Growth hormone combined with testosterone helps normalize penile conditions in microphallic rats of hypogonadotropic hypogonadism

Abstract

Introduction: Hypogonadotropic hypogonadism has been known as the most common cause of micropenis. Until now, testosterone therapy is the only effective treatment option in the management of micropenis. The tropic effect of growth hormone (GH) on penis has not been studied. While the underlying molecular mechanism is unclear, the growth hormone / insulin-like growth factor-1 (IGF-1) axis possesses proactive effects for the action of testosterone and its potent derivative, dihydrotestosterone.

This animal study was aimed to evaluate the role of GH, alone or in conjunction with testosterone on phallic growth.

Methods: Seven timed-pregnant Sprague-Dawley rats were obtained one week before parturition. After parturition, pups remained with their mother until two weeks of age. Male pups were discriminated by females by longer anogenital length on the third postnatal day, although this was not always possible. Five study groups among male pups were assigned to control (C), microphallus (MP), testosterone (T), GH (G) and GH plus testosterone (GT). Microphallus was induced by secondary hypogonadism using leuprolide acetate injection. Pre-pubertal administration of testosterone, GH or combination of both was started from seven days after birth and maintained up to 12 weeks of age. Phallic dimensions and histological markers of cavernosal integrity were assessed as efficacy measure. To assess bone growth, adjusted penile lengths were calculated as the ratio of penile and right tibial lengths. Testicular weights were also compared for evaluating gonadal safety. Comparison of phallic dimensions and various cavernosal histological and molecular markers such as expressions of smooth muscle actin, collagen Ⅰ and Ⅲ, the number of fat globules, sinusoidal density and expression of androgen receptor (AR) were made.

Results: Compared to C, MP showed significantly lower mean plasma level of testosterone. Treatment with either testosterone or GH resulted in corresponding increase in plasma levels. Comparing control group (C), microphallus (MP) showed prominent decrease of penile length, penile weight, testis volume, expressions of smooth muscle actin. CollagenⅠand Ⅲ and the number of fat globules was shown significant increase in MP. No monotherapy successfully normalized all tested penile dimensions, though certain phallic dimensions were enhanced by treatment of T. Combination treatment (GT) led to complete normalization of all phallic dimensions. Also, this effectively prevented deterioration of cavernosal histological markers where microphallic rats showed significant changes. Ratios of penile length / right tibial length were similar to those of penile lengths, indicating minimal effects of the present treatments on bone growth.

GH administration led to enhanced AR expression in cavernosum and alleviation of testicular volume loss. GH administration with testosterone was effective measure to enhance penile growth by augmenting AR with minimizing gonadal volume loss. This proof of concept study could be helpful to circumvent the problem of using testosterone monotherapy in human micropenis. The different physiological background on phallic growth between human and rats may hinder the application of the result to clinical situations.

Conclusion: Our results showed that the combination therapy of testosterone with growth hormone might be further treatment option of micropenis related to hypogonadotropic hypogonadism. The size and structural problems of microphallus could be effectively and safely addressed by combination treatment of growth hormone (GH) and testosterone.