PMC6861180_01
Results of the sniff test performed at patient's first referral. The first column indicates the 10 odorants employed; the second and the third columns indicate the minimum amount of each substance that the patient was able to detect on the right or left nostril, respectively (first threshold); in normal individuals, the first threshold is generally <3 mL. The patient was also asked to identify the substances, and the patient's answers are reported in the last column. The results are consistent with a severe smell defect. N/D, not detected.
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F1
Test was carried out, which was consistent with a severe smell defect (Figure 1). Considering the possible association with hypothalamus-pituitary-testis axis defects, the patient was then referred to the Endocrinology department. The patient had no cryptorchidism or micropenis at birth and had gone through physiological puberty, with complete development of primary and secondary sexual characteristics (Tanner stage 5); physical examination was unremarkable: he was 186 cm tall and weighed 75 kg (body mass index, BMI: 21.7 kg/m2), with normal arm span to height ratio and absence of gynecomastia; bitesticular volume was 35 mL, and he did not complain of any sexual symptom. The test is based on the presentation to the patient of progressively increasing volumes (from 1 up to 12 mL) of air saturated with the specific olfactory substance, which must be first detected (first threshold; normal <3 mL) and therefore recognized (second threshold); the different thresholds are recorded, along with any wrong substance identification (Figure 1).
(A) Spontaneous LH pulsatility assessed by frequent serum sampling. The graph depicts LH pulsatility assessed at the patient's first referral in 1994 (solid line) and upon hypogonadism symptoms' manifestation in 2017 (dashed line) (LH reference values 1.7-8.6 IU/L); gonadotropin's levels were measured at 20-min intervals for 3 consecutive hours; secretion still occurred in a pulsatile fashion at both time points; nevertheless, as far as one single LH peak was evaluated, the LH release profile appeared slightly flatter in 2017 compared to the 1994 assessment. (B) LH response to GnRH stimulation test. GnRH stimulation test was performed in 1994 (solid line) and then repeated in 2017 (dashed line). Blood was drawn before, and then 20, 30, and 60 min after intravenous GnRH administration; a >=400% increase from baseline was considered normal. LH curves were similar at the two time points and both responses resulted normal, as levels increased by 26 folds in 1994 and by 8 folds in 2017.
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F2
Stimulating Hormone (FSH) levels were 1.22 IU/L (n.v. 1.7-8.6) and 1.63 IU/L (n.v. 1.5-12.4), respectively, and they showed normal pulsatility on frequent serum sampling and normal response to GnRH test (Figures 2A,B); the remaining basal pituitary function was unaffected, as well (Table 1). Skull magnetic resonance imaging with contrast enhancement revealed absence of olfactory bulbs and tracts and hypoplasia of olfactory sulci, while hypothalamus, pituitary gland, and stalk were normal. Gonadotropin levels were inappropriately-low (LH 2.1 IU/L, n.v. 1.7-8.6, and FSH 4.2 IU/L, n.v. 1.5-12.4), but with preserved response to GnRH stimulus (Figure 2B); LH secretion still occurred in a pulsatile fashion as assessed on frequent serum sampling; nevertheless, as far as one single LH peak was evaluated, LH release profile appeared slightly flatter compared to the 1994 assessment (Figure 2A).