Male infertility

Contributors of Campbell-Walsh-Wein, 12th edition

Craig S. Niederberger, Samuel J. Ohlander, Rodrigo L. Pagani, and Marc Goldstein

Epidemiology

Infertility affects nearly one in six couples worldwide. Maternal age is the most important predictive factor of a couple’s fertility . Systematic reporting of in vitro fertilization (IVF) outcomes has led to a better understanding of female factor infertility, but this is not the case for male factor infertility, which is estimated to contribute to 50% of all cases of infertility . Furthermore, up to 27% of men in infertile couples are not being evaluated. While the need to workup male factor infertility is sometimes obviated by the existence of IVF, it is important to recognize that the goal of the male workup is for more than procreation. The goals of work up include

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Diagnose and treat reversible causes of infertility.
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Diagnose irreversible causes of infertility amenable to assisted reproductive technology (ART).
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Identify comorbidities that contribute to infertility or harm patient.
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Identify genetic mutations, when appropriate, that may harm patient or offspring.

The failure to conceive after 12 months of properly timed, unprotected intercourse remains the standard definition for infertility. Of couples that become pregnant by natural means, nearly 88% achieve pregnancy by 6 months. Thus, initiating workup sooner than 12 months is sometimes reasonable, especially in higher risk couples (i.e., advanced maternal age, family history of infertility). While the workup often begins with the woman, early simultaneous evaluation of the male partner could expedite the processes, potentially offer different treatment modalities, and identify undiagnosed comorbid conditions in the man.

Pathophysiology

Male reproductive physiology requires the coordinated release of hormones from the hypothalamic-pituitary-gonadal (HPG) axis, normal testis histology, a nonobstructed excurrent ductal system, an intact somatic and autonomic nervous system, and functioning external genitalia. Disorders in one or more of these domains can result in pathology ranging from decreased semen quality to the inability producing sperm.

The HPG axis at the simplest level requires gonadotropin-releasing hormone (GnRH) from the hypothalamus to act on the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH acts on the Sertoli cells to stimulate spermatogenesis, and LH acts on Leydig cells to produce testosterone, which is also required for normal spermatogenesis. This axis can be interrupted at any level. Prolactinomas can inhibit GnRH release via negative feedback while other pituitary lesions, like craniopharyngiomas, can disrupt the production of LH and FSH. Likewise, disturbances of androgen synthesis in the testicle can completely disrupt sperm production.

Intratesticular testosterone is necessary for sperm production and serum levels of <300 ng/dL are found in up to 45% of azoospermic men. Testosterone levels are highly susceptible to a number of host conditions, including medications or exposure to toxic metabolites, inflammatory or infectious conditions, childhood disease, and even overall health status. Estrogen levels are also important, as testosterone is aromatized to estrogen in adipose cells and can lead to decreased serum testosterone through negative feedback at the hypothalamic and pituitary levels. Furthermore, the balance of testosterone to estrogen (optimally >10:1) has also been shown to affect male fertility.

Similar to the HPG axis, the testicular microenvironment is tightly regulated, and even small perturbations can cause disruption of spermatogenesis. Spermatagonial stem cells (SSCs) undergo meiosis to ultimately become spermatids through the process of spermatogenesis. This process is exquisitely susceptible to the effects of toxins (environmental, chemotherapy), temperature (varicoceles, cryptorchidism), and radiation. This may result in changes ranging from decreased sperm count to the complete depletion of SSCs.

Spermatids undergo spermiogenesis to become mature spermatozoa, which are ushered into the epididymis. In the epididymis, the spermatozoa gain motility and are stored for reproduction. The autonomic and somatic nervous systems allow for sperm transport from the epididymis to the tip of the urethra during ejaculation, and injuries to either the nerves or pelvic floor musculature (from retroperitoneal lymph node dissection, low-anterior resection, abdominal perineal resection, and so on) can disrupt this process. Furthermore, at the corpus of the epididymis, the numerous efferent ductules condense into a single epididymal tubular structure, and interruptions to this tubular structure at any point can significantly affect semen parameters. Unilateral or bilateral blockages can occur in the epididymis and the vas deferens, and disruptions can occur in the ejaculatory duct and urethra.

Finally, genetic mutations, ranging from syndromes to isolated issues with sperm production, affect male fertility. The most common genetic cause of impaired fertility is Klinefelter syndrome (1:500 to 1:1000 male live births), resulting in hypergonadotropic hypogonadism and typically azoospermia. Complete microdeletions on the long arm of the Y chromosome in AZFa and AZFb result in azoospermia, while men with deletions in AZFc regions can still harbor sperm on microscopic testicular sperm extraction (mTESE). Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene can affect fertility due to segmental hypoplasia/aplasia of the excurrent ductal system. Heterozygous mutations in this gene are relatively common with an incidence of ∼1 in 25 non-Hispanic, white men.

Clinical manifestations

Men presenting for infertility vary widely in phenotype, making diagnosis based solely on history and physical impossible. The cornerstone for determining the etiology is evaluating for laboratory abnormalities in either semen parameters or hormonal workup. Table 13.1 shows normal semen parameters based on the World Health Organization references ranges, and Table 13.2 shows normal laboratory parameters (normal ranges of gonadotropins, estrogen, and prolactin may vary by laboratory).

Table 13.1

World Health Organization V Semen Parameter Reference Ranges

PARAMETER	5TH PERCENTILE OF FERTILE MEN	50TH PERCENTILE OF FERTILE MEN	95TH PERCENTILE OF FERTILE MEN
Volume (mL)	1.5	3.7	6.8
Concentration (M/mL)	15	73	213
Motility (%)	40	61	78
Morphology (%)	4	9	44

Table 13.2

Suggested Laboratory Values ^a

PARAMETER	SUGGESTED VALUES
FSH	<7.6 mIU/mL
LH	<9 MIU/mL
Estradiol	<57 pg/mL
Testosterone	>300 ng/dL
T:E ratio	>10:1
Prolactin	<13

E , Estradiol; LH , luteinizing hormone.

a Although reference ranges vary by lab, these reference values for follicle-stimulating hormone (FSH) and testosterone (T) are the commonly accepted levels and are important clinical indicators.

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