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Infertility affects 1 in 6 couples, and a male factor is partially or entirely responsible in at least 50% of cases.1,2 Historically, the issue of male infertility has not been as openly or prominently acknowledged in public discourse as female infertility, a disparity that may contribute to delays in workup and diagnosis of the male partner relative to the female. Meanwhile, male infertility may be growing more prevalent; there is evidence that sperm counts in many parts of the world are declining.3 It is important for clinicians to understand the different forms of male infertility and how to facilitate appropriate and timely workup for their patients.

Thousands of genes are involved in spermatogenesis, and mutations in one or more of them can result in male infertility. The etiologies of male infertility fall into four categories: disorders of the hypothalamic-pituitary axis (HPA), quantitative defects of spermatogenesis, qualitative defects of spermatogenesis, and ductal obstruction or dysfunction. These categories are associated with different genetic derangements, and workup and counseling should be tailored accordingly. In this chapter, we will review the most common forms of male infertility and the genetic tests used to diagnose them. See Fig. 5-1 for an algorithmic overview.


Brief algorithm for genetic workup in the infertile male. Semen analysis and physical examination are the cornerstones to further workup. When the vas deferens is absent (CBAVD), the semen volume will be low as well. CFTR, Cystic fibrosis transmembrane conductance regulator; FSH, follicle-stimulating hormone; IHH, idiopathic hypogonadotropic hypogonadism; YCMD, Y chromosome microdeletion assay.


The HPA is responsible for the hormonal regulation of male fertility. The details of this are covered in Chapter 9. Briefly, the hypothalamus releases gonadotropin-releasing hormone (GnRH), which acts upon the anterior pituitary gland; the anterior pituitary gland in turn produces follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate testicular function. The testes contain germ cells, which develop into sperm; Sertoli cells, which support spermatogenesis; and Leydig cells, which produce testosterone.

Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism can be congenital or acquired. The former involves a deficit in GnRH production and causes infertility due to inadequate stimulation of the testes. Classic features include delayed puberty, low testicular volume, gynecomastia, a eunuchoid body habitus, sparse or absent body hair, and reduced spermatogenesis. The severity of symptoms can vary, however, and patients with mild symptoms may not be diagnosed until they present for fertility evaluation.

The genetics of congenital hypogonadotropic hypogonadism are complex. Many different genes have been implicated in its development, and yet for 60% of cases, the cause remains unknown. In addition, the inheritance pattern for congenital hypogonadotropic hypogonadism does not always abide by Mendelian laws: in many cases, inheritance is digenic or oligogenic rather ...

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