This chapter should be cited as follows:
Perheentupa A, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.421093
The Continuous Textbook of Women’s Medicine Series – Gynecology Module
Volume 15
Reproductive medicine for the obstetrician and gynecologist
Volume Editors:
Professor Luca Gianaroli, S.I.S.Me.R. Reproductive Medicine Institute, Italy; Director of Global Educational Programs, IFFS
Professor Edgar Mocanu, RCSI Associate Professor in Reproductive Medicine and Surgery, Rotunda Hospital, Ireland; President, IFFS
Professor Linda Giudice, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, USA; Immediate Past President, IFFS
Published in association with the
International Federation of
Fertility Societies
Chapter
Fertility Investigation of the Male
First published: November 2024
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INTRODUCTION
It is estimated that in couples suffering from infertility, male factors are attributable of half the cases.1 Appropriate diagnostic workup of the male partner should be considered to be just as important as evaluating the female factors. Optimizing the male fertility prior to subjecting the female to the invasive treatments should always be attempted. These efforts not only improve the results of the fertility treatments, but also in the best case scenario may obliviate treating the woman altogether. It is important to also understand that the search for the etiology may reveal causes that may have long-lasting effects on the man’s general long-term well-being.2,3,4 Significant hypogonadism and Klinefelter syndrome are excellent examples of conditions that should be identified, and the infertility treated. Furthermore, all the involved health risks should be discussed, and a future follow-up protocol agreed with the patient to ensure appropriate prevention methods and timely treatment.
SEMEN ANALYSIS
Basic semen analysis is traditionally the primary and most widely used method to evaluate male fertility. The semen analysis consists of measuring semen volume, total number and concentration of sperm as well as their motility and morphology, the values that are considered normal can be seen in Table 1. The WHO 2021 laboratory semen manual5 outlines the methods for examination of human semen. It is important to understand that semen analysis has clear limitations and the results reflect male reproductive potential only to a certain degree.6 Over interpretation of the findings should be avoided. In case of abnormal findings, semen analysis should always be repeated. Careful evaluation of the etiology of male infertility should always be carried out when semen analysis is repeatedly abnormal (Table 2).7
1
WHO 2021 semen manual normal values.5
Parameter | Normal value |
Semen volume | ≥1.4 ml |
Sperm concentration | ≥16 million/ml |
Total sperm number | ≥39 million |
Progressive motility (%) | ≥30% |
Normal forms (%) | ≥4% |
2
Terminology in describing the result of semen analysis.7
Normospermia | Normal semen |
Hypospermia | Lower than normal semen volume |
Aspermia | No ejaculate |
Oligozoospermia | Decreased concentration of sperm in the ejaculate |
Asthenoszoospermia | Decreased % of motile sperm |
Teratozoospermia | Decreased % of sperm with normal morphology |
Azoospermia | No sperm in the ejaculate |
Leukospermia | Increased leucocytes in semen (typically >1 mill/ml) |
Necrozoospermia | No viable sperm in the ejaculate |
Medical history together with careful physical examination form the basis of a detailed evaluation of male fertility. Medical history may be most logical following a chronological order of events, starting with whether the testicular descent took place normally. Timely pubertal development is of importance. All earlier significant diseases and procedures need to be considered, paying particular interest to events concerning the testis and the inguinal region: testis torsion, orchitis, epididymitis, sexually transmitted diseases and any inguinal surgery.8,9 Lifestyle plays a very significant role in modifiable factors. Deleterious habits need to be identified and appropriately adjusted to improve fertility and optimize natural fertility as well as results of fertility treatments. Sedentary lifestyle is associated with male subfertility compared to a physically active lifestyle.10 Moderate physical exercise may be able to improve male fertility.11 Decreased fertility due to overtraining is a very rare problem even in competitive athlete men. Smoking and other tobacco products affect male fertility significantly and clearly increase the risk of spontaneous miscarriage.12,13 These effects are not always reflected in semen analysis or measured hormone levels. The use of alcohol should be minimized when pregnancy is desired, particularly when it is not achieved without delay. The use of recreational drugs affects hormonal regulation of testicular function and should clearly be avoided.14 The role of a healthy diet is important, not only in weight control, but also from the perspective of reproductive health. The so-called Mediterranean diet appears to be perhaps closest to what could be considered a fertility diet.15,16,17 In addition to the lifestyle choices, work-related exposures may be of importance, particularly to chemicals and air pollution,18,19 but perhaps also exposure to constant heat.
Current and past medical conditions and their treatments and medications are clearly relevant.20 It is worth mentioning that the detailed effects of many medications on male fertility and sperm quality are not completely known.
The deleterious effect of α-blockers, opioids, ketoconazole, Ca-channel blockers and selective serotonin reuptake inhibitors (SSRI) medications are well recognized.21 As some patients do not consider hormonal products as medications, the use of testosterone and anti-hair loss medication (5α-reductase inhibitors) should be inquired separately.22,23 Men using anabolic steroids are usually aware of the fertility suppressive effect; however, it is quite common to mislead or underestimate the use of these prohibited substances. All symptoms should be evaluated, particularly those associated with hypogonadism, the loss of libido as well as presence of erectile dysfunction are considered most important.
All proof of previous fertility is important, initiated pregnancies earlier, either with the current partner, but equally importantly with previous partner(s). It may be logical to begin the medical history by asking about the length time of the active wish for a pregnancy, i.e., duration of unprotected intercourse, also considering periods of separation.
Family medical history may reveal important details, is there anything to suspect decreased fertility or recurrent pregnancy loss in parents or siblings?
General physical examination should aim to identify normal signs (or the lack of) androgenic effects. Male pubertal development is not possible without sufficient androgen production;24 however, insults to the hypothalamic-pituitary-testicular axis after puberty will not be quite as easy to recognize. Overly muscular appearance particularly when associated with skin striae and acne should raise the suspicion of androgen misuse. Lack of beard growth and straight frontal hairline may reflect low androgen effect. High BMI and obesity should bring the question about dietary inadequacy and insufficient physical exercise. Loss of smell is typical of Kallman’s syndrome (hypogonadotropic hypogonadism).25 Gynecomastia may be a consequence of androgen use, but also is caused abnormal estradiol and/or hCG production, which needs to be appropriately ruled out as it may a sign of testicular tumor.26 All surgical scars should be noted, and the possible importance of the earlier surgery be considered.
ANDROLOGICAL EXAMINATION
The examination is best performed with the patient in the standing position, exposure to cold should be avoided so that the normal testes remain in the scrotum. The most important part of the examination is the testis. Normal size for an adult testis is between 12 and 30 ml. As evaluation of the testicular size carries a significant margin of error, the use of an orchidometer is advised, ultrasound measurement gives the most reliable results.27 In addition, abnormalities of scrotal content can be visualized. The size of the testes reflects the amount of spermatogenic cells within the seminiferous tubuli, it has little to do with the efficiency to produce and secrete testosterone. In cases of azoospermia, the size of the testis is typically associated with the presence of spermatogenesis. A normal size testis is likely to host spermatogenesis and obstructive azoospermia is the likely diagnosis if no sperm are seen in semen. In contrast, a small testis is typically a sign of absent or very poor spermatogenesis, i.e., non-obstructive azoospermia (NOA) (Table 3). NOA is often also reflected by abnormally soft testis.28
3
Evaluation of azoospermia based on the observed testicular volume, serum testosterone and FSH measurements. The probable diagnosis is suggested.
Testis volume | S-testosterone | FSH | Likely diagnosis | Suggested treatment |
Normal ≥15 ml | norm (>12 nmol/l) | norm <10 IU/L | OA | TESA |
norm | elevated | arrest | TESA/MD-TESE | |
Small ≤10 ml | norm/low | elevated | NOA/arrest | MD-TESE if possible |
low | low (<3 IU/L) | hypohypo | hCG + FSH | |
Very small ≤5 ml | norm/low | high (>15 IU/L) | NOA | MD-TESE if possible |
low | low (<3 IU/L) | hypohypo | hCG + FSH |
Algorithm to assist in diagnosis and treatment of azoospermia
OA, obstructive azoospermia; NOA, non-obstructive azoospermia; arrest, spermatogenic arrest; hypohypo, hypogonadotropic hypogonadism; TESA, testicular sperm aspiration; MD-TESE, microscopic testicular sperm extraction; hCG, human chorionic gonadotropin.
The testes are normally located low in the scrotum and not near the inguinal canal. High location may cause the testicular temperature to be elevated compromising spermatogenesis.29,30 Inguinal scars should also be noted marking inguinal surgery or orchidopexy. In severe cases, when the testes are unpalpable, the localization may be verified using MRI.
Ductus deferens should be present and palpable on both sides. An important anatomical structure to identify in azoospermic patients is the vas deferens. This may be absent in cystic fibrosis causing an obstructive azoospermia despite normal spermatogenesis within the testis.31
The epididymis is located on the posterior side of the testis. Distension of the epididymis may indicate an obstruction, tenderness may be a sign of epididymitis.
Varicocele is an abnormal enlargement of the pampiniform venous plexus, which is far more commonly present on the left side. Varicocele is associated with decreased semen quality, the more severe the varicocele, the more pronounced the semen abnormality.32 Evaluation of the varicocele in men with fertility issues is primarily clinical. When varicocele can be palpated only during Valsalva maneuver, it is considered grade 1. When the varicocele can be palpated without Valsalva, it is considered grade 2. When varicocele is visible without palpation, it is considered to be grade 3. Benefits in the form of improved semen quality may not be expected when findings that are only apparent during Valsalva or ultrasonography are treated.33
HORMONAL EVALUATION
Spermatogenesis is under the regulation on the pituitary gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). The synthesis and secretion of the gonadotropins from the anterior pituitary is stimulated by gonadotropin-releasing hormone (GnRH), which is secreted into the portal of the pituitary from the hypothalamus. FSH binds to the Sertoli cells, which support the complex process of spermatogenesis within the seminiferous tubuli of the testis. LH, in turn, binds to the LH-receptor in the Leydig cells within the testis stimulating the secretion of testosterone. Androgen-binding protein ensures that a high concentration of testosterone is maintained in the testis. This, in concert with the function of the Sertoli cells, is considered important for qualitatively and quantitively normal spermatogenesis (Figure 1). Physiological levels of testosterone reflect sufficient production by the Leydig cells in the testis (Figure 2).
Permission is awaited to use this illustration
1
Spermatogenesis. The process through which mature sperm with a haploid number of chromosomes are produced in the testis from diploid primordial germ cells through mitotic and meiotic divisions. (Source: Encyclopaedia Britannica, 2013)
Permission is awaited to use this illustration
2
Hormonal regulation of the testicular function.34
Insufficient function of spermatogenesis may be caused by lack of required gonadotropin stimulation, which is typically associated with low serum testosterone concentration. In a classical Kallmann syndrome the gonadotropins and testosterone levels are very low. Induction of puberty is required to bring about the secondary male characteristics. Hypogonadotropic hypogonadism is important to identify as sufficiently long hormonal therapy most often will lead to spermatogenesis and sperm in the semen.25 When evaluating low gonadotropin levels suggestive of hypogonadotropic hypogonadism in men with no signs of hypogonadism, it is important to keep in mind the possible use of testosterone or even anabolic steroids, particularly the latter is often easy to suspected based on the man’s physical appearance.
Normal FSH levels together with normal testosterone levels and normal testicular volume suggest normal spermatogenesis. In azoospermic men, this most likely reflects an obstruction or even lack of ductus deferens. However, late stage spermatogenic arrest may also be found in some of these men.35
In men complaining of lack of libido, erectile dysfunction, gynecomastia in association with decreased testosterone concentration should be measured to rule out prolactin-secreting pituitary tumor. Multiple drugs, most notably psychiatric drugs, have a well-known effect increasing prolactin levels. Prolactin is a stress hormone and the levels are often increased even in the absence of an identified abnormality.
Inhibin B and anti-Mullerian hormone (AMH) are secreted by the Sertoli cells; however, the concentrations of these hormones are not able to predict the likelihood of sperm recovery in men with NOA.
GENETICS INVESTIGATIONS
Chromosome analysis should be carried out whenever severely compromised spermatogenesis is suspected, this should be performed when the sperm concentration is below 3 million/ml.36 Chromosomal abnormalities may reveal sex chromosome aneuploidies, most often 47, XXY, i.e., Klinefelter syndrome. Different structural aberrations may also be observed (e.g., translocations, inversions, insertions). A large proportion of the genes that regulate spermatogenesis are located in the Y chromosome. Y chromosome microdeletions may result in poor sperm concentration, although more commonly in complete lack of spermatozoa in semen, azoospermia. The most common Y microdeletions are named a, b and c (AZFa, AZFb and AZFc, respectively), depending on the extent of the observed deletion. AZFc, which is the most common one, does not always result in complete lack of sperm, but in severe oligozoospermia.37 Even in azoospermia, AZFc carries a fairly favorable chance of finding sperm with the method of microscopic testicular sperm extraction (MD-TESE).36 In contrast, AZFa and AZFb are considered to have a very poor prognosis for retrieving sperm and are always associated with azoospermia. In addition, other genetic analysis may be appropriate depending on the individual’s genetic background, i.e., CFTR for cystic fibrosis.
GENETIC COUNSELING
Whenever genetic abnormalities are diagnosed during the male infertility workup, it is important to refer not only the man, but rather the couple for genetic counseling.38 The genetic findings have significance in choosing the appropriate treatment as well as in evaluating the likelihood of success with the treatment. Whereas sperm retrieved from the testis of men with Klinefelter syndrome are not considered to carry significant risks for the offspring, it is clear that male offspring born to a father with AZFc will have the same genetic abnormality in their DNA.39 As the genetic background of each individual has an impact on the kind of analysis required for infertility workup, collaboration with the geneticists in choosing the most appropriate tests is essential.
IMAGING
Scrotal ultrasound enables a reliable measurement of the testicular volume. It is indicated with clearly decreased sperm counts and should always be performed to rule out testicular malignancy in these men. Testicular malignancy is one of the most common cancers in young adult men.40 Poor semen quality as well as history of cryptorchidism are well recognized risk factors for testis cancer and highlight the importance of ultrasound imaging of the testicular tissue in these men.41,42 Microlithiasis is a fairly common finding among men with poor semen quality.43
Abnormalities in pituitary function may require imaging with MRI to rule out pathologies, i.e., prolactinomas.
SPERM DNA FRAGMENTATION
The basic semen analysis gives no indication of the presence of abnormally high DNA fragmentation in the sperm.44,45 Although still a contentious topic, it is clear that men with elevated sperm DNA fragmentation (SDF) have a lower chance of establishing a spontaneous pregnancy and the risk of miscarriage is increased. Evaluating SDF may have a role in men having to resort to assisted reproductive technology (ART).
There are different methods of evaluating SDF. However, no consensus exists as to which of these should be preferably applied. It is logical that the obvious reasons causing SDF should be removed/minimized, including cessation of smoking, adjusting medications, performing varicocelectomy if clinically clear. Shortening the ejaculatory abstinence has also been observed to decrease SDF.46,47
TESTICULAR BIOPSY
Testicular sperm aspiration (TESA) or testicular sperm extraction (TESE) may be used to retrieve sperm directly from the testis in cases of obstructive azoospermia (OA). In OA, the male reproductive hormone levels (testosterone, FSH and LH) are all normal and the testis are normal in size as well as consistency. In borderline cases, the distinction between OA and non-obstructive azoospermia (NOA) may be challenging and can only reliably be determined by predisposing the testis to sperm retrieval. In OA cases, mature sperm is easy to retrieve and can be subsequently utilized for fertilizing the oocyte with intracytoplasmic sperm injection (ICSI).48 However, occasionally normal size testes will unfortunately reveal spermatogenic arrest with little or no mature spermatozoa. Some of the borderline cases may turn out to be Sertoli cell only in diagnosis with no germ cells of any stage. Distinction between these differences on a fresh unstained biopsy sample requires experience from the biologist/embryologist evaluating them. However, with the appropriate staining the pathologist will be able to provide a reliable histopathological diagnosis. This can be useful when counseling the patient whether to undergo a microdissection testicular sperm extraction (MD-TESE) for possible sperm retrieval. In essence testicular biopsies are primarily performed for therapeutic purposes rather than for diagnostics; however, important information from the histopathology should be used for evaluating future treatment options and their likelihood of success.
There is an on-going discussion about the possible benefit of using testicular sperm in cases with elevated sperm DNA fragmentation for ICSI in order to improve embryo quality and the chance of a pregnancy.49
PRACTICE RECOMMENDATIONS
- Infertility is very commonly caused by male factors. The male partner should be an integral part of the infertility assessment as well as the treatment.
- Lifestyle changes are an important part of optimizing fertility in the male partner as well as the female partner.
- Semen analysis is the primary method of evaluating male fertility. Abnormal findings require analysis of a repeat sample. Avoid over interpretation of semen analysis.
- Hormone measurements of testosterone and gonadotropins must always be performed when the semen sample is repeatedly abnormal.
- Karyotype and Y chromosome microdeletions should be analyzed in all men with poor semen quality (<3 mil/ml sperm concentration).
- Careful evaluation of the function of hypothalamus-pituitary-testicular axis is required in order to choose the optimal treatment for men with azoospermia.
- Poor male fertility is associated with compromised long-term male health.
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