Response to “Gonadotropin Treatment of Cryptorchidism in Congenital Hypogonadotropic Hypogonadism—Age Is No Limit?”

Abstract

De Silva et al. (Clinical Endocrinology, Vol 101, Issue 3, September 2024, Pages 282–285) [1] recently described three young adults with hypogonadotropic hypogonadism (HH) treated with gonadotropin therapy to induce testicular descent. Our recent experience in two adolescents with HH supports the authors' proposal that age is not a limiting factor in the use of gonadotropins to induce testicular descent, but highlights the mode of gonadotropin use remains highly variable.

Patient 1 was evaluated at age 3 months and 8 years because of a family history of possible Kallmann syndrome in two maternal uncles. At age 8 there was concern that the testes were incompletely descended, but surgical review or other management was not pursued. No abnormality was demonstrated on limited genetic testing at that time. He re-presented at age 15.1 years with delayed puberty. Genital stage was 1 and pubic hair stage 2 with both testes undescended and located in the inguinal canals with clinical volume estimated to be 2 mL. It had become clearer that he was anosmic and he demonstrated synkinesis. A diagnosis of Kallmann syndrome was made. Ultrasound confirmed the testicular location and demonstrated absence of the right kidney. A Triptorelin stimulation test was consistent with HH and a comprehensive gene panel was undertaken in the patient and his mother, with no abnormalities found.

He was assessed by a paediatric surgeon who confirmed a diagnosis of undescended testes, likely to require surgical intervention. He was commenced on recombinant human chorionic gonadotropin (hCG) injections (Ovidrel) at a dose of 20 mcg twice weekly, increased after 3 months to 30 μg twice weekly and increased after another 3 months to 40 μg twice weekly. The left testis had descended after 3 months of treatment. The right testis was partially descended after 6 months of treatment and fully descended after 9 months of treatment. After 12 months of treatment both testes remained descended and were 4 mL in volume with genital stage 4 and pubic hair stage 3. Surgical review confirmed that orchidopexy was no longer required. Recombinant follicle-stimulating hormone (FSH) was added to his therapy after 12 months.

Patient 2 was diagnosed with congenital hypopituitarism after presenting with a micropenis and neonatal hypoglycaemia. He has remained on growth hormone therapy, thyroxine and hydrocortisone replacement since diagnosis, and was treated with a short course of testosterone during the mini-puberty period of infancy. Testes were noted to be descended during infancy, and also documented to be palpable bilaterally at age 11 years. At age 12 years, the right testis was not palpable. By the time of pubertal induction, the right testis remained impalpable while the left testis was retractile. He was commenced on intramuscular testosterone from age 14 years, with doses grading up gradually over 18 months. Ultrasound located the right testis in the inguinal canal and left testes in the scrotum; each with a volume of 0.5 cc. Upon surgical review, he was placed on a list for orchidopexy. As internal endocrine department protocols were recently developed for gonadotropin use in the induction of puberty, the patient and parents were counselled on switching to gonadotropins to continue pubertal induction, with the theoretical benefit of inducing testicular descent. After discussion with the surgeon, the scheduled orchidopexy was cancelled. Upon starting recombinant hCG, he was inadvertently administered a higher dose than prescribed (Ovidrel 250 mcg twice weekly) for 4 weeks. Despite the high dose, there were no observable adverse effects, and the testosterone level remained within acceptable range at 4 nmol/L. He was continued on a lower dose (Ovidrel 50 mcg twice weekly). By 4 months of treatment, the testes were palpable in the scrotal sacs bilaterally and documented on ultrasound to be 0.8 cc bilaterally. According to current Australian criteria, recombinant FSH was added after 6 months of hCG treatment, as combined gonadotropin treatment will be required to induce spermatogenesis.

Our cases demonstrate that the monotherapy phase of hCG was sufficient for the purposes of inducing testicular descent; supporting the data that placental hCG and pituitary luteinising hormone (LH) have key roles in testicular descent which cannot be achieved with androgen action alone [2].

Two other retrospective studies have described testicular descent in patients with HH aged 1.5–27 years on varying regimens, ranging from pulsatile gonadotropin releasing hormone treatment via a pump, at least 6 months of hCG followed by addition of human menopausal gonadotropin (hMG), simultaneous hMG and hCG or pretreatment hMG followed by combined therapy [2, 3]. These reports add further evidence that gonadotropin treatment is likely to be effective in inducing testicular descent in HH in all age groups. A variety of regimens have proven successful.

Our cases highlight that puberty is a critical time when undescended descended testes in HH may first come to the attention of the clinician; either due to delayed presentation of HH or inadequate testicular descent (ascending testes) becoming evident with increased linear growth. We propose that gonadotropin therapy should be considered the first line option for pubertal induction in patients with definite HH in whom undescended testes are detected at the time of pubertal induction, liaising closely with surgical colleagues while awaiting response to medical therapy. Further studies are required to determine the optimal mode and doses of gonadotropin therapy specifically to induce puberty in boys with HH and, where present, for successful testicular descent in this rare group of disorders.