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Infertility (defined as a failure to conceive after 1 year of unprotected intercourse) affects about 15% of couples attempting a pregnancy, and most experts agree that male infertility (alone or in combination with female infertility) accounts for about half of these cases. The causes of male infertility range from congenital absence of the vas deferens or incomplete spermatogenesis to subtle pathologies of sperm shape and function. In contrast, female infertility is usually caused by tubal blockage, uterine or endometrial abnormalities, or abnormal levels of reproductive hormones. Female infertility is relatively easily diagnosed by hormone assays, menstrual cycle analysis, and radiologic studies. The male partner in an infertile couple is often overlooked or incompletely evaluated, even though male factors may be a major contributing factor. Endocrine abnormalities (eg, isolated androgen deficiency) are exceedingly rare (about 1%) among males of infertile couples. Since subtle sperm dysfunctions not obvious by microscopic semen analysis may preclude fertilization, a normal semen analysis (SA) is not necessarily predictive of fertility. In fact, a complete lack of sperm in semen (azoospermia) is the only highly predictive finding for infertility by SA.
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Infertility (defined as a failure to conceive after 1 year of unprotected intercourse) affects about 15% of couples attempting a pregnancy, and most experts agree that male infertility (alone or in combination with female infertility) accounts for about half of these cases.
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Absence of spermatozoa in the semen may be caused by either failure of the testes to produce sperm (ie, male sterility) or a blockage of the excurrent ducts of the male genital tract. The former is nonobstructive azoospermia (NOA), and the latter, obstructive azoospermia (OA). When azoospermia is discovered by SA, a medical history and physical examination by a qualified physician is recommended. Testicular biopsy may also be performed to differentiate NOA from OA. OA may be congenital or acquired. Vasectomy is usually an elective minor surgery leading to azoospermia for contraception, but the vas or epididymis also may become unknowingly blocked after a sexually transmitted infection. Azoospermia may persist after vasectomy reversal. Congenital bilateral absence of the vas deferens (CBAVD) is found in men carrying one of the many cystic fibrosis alleles, as well as in men with clinically apparent cystic fibrosis. In all these cases of OA, spermatozoa are almost always able to be retrieved from the testis by a urologic surgeon. Testicular sperm are not capable of fertilization except by intracytoplasmic sperm injection, in which individual sperm are microinjected into an oocyte in an in vitro fertilization (IVF) laboratory. In the case of a cystic fibrosis carrier, the partner should be checked to determine if she is also a carrier for cystic fibrosis so that the couple understands their risk to conceive a child.
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Absence of the vasa deferentia may be determined by palpation on physical exam, and may be suggested by absence of fructose in the semen. Fructose is made exclusively in the seminal vesicles, and these glands contribute about 60% of the semen volume. Since they are embryonic outgrowths of the vasa deferentia, they are usually absent in men with CBAVD.
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Two reasons for NOA are absence of germ cells in the testis (Sertoli-only syndrome) and failure of spermatogenesis (only mitotic cells or no late stages of sperm production). These conditions may be genetic, due to failure of primordial germ cells to migrate to the testis, or acquired through exposure to toxicants. In addition, microdeletions in the Y chromosome in specific regions are associated with NOA or severe oligozoospermia. Testosterone or androgen therapy (see above) for low testosterone or bodybuilding will often result in azoospermia or oligozoospermia due to inhibition of the hypothalamic–pituitary axis, decreased LH, and subsequent lowering of the high intratesticular:plasma ratio of testosterone required for sperm production. Men with testicular and other cancers may exhibit NOA or oligozoospermia. Conversely, men with NOA or oligozoospermia are at increased risk for later development of testicular cancer.
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Spermatozoa may not be entirely missing in NOA. A few stem cells throughout the testis may be present, although a random biopsy may not detect any. In such cases, exceedingly low numbers of sperm may be present in the semen, possibly on a cyclical basis. Cryptozoospermia is the presence of very rare sperm in the semen. Often, high levels of FSH are associated with NOA, due to dysfunctional Sertoli cells and lack of the Sertoli hormone inhibin. However, high FSH has not proven to be a good indicator of the absolute absence of spermatogenesis. The surgical technique known as microsurgical testicular sperm extraction has proven to be useful in these cases. Under the surgical microscope, a few seminiferous tubules might be located that have complete spermatogenesis. Highly trained staff in the andrology or embryology laboratory are needed to identify and recover sperm from the testis in these cases.
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In other cases of male infertility, sperm will be present in the semen. The human, unlike almost any other species, produces spermatozoa with numerous defects. “Normal” values for human SA are both surprisingly poorly established and highly variable from 1 ejaculate to another, and between different men. Although a typical ejaculate contains 200 to 300 million sperm, fertilization only takes 1, and at the time of fertilization there are only about a dozen sperm associated with the egg. If only 1% of sperm are functionally and structurally normal, then the typical ejaculate will contain about 2 to 3 million of these “good sperm.” Apparently this is enough to help propagate the human population. SA helps identify men who have a few “good sperm,” and diagnose specific sperm problems that may permit therapy or advanced reproductive techniques, or help guide decisions by the couple.
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Diagnosis and Laboratory Test Interpretation
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SA is the cornerstone of male infertility diagnosis, and should be performed early in the evaluation of the infertile couple. Collection of a semen sample should take place after 2 to 5 days of sexual abstinence. Longer abstinence is associated with lower motility and higher leukocyte counts, and shorter periods usually lead to lower volumes and sperm counts. A sterile plastic container, known not to be toxic to sperm, is required. Usually a sterile urine collection cup is satisfactory. If the sample is not collected in a special collection room near the lab, it should be transported in a tightly sealed collection cup in a sealed plastic bag, protected from light, heat, and cold. A temperature between room temperature and body temperature is adequate. Seminal fluid characteristics are measured after allowing semen to liquefy (due to the enzymatic action of PSA) for 15 to 30 minutes at 37°C or at room temperature. Analysis should be completed within 60 minutes after ejaculation. In vivo, sperm typically swim out of semen into the cervical mucus within a half hour. Semen may contain hepatitis, HIV, and other pathogens. Basic precautions for handling potentially infectious body fluids must be followed.
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Semen analysis (SA) is the cornerstone of male infertility diagnosis, and should be performed early in the evaluation of the infertile couple. If SA is abnormal, it should be repeated after at least 1 month. SA parameters can vary substantially within an individual. Therefore, a single abnormal specimen should not be used to establish a diagnosis.
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The main tests in SA are ejaculate volume, sperm count, sperm motility, sperm morphology, and leukocyte count. Aside from azoospermia, findings that may contribute to a couple's infertility include low sperm concentration or total number of sperm (oligozoospermia), poor sperm motility (asthenozoospermia), very poor sperm morphology (teratozoospermia), or any combination of the 3. Additionally, a high number of neutrophils or macrophages in the semen (leukocytospermia) may affect sperm function by inducing oxidative stress through the generation of reactive oxygen species. Leukocytes are likely present in all semen samples. There is lack of consensus on the number that is considered abnormal, with authorities suggesting various cutoffs from 200,000 to 1 million per mL of semen.
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A semen fructose analysis may be considered if there is unexpected azoospermia. Sperm viability is important to determine when motility is very low. Sperm agglutination and the presence of antisperm antibodies may indicate an immunologic basis for infertility. These highly specialized tests typically are performed in laboratories certified specifically for SA.
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Interpretation of sperm morphology is controversial, largely because of a lack of supporting data relating sperm morphology to fertility. Very few human sperm are “perfect”; in fact, if at least 4% of sperm have normal morphology, then the specimen morphology is generally considered to be normal. The clinical significance of sperm morphology is best understood when most of the sperm have specific defects. The absence of acrosomes (the specialized structure at the tip of the sperm head) is associated with inability to fertilize eggs, and, sometimes, inability to activate oocytes to complete meiosis. Abnormal midpieces or tails may be associated with poor motility.
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If SA is abnormal, it should be repeated after at least 1 month. SA parameters can vary substantially within an individual. Therefore, a single abnormal specimen should not be used to establish a diagnosis.