Clinical Presentation and Assessment

Y-chromosome microdeletion testing begins with an AUA-recommended infertility work-up consisting of a detailed medical and reproductive history, physical examination, and two semen samples67 (Figure 5.7). It is important to rule out any reversible causes of infertility before undergoing further testing. Patients with YCMD will not present with an obvious etiology for infertility and often their histories will not provide anything substantial. Since most YCMD deletions occur spontaneously, patients will not report a family history of infertility. The only significant finding on physical examination could be small testis size; however, this finding is not unique to YCMD.68-69

Clinical algorithm for the assessment of male infertility patients

FIGURE 5.7 Clinical algorithm for the assessment of male infertility patients.

Semen analysis is a useful tool in understanding male infertility and is used as an indication for genetic testing. The AUA practice guideline for infertility recommends that genetic testing be ordered in nonobstructive azoospermic or oligozoospermic (sperm count less than 5 million/mL) men.67 Despite the clinical usefulness of the semen analysis, it is not a direct measure of fertility.70 Patients with semen values below World Health Organization recommended ranges can conceive without the help of assisted reproductive technologies. On the other hand, men with semen variables within the same reference values may be infertile. The only true independent predictor of fertility potential from a semen sample is azoospermia. Other means to determine more precise male reproductive potential such as adjunctive blood or nonspermatic semen analysis are being explored; however, findings from these tests are not significant enough to impact clinical management.71-74 Despite these predictive limitations, semen analysis is still regarded as one of the most useful clinical tools in the diagnosis of infertility.

A dysfunctional endocrine system is a well-recognized cause of infertility; however, it is not common and only recommended in men with abnormal semen analysis, impaired sexual function, or other clinical findings suggestive of endocrine disruption. The strongest indication for endocrine evaluation based on semen analysis is a semen concentration of less than 10 million/mL.13-67 Initial testing includes FSH and total testosterone with repeat total testosterone, free testosterone, prolactin, luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) indicated for low initial testosterone. Since men with YCMD fall into this category of low semen concentration, many will undergo an endocrine evaluation. Men with YCMD on endocrine evaluation may have elevated FSH with low to normal testosterone; however, this finding may not be true in all cases.58-68 The increase in FSH is the response to a lack of spermatogenesis in YCMDs. This endocrine profile is similar to primary testicular failure, however, with a reduced magnitude.

The next step is to determine whether the azoospermia is considered nonobstructive (NOA) or obstructive azoospermia (OA). OA occurs in about 15%-20% of men with azoospermia and can occur anywhere along the course from the testicle to the ejaculatory ducts. OA is usually detected with a good history and physical examination. Men with OA have a history of genital surgery, infection, or congenital abnormalities. On physical examination they demonstrate normal testicular volume and indurated epididymis, whereas NOA exhibits small, soft testes with a flat, soft epididymis.69 Another difference between OA and NOA is the hormonal profile. OA will have normal FSH levels, whereas NOA will have elevated FSH.

Once a diagnosis of NOA is established, genetic causes for infertility can be considered. Genetic screening for infertility consists of screenings for cystic fibrosis gene mutation, karyotype analysis, and YCMD testing, which are ordered at the same time. Even with the help of these genetic tests, the causes of infertility may still be unknown. Currently, all known genetic disorders of infertility only account for 30% of cases.4 This means that 70% of genetic causes of infertility are still unknown. This high percentage results from the complexity of spermatogenesis. Thousands of genes must coordinate to produce mature sperm and the failure of just one of these genes can disrupt the entire process. Given the sheer number of genes involved and our limited knowledge of the genome, it is possible that a large majority of male infertility is from unknown causes. Although these three tests account for some of the genetics of infertility, they are by no means exhaustive.

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