Replacement of Male Mini-Puberty

Dimitrios T. Papadimitriou; Dionysios Chrysis; Georgia Nyktari; George Zoupanos; Eleni Liakou; Anastasios Papadimitriou; George Mastorakos


J Endo Soc. 2019;3(7):1275-1282. 

In This Article

Abstract and Introduction


Context: Clinical management of congenital hypogonadotropic hypogonadism (CHH) remains a challenge in pediatric endocrinology.

Objective: To investigate whether daily subcutaneous injections of the recombinant human LH/FSH preparation could mimic the physiological male mini-puberty.

Design and Setting: The REMAP (REplacement of MAle mini-Puberty) study with up to 10 years of follow-up.

Patients and Intervention: Ten neonates or infants, all with bilateral cryptorchidism in intra-abdominal/inguinal position and micropenis with the absence of neonatal male mini-puberty, received daily subcutaneous injections of Pergoveris® (LH/FSH 75/150 IU) for 3 months.

Main Outcome Measures: Restoration of bilateral cryptorchidism/micropenis and the Leydig/Sertoli cells function.

Results: At the end of treatment, median LH and FSH, both undetectable before treatment, reached high normal levels of 4.45 IU/L and supranormal levels 83 IU/L, respectively; median inhibin-b and anti-Mullerian hormone levels increased from subnormal (27.8 and 1.54 ng/mL, respectively) to normal levels (365 and 150 ng/mL, respectively); median testosterone increased from just detectable (0.02 ng/mL) to normal levels (3.3 ng/mL). Stretched penile length increased from a median of 2 to 3.8 cm. During therapy, all testes descended to the scrotal position (by the end of the first month in three patients, the second month in four patients, and the third month in three patients), measuring 1.5 mL and appearing normal in ultrasonography. Three infants received additional treatment with testosterone enanthate. In two infants, one of two testes regressed in the low inguinal area; both infants were successfully treated surgically. After 1 to 10 years of follow-up, all testes are still in scrotal position and have slightly regressed in size.

Conclusions: The proposed regimen mimics neonatal male mini-puberty and successfully treats infants with micropenis and cryptorchidism in CHH.


Clinical management of congenital hypogonadotropic hypogonadism (CHH), a rare disorder caused by the deficient production, secretion, or action of GnRH,[1] remains a challenge in pediatric endocrinology.[2,3] A higher presence of congenital male tract anomalies (i.e., micropenis and monolateral or bilateral cryptorchidism) is found in isolated hypogonadotropic hypogonadism,[4] which is a rare, highly heterogeneous disorder characterized by abnormal pubertal development and/or infertility (the number of familial cases is probably underestimated[5]). Isolated hypogonadotropic hypogonadism refers to a wide spectrum of reproductive phenotypes, including GnRH deficiency with anosmia (Kallmann syndrome) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH),[6] with the prevalence of cryptorchidism being nearly three times greater in Kallmann syndrome than in nIHH despite comparable testicular volumes.[7] This phenotypic heterogeneity is accompanied by a considerable genetic heterogeneity, with more than 35 genes implicated but with the genetic basis being uncovered in about half the patients.[6,8,9] Micropenis has been traditionally successfully treated, usually with three monthly injections of testosterone enanthate, ideally in the postneonatal period or in early infancy.[10] However, when bilateral cryptorchidism coincides with micropenis, two surgical operations are usually required. Even after successful surgery, the hypoplastic testes with the deficient proliferation of immature Sertoli cells before and during puberty, due mainly to the lack of the male mini-puberty in the neonatal period as well as the subsequent midinfancy surge in pulsatile gonadotropin secretion, result in azoospermia and infertility in adulthood.[11] Mini-puberty consists of activation of the hypothalamic–pituitary–gonadal axis during the neonatal period, resulting in high gonadotropin and sex steroid levels and allowing penile and testicular growth and the proliferation of gonadic cells.[12] During this phase, serum T and gonadotropin levels rise rapidly and peak at the age of 3 months, approaching adult male levels, before the mid-childhood quiescence by about 6 months of age,[13] providing a 6-month window of opportunity of making early diagnoses in patients with suspected sexual reproductive disorders[12] who would demonstrate abnormally low FSH, LH, and testosterone levels.[13] Thus, precise and early diagnosis in CHH offers the advantage of a definitive prepubertal diagnosis,[13] enabling the prompt initiation of preplanned pubertal-induction at a median age of pubertal onset, preventing negative physical and psychological sequelae, preserving normal peak bone mass, and hopefully restoring fertility in affected patients.[3]

The aim of the REMAP (REplacement of MAle mini Puberty) study in neonates and infants with micropenis and/or cryptorchidism due to hypogonadotropic hypogonadism, ISRCTN13007297, was to investigate whether daily subcutaneous (SC) injections of the commercially available recombinant LH plus FSH preparation (Pergoveris®) for 3 months could mimic physiological male mini-puberty by resolving bilateral cryptorchidism, repairing micropenis and restoring the Leydig and Sertoli cell function.