Abstract: Congenital hypogonadotropic hypogonadism (CHH) is characterized by isolated GnRH deficiency in the absence of central anatomical causes. Classically considered to be a permanent disorder, CHH reversal has been reported in up to 15% of cases. However, reversal may not always be life-long, as hypogonadism relapse can occur in a subset of patients. Criteria for reversal normalization of circulating sex steroids, and spontaneous fertility. We report a 26-yrs-old man, who presented with incomplete pubertal incomplete pubertal development, infertility, low libido, sporadic sexual activity with no ejaculation and normal sense of smell, as confirmed by a formal smell test. Physical examination revealed eunuchoid body proportions, pubic hair tanner stage 3, penis length, 4 cm, and testicular sizes 2.8×1.7 cm (right), and 2.7×1.5 cm (left). Hormonal evaluation showed testosterone (T), 35 ng/dl, LH, 0.8 U/L FSH: 1.53 U/L (IFMA), and otherwise normal pituitary function. Hypothalamic-pituitary imaging was normal. Genetic analysis revealed a homozygous GnRHR mutation (p.Q106R/p.Q106R), previously known to be partially inactivating. He was diagnosed with normosmic CHH and started on testosterone replacement therapy (TRT) with intramuscular testosterone cypionate 200 mg every 3 weeks. After one year his wife was pregnant while he was still on TRT. Treatment was discontinued, and further evaluation showed an increment in the testicular size (4,0×2,5 cm, bilaterally), T, 209 ng/dl, LH, 4.2 U/L, FSH, 8.1 U/L, sperm count of 17×106/ml. One year after therapy withdrawal he complained again of low libido and lack of energy, suggesting relapse of the hypogonadism. Hormonal evaluation showed T, 66 ng/dl, and LH, 3.8 U/L. Three years after proper TRT with intramuscular testosterone cypionate 200mg injections every 14 days, his wife had a new spontaneous pregnancy. After discontinuation of testosterone replacement, a new spermogram confirmed fertility in addition to normal sexual hormones level. This case shows a recurrent atypical spontaneous fertility in the course of TRT in a CHH patient. Unlike hCG therapy, TRT is not supposed to induce gonadal maturation or fertility in these patients, by the significant negative regulatory effect of GnRH pulse frequency. Nevertheless, it has been speculated that testosterone exposure could act as a trigger to reversal, by stimulating GnRH neuronal plasticity in predisposed patients. Spontaneous testicular growth and/or fertility are indicatives of CHH reversal. Long-term follow-up with physical examination, assessment of the possibility of reversal, relapse and counselling about fertility is necessary for all CHH patients.
18 - 21 May 2019
European Society of Endocrinology