Materials and Methods
Ten neonates and infants were included, all with bilateral cryptorchidism in the intra-abdominal or inguinal position and micropenis ≤2 cm (≤2 SDS). The absence of neonatal male mini-puberty was confirmed with at least three repeated measurements at 8 hours of undetectable LH, FSH, and testosterone from 15 days of life up to 3 months of age. Penile length was measured by the method of Schonfeld with the penis being stretched to resistance. Five patients had Kallmann syndrome diagnosed at the neonatal period before bilateral cryptorchidism (abdominal in two cases and inguinal position in three cases) and micropenis; one patient had syndromic features and neurodevelopmental delay, one had normosmic idiopathic hypogonadotropic hypogonadism (nIHH) (testes in inguinal position), one had CHARGE syndrome (coloboma, heart defects, atresia of the choanae, retarded growth and development, genital-urinary anomalies, and ear defects) diagnosed at birth before choanal atresia (testes in abdominal position), two had septo-optic dysplasia (testes in abdominal position) diagnosed in the Neonatal Intensive Care Unit (one because of symptomatic hypoglycemia and cholestatic jaundice and one due to severe diabetes insipidus with a sodium of 174 mmol/L at 12 hours of life), and one had congenital panhypopituitarism diagnosed before hypogonadism and cholestatic jaundice (one testicle in the abdominal position and one in the inguinal position). Brain-pituitary MRI showed unilateral hypoplasia/absence of the olfactory tract in three cases and unilateral/complete absence of the olfactory bulbs in the other two cases of Kallmann syndrome but was normal in the patient with nIHH. Hypoplastic pituitary and optic nerve atrophy was noted in the septo-optic dysplasia cases, aplastic pituitary in the panhypopituitarism case, and cerebellar hypoplasia in the CHARGE syndrome case.
All subjects started treatment at the median age of 0.35 years (0.19 to 0.78) for 3 months with daily subcutaneous injections of Pergoveris® (recombinant human LH 75 IU and FSH 150 IU), receiving a total dose of 6750 IU of LH and 13,500 IU of FSH, and were monitored clinically monthly. Parents were trained and performed the injections at home.
LH and FSH were measured with an Elecsys immunoassay analyzer (Roche).[21,22] Testosterone was measured by liquid chromatography/tandem mass spectrometry. Serum anti-Mullerian hormone (AMH) was measured using the AMH/Mullerian-inhibiting substance ELISA kit (Immunotech-Beckman, Marseilles, France). Serum inhibin-b was measured using specific Generation II ELISA (Demeditec Diagnostics GmbH, Kiel, Germany).
Data are reported as median and range.
Ethical Approval and Permissions
The study was approved by the institutional Scientific Board and Ethics Committee. Written informed consent was obtained from both parent because this comprised an off-label treatment. The Greek National Organization for Medicines issued permission for the off-label use of Pergoveris for each of the cases, and the primary health insurance covered 100% the cost of the injections [90 injections with a total cost ~6000€ (~$6731 US)].
J Endo Soc. 2019;3(7):1275-1282. © 2019 Endocrine Society