Introduction: Since the phenotype and clinical need of the hypogonadal individuals changes dramatically over time, versatile therapies are needed.
Areas covered: The authors review the available evidence on possible therapies.
Expert opinion: In the case of primary hypogonadism starting early in life, substitution with testosterone (T) is the only choice. For secondary congenital hypogonadism, we recommend starting with gonadotrophins to allow the testes to reach pubertal size. Thereafter, T replacement therapy can be administered until fertility is desired. At that time, gonadotrophins should be employed until fathering occurs. Antiestrogens are an alternative, however, their efficacy has not been adequately tested. In the presence of increased estrogen production symptoms (breast tenderness and gynecomastia), a short-term trial with non-aromatizable androgens (dihydrotestosterone mesterolone or oxandrolone) could be advisable. However, after a few months of therapy, switching to other aromatizable preparations is recommended, to prevent bone loss. When prostate safety is concerned, the use of steroidal or non-steroidal selective androgen receptor modulators that are less susceptible to 5α reduction might be advisable. An attractive possibility is the combined use of testosterone with 5α inhibitors. Theoretically, also estrogen receptor-beta ligands could be employed, however the development of these compounds, although promising, is still in its infancy.