The number of couples seeking fertility treatment is increasing worldwide and accounts for about 10-15% of all couples trying to conceive. It is most often the woman who initiates the search for professional help. Therefore, gynecologists are usually among the first to encounter couples struggling with infertility. The man's need for treatment must not be neglected. Impaired male fertility is present in at least 50% of these couples. This article will provide an overview of the most important factors that gynecologists should focus on when assessing the man, as well as current diagnostic and therapeutic approaches.
Infertility or childlessness is a couple's problem and must be managed accordingly. Infertility is defined as one year of regular intercourse without achieving pregnancy. The diagnostic process for the assessment of the man includes a thorough history, physical examination and a semen analysis. If necessary, the assessment can be supplemented with ultrasound examination of the testicles and prostate (TRUS, transrectal ultrasound), hormone assessment and, if necessary, genetic assessment.
Causes of male infertility
In about a third of the men who are examined, the cause of their reproductive problems will be "idiopathic", meaning that the exact cause is unknown. In the remainder, a somatic cause is found.
Underlying health conditions and comorbidity
In some cases, however, the examination may reveal underlying health conditions that may contribute to fertility problems. Findings from the semen analysis may be closely related to general health. Abnormal findings in the semen analysis may be indicators of an increased risk of cardiovascular disease, diabetes mellitus and certain cancers. Thus, the examination can serve as an early warning system for such potential health problems, which may allow for early intervention and treatment.
Focusing on specific factors in the patient's history can be an important part of evaluating their fertility status. Infections, such as mumps, can lead to a significant reduction in fertility. Approximately 20-30% of men who contract mumps develop orchitis 1-2 weeks after mumps. Of these, 30-50% may subsequently suffer from atrophy of one or both testicles, leading to reduced fertility and/or hypogonadism. In addition, infections with fever can affect sperm quality (decrease in spermatogenesis) which normalizes when a new generation of sperm is produced, after approximately ≥3 months.
Other conditions can also affect sperm quality and fertility, including diabetes, gastrointestinal diseases, cardiovascular diseases, liver or kidney failure, previous chemotherapy, and even psoriasis. Neurological comorbidity can particularly affect ejaculation and erectile function.
Patients' medical history should also include any previous pregnancies that they have contributed to, whether wanted or unwanted. Visual or smell disturbances, decreased libido, erectile dysfunction, depressed mood, lack of energy, or loss of muscle strength should also be assessed.
Childhood medical history is also important, such as undescended testicles (cryptorchism), which occurs in 1-3% of male infants. The risk of azoospermia increases 25-fold, even if surgical intervention (orchidopexy) is performed during the first year of life. Impaired function of the contralateral testicle can be seen in up to 70% of unilateral cryptorchidism. Testicular torsion, which occurs in 1/4000 children, must be corrected within six hours to avoid reduced fertility or orchidectomy.
Body weight is another important factor, as both overweight and underweight men can experience fertility problems. Surgeries or trauma to the genitals, pelvis, groin, retroperitoneal, or cranial area can also affect male fertility.
Medication
The effects of medications are often underestimated. For example, anabolic steroids and medications such as tricyclic antidepressants, monoamine oxidase inhibitors, haloperidol, lorazepam, and spironolactone may be of importance for male fertility.
Other causes
The effects of cell phone use are still unclear. Prolonged exposure to heat is detrimental to sperm quality, and poor nutrition can also affect fertility. A healthy diet that includes omega-3 fatty acids, antioxidants (such as vitamin E, vitamin C, beta-carotene, selenium, zinc, cryptoxanthin, leukopenia), vitamin D, and folic acid, while avoiding saturated fatty acids, is beneficial for sperm quality. Therefore, diets based on fish, seafood, chicken, grains, vegetables, and fruits are advantageous compared to soy, potatoes, cheese, alcohol, whole milk, coffee, or sweets.
Somatic examination
Performing a physical examination is essential to identify potential reproductive health problems. Abnormal body composition and hair patterns can be symptoms of conditions such as hypogonadism or Klinefelter syndrome. During a genital examination, it is important to examine the penis for conditions such as epispadias or hypospadias and phimosis.
Palpation of the scrotum can give an impression of testicular volume, which is typically around 15 ml but may be less in hypogonadism. Normally, the texture of the testicles is firm and smooth. Hard or uneven masses may indicate testicular tumor. The presence of the vas deferens should be verified by palpation. Absence may indicate congenital agenesis of the vasa deferentia (CBAVD). It is also important to screen for the presence of varicocele, which can range from being palpable during Valsalva maneuver (I°), via palpable without Valsalva maneuver (II°) to visible (III°).
Supplementary medical investigations
Ultrasound
If any anomalies have been identified by physical examination or history, scrotal and/or transrectal (duplex) sonography is necessary. If semen analysis results are abnormal, a genital ultrasound is also necessary to further investigate the underlying cause.
Sperm analysis – what do you look for?
Semen analysis is one of the most important diagnostic tools in the evaluation of male fertility. However, since sperm quality can be affected by a number of factors, a single analysis may not be sufficient to accurately determine fertility status. For this reason, a new semen analysis should be repeated after at least three months if the initial analysis revealed abnormal findings. It is essential that patients refrain from ejaculation for 3-5 days prior to providing the sample, which should be collected in a sterile cup.
It is recommended that the semen analysis be processed according to the latest WHO guidelines. Patients can perform the sample collection by masturbation at home as long as the time between ejaculation and semen analysis does not exceed one hour.
However, semen analysis does not always accurately distinguish between “fertile” and “infertile.” Abnormal results rather indicate that testicular function may be impaired. Therefore, it is important that further endocrine and physical examinations be performed.
Asthenozoospermia, a condition in which sperm motility is reduced, can be caused by infections, varicocele, chronic inflammation of the epididymis, or medications such as sulfasalazine.
Teratospermia is a condition in which sperm morphology is abnormal. The pregnancy rate for teratospermia depends on the severity. If sperm morphology falls below 4%, the pregnancy rate for IVF or IUI may be reduced, as only normally shaped sperm can fertilize the egg.
azoospermia is a condition in which there are no detectable sperm in the ejaculate. It is a common condition affecting 15% of men being evaluated for infertility. Various causes can lead to azoospermia, and it is important to distinguish between obstructive and non-obstructive azoospermia for effective treatment.
Obstructive azoospermia (OA) can be caused by conditions such as CBAVD (Congenital bilateral absence of the vas deferens), where there is a high probability of retrieving mature sperm via TESE/MESA (testicular sperm extraction/microsurgical epididymal sperm aspiration, see below).
If azoospermia is present, testicular ultrasound should be performed to assess volumetric and pathological patterns and TRUS (transrectal ultrasound) to assess prostatic cysts and dilated ejaculatory ductus.
If testicular volume, FSH and serum testosterone levels are normal, obstructive azoospermia is likely present. Semen volume and biochemical markers such as pH, alpha-Glucosidase or fructose can provide more insight into the “level” at which sperm transport is compromised.
The cause of the obstruction may be postinflammatory (even unilateral epididymitis causes OA in one in 10 patients), iatrogenic, or posttraumatic. “Central” obstruction is present in 5% of patients with OA. 5% of OA patients have unilateral renal agenesis or aplasia, which requires ultrasound examination of the retroperitoneum.
Non-obstructive azoospermia (NOA) may have genetic causes such as AZF microdeletion and Klinefelter syndrome, primary testicular tissue damage (which is often associated with increased FSH levels) and central regulatory problems (most likely concomitant low FSH levels). FSH levels correlate negatively with testicular volumes and positively with impaired spermatogenesis. Inhibin B, on the other hand, correlates negatively with impaired spermatogenesis. However, the combination of FSH and Inhibin alone does not reliably predict the outcome to be expected after TESE. On the other hand, preoperative FSH levels appear to correlate with pregnancy and live birth rates after TESE-ICSI. Testosterone levels are reduced in 30% of NOA patients. Another cause of NOA (which is largely underestimated) may be exogenous testosterone therapy.
If the sperm concentration is less than 5 million sperm/ml, genetic testing is required. Karyotyping is required to screen for Klinefelter syndrome, while screening for AZF microdeletion is required for Y-chromosomal microdeletion in region Yq11. Microdeletions in regions AZFa or AZFb are often associated with spermatogenesis arrest and Sertoli-only cell syndrome. In such cases, we will not find mature sperm that can be used for ICSI after TESE. Microdeletions in AZFc (80% of all AZF microdeletions) have a higher chance of achieving positive TESE results. CFTR mutation is also important in the pathogenesis of CBAVD (85%) and can have significant implications for the health of the unborn child. A heterozygous CFTR mutation does not lead to reduced fertility, as do homozygous or compound-heterozygous forms. Another possible cause of CBAVD has recently been described with a loss-of-function mutation in ADGRG2 (X-chromosomal).
Treatment options
Male infertility is treated based on the clinical situation. To differentiate between the different treatment options, it is important to include testosterone, free testosterone, FSH, LH, prolactin, hCG, TSH, etc. in the diagnostic workup.
OA OR NOA
If a man has previously undergone a vasectomy but now wishes to father a child, vasovasostomy is an option, with a success rate of up to 90%. It is important to note that it can take 6-9 months for sperm parameters to normalize after the procedure.
For men with OA or certain forms of NOA, surgical sperm retrieval is an option. Microsurgical epididymal sperm aspiration (MESA) is one such technique, but it requires a precise indication as it can lead to irreversible obstruction of the epididymis. It also requires high expertise and is often combined with testicular sperm extraction (TESE).
TESE involves the surgical extraction of small testicular biopsies and is considered the modern method. During the procedure, multifocal biopsies should be performed. Clinical results are better than “blind” percutaneous needle aspiration (TESA). In cases of severe damage to the testicular tissue, micro-TESE is a valuable alternative, where tubules with intact spermatogenesis can be identified by microscopy since they appear larger in diameter compared to surrounding tissue without sperm production.
Hypogonadism
Hormone therapy is a common treatment approach for male hypogonadism. However, a common mistake in this therapy is to add testosterone if the couple wants to conceive. Testosterone therapy has detrimental effects on spermatogenesis. For diagnostics, testosterone levels should be measured between 07.00:11.00 and 12:30. The normal range for healthy young men is 8-250 nmol/l. If testosterone levels are lower or marginally within the normal range, a new blood test should be performed. Loss of libido can already be seen in men with low values within the normal range, while erectile dysfunction usually occurs if serum testosterone is <XNUMX nmol/l. Testosterone is measured and assessed together with SHBG and total testosterone. Free testosterone should be > XNUMX pmol/l. Testosterone deficiency can lead to anemia, so Hb values should be included in the individual assessment.
For patients suffering from primary hypogonadism (testicular failure), no medical intervention is possible. Testosterone supplementation may be appropriate for a generally improved quality of life. For secondary hypogonadism (e.g. hypothalamic or pituitary insufficiency), hCG and/or FSH, GnRH (pulsatile) can be used. Erectile dysfunction can be treated with PDE-5 inhibitors, Yohimbine, etc.
Acute genital infection
For patients with acute genital infection/epididymitis/epididymoorchitis without hypogonadism, antibiotic treatment should be considered, and partner treatment may be necessary. If there are problems related to an older infection that has occurred in the patient's history, antiphlogistic treatment can be given.
Inflammatory cause
If spermatogenesis is affected by an inflammatory cause, antiphlogistic treatment, antioxidants, mast cell inhibitors, pentoxifylline, etc. can be used. If a non-inflammatory cause affects spermatogenesis, rFSH, anti-estrogen treatment can be used, while alpha-sympathomimetics, imipramine, and the like can be used in the case of transport defects (e.g. in retrograde ejaculation).
Immunological infertility
For immunological infertility (autoantibodies against sperm cells), glucocorticoids can be used.
Idiopathic infertility
Idiopathic infertility can be treated with rFSH, antiestrogen therapy, etc., based on the patient's clinical condition. However, such treatment must be labeled as experimental.
Conclusion
- Gynecologists have a very important function when it comes to examining men and referring patients who find findings during the examination that require further investigation, for example to a urologist/andrologist.
- Assessment of the man should take place in parallel with assessment of the woman, as involuntary infertility is a couple's problem.
- If clarifying findings are made on the male or female side, prompt referral to a fertility specialist may be necessary.
- Avoid testosterone treatment in men if the couple wishes to achieve pregnancy.
