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Infertility is defined as the failure to conceive despite 1 year of regular unprotected intercourse. Approximately 15% of couples will experience infertility, and of these, 20% will have a male factor that is solely responsible; male factors will contribute in an additional 30% of cases. In general, male infertility is identified by abnormalities on a semen analysis; however, other issues can contribute to infertility despite normal semen.

The causes of male infertility are widely varied and are best evaluated by a urologist. Some causes of male infertility can be identified and reversed (or improved) with specific surgery or medication while other causes can be identified but not reversed. Occasionally, the underlying cause of infertility or an abnormal semen analysis cannot be identified, in which case it is termed idiopathic. These cases may be amenable to empiric treatment to improve the chances of conception. Before discussing the diagnosis and treatment of male infertility, a review of basic reproductive endocrinology, physiology, and anatomy is in order.

The Hypothalamic–Pituitary–Gonadal Axis

The hypothalamic–pituitary–gonadal (HPG) axis plays a critical role in both the endocrine (testosterone production) and exocrine (sperm maturation) functions of the testes. Several endocrine concepts must be reviewed.

Hormone Classification (Figure 44–1)

Figure 44–1.

Two kinds of hormone classes mediate intercellular communication in the reproductive hormone axis: peptide and steroid.

Both peptide and steroid hormones are required for communication in the reproductive axis. Peptide hormones are small secretory proteins that bind receptors on the cell surface membrane and induce a series of intracellular events. Hormone signals are transduced by second-messenger pathways whose actions culminate in the phosphorylation of various proteins that alter cell function. The key peptide hormones of the HPG axis are luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Steroid hormones are derived from cholesterol and, unlike peptide hormones, are not stored in secretory granules. As a result, steroid secretion is limited by the rate of production. Since they are lipophilic, steroid hormones are generally cell membrane permeable. In plasma, steroid hormones are largely bound to serum proteins, with only a small “free” component available to diffuse into the intracellular space and bind receptors. Once bound to an intracellular receptor, steroids are translocated to deoxyribonucleic acid (DNA) recognition sites within the nucleus where they act by regulating the transcription of target genes. The key steroid hormones of the HPG axis are testosterone (T) and estradiol (E2).

Feedback Loops

Normal endocrine and exocrine function of the testes depends on the orchestrated action of numerous hormones. Positive and negative feedback is the principal mechanism through which hormonal regulation occurs. By this mechanism, a hormone can regulate the synthesis and action of itself or of another hormone. Further coordination is provided by hormone action at multiple sites and ...

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