Primary Testicular Failure: An Overview

Primary testicular failure (PTF) or hypergonadotropic hypogonadism refers to conditions where testes fail to produce sperm despite adequate hormonal support. Primary testicular failure is major cause of non-obstructive azoospermia and oligospermia. It affects approximately 1% of all men and 10% of those seeking fertility evaluations [1]. Non-obstructive azoospermia i.e. defect in spermatogenesis can be primary (testicular pathology) or secondary (pathology outside testes; mostly hypothalamo-pituitary axis or pretesticular). The pre-testicular (hypogonadotropic hypogonadism) causes of azoospermia may be defined as extragonadal endocrine disorder originating in the pineal, hypothalamus, pituitary, or adrenals, which have an adverse effect on spermatogenesis through aberrant hormonal action. The testicular (hypergonadotropic hypogonadism/ primary testicular failure) causes of azoospermia are primary defects of the testes. Primary testicular failure is classified into four distinct subtypes viz., sertoli cell only syndrome (SCOS), germ cell/maturation arrest (GCA/MA), hypospermatogenesis (HS) and tubular fibrosis (TF) according to histopathology/cytology findings although accurate categorization is only possible by multiple testicular biopsies/fine needle aspiration cytology (FNAC). However, often one may find differences in subtypes between testes viz., SCOS in one side and tubular fibrosis in other side or any other combinations and these cases are usually labeled as mixed group. In addition many patients may present as complete germinal cell aplasia in some tubules whereas complete spermatogenesis in adjacent tubules (focal germinal cell aplasia) or some tubules with sertoli cells only/hyaline sclerosis and other tubules with complete spermatogenesis or any combinations. This categorization should be considered as a description of histopathologic phenotypes of spermatogenic failure, and not as manifestations of disease entities. Sometimes, patients may present as hypospermatogenesis/maturation arrest initially and later as sertoli cell only syndrome/testicular fibrosis over a period of few years hence diagnosis may change with time. Sertoli cell only syndrome or germ cell aplasia applies to a testis, in which germ cells at any stage are absent, but the tubular architecture is not affected by fibrosis, and supporting cells continue to be present. Sertoli cells play a central role in development of a functional testis, and hence in the expression of a male phenotype. Sertoli cell only syndrome is a common finding of non-obstructive azoospermia. It is a histopathologic phenotype of spermatogenic failure and described first by Castillo et al. [2], in complete germ cell aplasia, the tubules are reduced in diameter, contain only sertoli cells and no other cells involved in spermatogenesis are present. The primordial germ cells either do not migrate from the yolk sac into the future gonads or do not survive in the seminiferous tubules. Germ cell aplasia can also be focal with a variable percentage of tubules containing germ cells, but even in these tubules, spermatogenesis is often have limited activity [3] and hence, should be categorized as hypospermatogenesis. Maturation/Germ Cell arrest is the interruption of normal germ cell maturation at a specific cell stage including spermatogonia, spermatocyte or spermatid level. In hypospermatogenesis all the stages of spermatogenesis are present in some or all tubules, but they are reduced in number. Tubular fibrosis presents as thickening of peritubular membrane and hyaline deposition on basement membrane with absence of germ cells and sertoli cells.