2 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 amenorrhoea of COC. Biochemical assessment revealed 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 Tanner 4 breasts; MRI demonstrated normal olfactory bulbs and pituitary. The diagnosis was therefore revised to congenital HH (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>Gp in GNRHR. At reassessment of HRT aged 32yrs, she remained amenorrhoeic. Ultrasound showed normal ovarian morphology, antral follicle count 17 and endometrial thickness 5.8 mm; hormonal assays: LH 5.0 IU/l, FSH 8.3 U/l, oestradiol 162 pmol/l, AMH 12.2 pmol/l, testosterone 1.6 nmol/l (RR <2.0), SHBG 35 nmol/l (RR 30-100 nmol/l). She then achieved ~20 kg weight loss (BMI 41.8 to 35.2 kg/m2) on GLP-1-agonist. GnRH test (Gonadorelin 100 mg) 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 (9.6 nmol/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 (oestradiol 800 pmol/l).
Conclusion and discussion: CHH was diagnosed based on primary amenorrhoea, 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). However, CHH reversal is far less commonly reported in women. 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, to identify alternate pathology and to identify recovery of reproductive function in CHH reversal.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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