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Endocrine Abstracts (2024) 100 OC1 | DOI: 10.1530/endoabs.100.OC1

1Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College School of Medicine, Imperial College London, London, United Kingdom; 2Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, United Kingdom; 3Department of Paediatric Endocrinology, Queen Mary University of London, London, United Kingdom

Case history: A 25-year-old woman presented with secondary amenorrhoea present since aged 18yrs. She had spontaneous albeit late menarche aged 16yrs and five menstrual periods over the subsequent two-years, before complete menstrual cessation. She denied other medical history, psychological stress, excessive exercise, or regular medications. Notably, she reported normal sense of smell via her right nostril, but anosmia via her left nostril. Family history included a diagnosis of Kallmann syndrome (heterozygous for FGFR1-variant) in both her mother and sister, having presented with primary amenorrhea and anosmia. Her mother required ovulation induction to conceive. On examination, her BMI was 23.7 kg/m2 and she had normal secondary sexual characteristics.

Investigations: Unilateral left-sided anosmia was confirmed with a validated smell-test (UPSIT) and MRI-brain revealed absent left olfactory nerve, bulb, and sulcus. Hormonal assays revealed undetectable oestradiol (<100 pmol/l), and low LH (0.2 IU/l) and FSH (0.4 IU/l) consistent with hypogonadotrophic hypogonadism. Pelvic-ultrasound demonstrated thin endometrium (3 mm). Whole-exome sequencing identified heterozygous FGFR1 and IL17RD variants, consistent with congenital hypogonadotrophic hypogonadism (CHH). GnRH testing (100 mg) induced an LH-rise of 24.8 IU/l indicating preserved pituitary function. An intravenous bolus of kisspeptin-54 (9.8 nmol/kg) elicited a subnormal early LH rise (3.4 IU/l), greater than typically seen in CHH, but earlier and smaller than observed in healthy women. Intranasal kisspeptin-54 (12.8 nmol/kg) delivered to the right nostril induced a small rise in LH (0.5 IU/l), whereas kisspeptin-54 to the left nostril didn’t induce any LH-rise.

Conclusions: CHH typically presents with primary amenorrhoea, and isn’t usually considered in patients with secondary amenorrhoea. This lady had a family history of Kallmann syndrome (KS), raising the possibility, however this may not always be present. KS is CHH with anosmia and usually indicates defective GnRH-neuronal migration. KS is typically associated with bilaterally reduced (microsmia) or absent (anosmia) sense of smell. Unilaterally hypoplastic or absent olfactory structures on MRI are reported, although smell disturbance is typically bilateral. Patients with KS can have partial forms, which are difficult to detect, or even spontaneous reversal of their condition. Reversal of CHH/KS is less commonly reported in women. Kisspeptin stimulates hypothalamic GnRH-neurons and can be used to assess hypothalamic function. Endocrine responses to kisspeptin are usually minimal in CHH. This patient had a subnormal response to kisspeptin, greater than typically observed in CHH but less than in a healthy woman. Given her spontaneous puberty and unilateral anosmia, she appears to have a partial/unilateral form of KS, not previously reported in the literature.

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