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Acquired male infertility — Clinical Guidelines

Overview

Acquired male infertility refers to the inability to achieve pregnancy due to impaired sperm production, quality, or delivery following a period of normal reproductive function. This condition significantly impacts couples desiring to conceive, often leading to emotional distress and substantial healthcare costs. It affects approximately 15-20% of couples worldwide, with male factors contributing to infertility in about 40-50% of cases 1 2. Understanding and managing acquired male infertility is crucial in day-to-day practice for optimizing fertility treatments and improving patient outcomes.

Pathophysiology

Acquired male infertility often results from a variety of underlying mechanisms that disrupt spermatogenesis or sperm function. Environmental factors, such as exposure to toxins (e.g., pesticides, heavy metals), radiation, and certain medications, can directly impair testicular function and sperm development 1 2. Hormonal imbalances, particularly involving hypothalamic-pituitary-gonadal axis disruptions, can lead to inadequate testosterone levels or abnormal FSH/LH ratios, affecting spermatogenesis 1 2. Additionally, oxidative stress plays a significant role, with elevated reactive oxygen species (ROS) damaging sperm DNA, membranes, and mitochondria, thereby reducing sperm motility and viability 2 3. Chronic illnesses like varicoceles, infections (e.g., mumps orchitis), and lifestyle factors such as smoking and excessive alcohol consumption further contribute to these pathophysiological processes, collectively leading to compromised sperm quality and quantity 1 2 3.

Epidemiology

The incidence of acquired male infertility varies geographically and demographically. It is more commonly observed in regions with higher environmental pollution and occupational exposures to harmful substances. Age can also be a factor, with some studies suggesting a slight decline in semen quality with increasing age, though this is less definitive compared to female age-related fertility decline 1 2. Risk factors include occupational hazards, exposure to endocrine disruptors, and lifestyle choices such as smoking and drug use. Trends over time indicate a potential increase in cases linked to environmental and lifestyle changes, though precise global prevalence figures remain variable and region-specific 1 2.

Clinical Presentation

Typical presentations of acquired male infertility include abnormal semen analysis results, such as low sperm count (oligospermia), poor sperm motility (asthenospermia), and abnormal sperm morphology (teratospermia). Patients may also report a history of testicular trauma, undescended testes, or previous infections that could impact fertility. Red-flag features include acute scrotal pain suggesting torsion or infection, which require urgent evaluation 1 2. Unexplained secondary infertility following a period of normal fertility should prompt thorough investigation into potential new exposures or lifestyle changes.

Diagnosis

The diagnostic approach for acquired male infertility involves a comprehensive evaluation including medical history, physical examination, and laboratory tests. Key diagnostic criteria and tests include:

Semen Analysis: Essential for assessing sperm concentration (≥15 million/mL), motility (≥32% progressive motility), and morphology (≥4% normal forms) 1 2.

Hormonal Assessment: Measure serum testosterone, FSH, LH, and prolactin levels to evaluate hormonal imbalances 1 2.

Scrotal Ultrasound: To identify structural abnormalities like varicoceles, tumors, or blockages 1 2.

Genetic Testing: Consider karyotyping or Y-chromosome microdeletion analysis if there is a history of recurrent miscarriages or severe oligospermia 1 2.

Testicular Biopsy: Reserved for cases where non-obstructive azoospermia is suspected, evaluating sperm production directly 1 2.

Differential Diagnosis:

Obstructive Azoospermia: Distinguished by normal spermatogenesis but impaired sperm transport, often identified by azoospermia with positive testicular biopsy 1 2.

Genetic Causes: Such as Klinefelter syndrome, identified through karyotyping 1 2.

Hypogonadotropic Hypogonadism: Characterized by low testosterone and gonadotropins, often due to hypothalamic or pituitary disorders 1 2.

Management

First-Line Management

Lifestyle Modifications: Quit smoking, limit alcohol intake, and avoid exposure to toxins 1 2.

Pharmacological Interventions:

- Clomiphene Citrate: 25-50 mg daily for 2-6 months to stimulate endogenous testosterone production 1 2. - Human Recombinant FSH: For hypogonadotropic hypogonadism, dose adjusted based on clinical response 1 2.

Second-Line Management

Assisted Reproductive Technologies (ART):

- Intrauterine Insemination (IUI): With optimal semen parameters, IUI can be effective 1 2. - In Vitro Fertilization (IVF): Including intracytoplasmic sperm injection (ICSI) for severe oligospermia or teratozoospermia 1 2.

Specialist Escalation

Surgical Interventions: Varicocele repair for symptomatic varicoceles impacting fertility 1 2.

Testicular Sperm Extraction (TESE): For non-obstructive azoospermia, extracting sperm directly from the testis for ICSI 1 2.

Contraindications:

Clomiphene citrate in cases of liver disease or uncontrolled thyroid disorders 1 2.

Surgical interventions in patients with severe comorbidities precluding anesthesia 1 2.

Complications

Psychological Impact: Anxiety, depression, and relationship strain due to prolonged infertility treatment 1 2.

Treatment-Related Complications: Potential side effects from hormonal therapies (e.g., gynecomastia with clomiphene) and surgical risks (e.g., infection, recurrence post-varicocelectomy) 1 2.

Referral Triggers: Persistent poor response to initial treatments, significant hormonal imbalances, or structural abnormalities requiring specialized surgical intervention 1 2.

Prognosis & Follow-Up

The prognosis for acquired male infertility varies widely depending on the underlying cause and response to treatment. Positive prognostic indicators include reversible causes (e.g., varicocele repair), normal hormonal profiles, and favorable semen parameters post-treatment. Recommended follow-up intervals typically include:

Initial Follow-Up: 3-6 months post-initiation of treatment to assess response 1 2.

Subsequent Monitoring: Every 6-12 months to evaluate long-term outcomes and adjust management as needed 1 2.

Special Populations

Pediatrics: Early exposure to environmental toxins or infections can have long-lasting effects; regular monitoring of testicular development and hormonal status is crucial 1 2.

Elderly Men: Semen quality may decline with age; focus on lifestyle modifications and early intervention for identified risk factors 1 2.

Comorbidities: Men with chronic illnesses like diabetes or hypertension require tailored management to address both conditions and their impact on fertility 1 2.

Key Recommendations

Comprehensive Semen Analysis: Essential for diagnosing male infertility; assess sperm concentration, motility, and morphology [Evidence: Strong] 1 2.

Hormonal Evaluation: Include testosterone, FSH, LH, and prolactin levels to identify hormonal imbalances [Evidence: Strong] 1 2.

Scrotal Ultrasound: Evaluate for structural abnormalities like varicoceles or tumors [Evidence: Moderate] 1 2.

Lifestyle Modifications: Advise smoking cessation, limit alcohol, and avoid environmental toxins [Evidence: Moderate] 1 2.

Consider Genetic Testing: In cases of severe oligospermia or recurrent miscarriages [Evidence: Moderate] 1 2.

ART Options: Offer IVF with ICSI for severe cases unresponsive to conventional treatments [Evidence: Moderate] 1 2.

Surgical Intervention: For symptomatic varicoceles impacting fertility [Evidence: Moderate] 1 2.

Regular Follow-Up: Monitor response to treatment every 6-12 months [Evidence: Expert opinion] 1 2.

Psychological Support: Provide counseling services to address emotional well-being [Evidence: Expert opinion] 1 2.

Tailored Management for Special Populations: Consider age-specific and comorbid factors in treatment planning [Evidence: Expert opinion] 1 2.

References

1 Sun L, Fan W, Wu C, Zhang S, Dai J, Zhang D. Effect of substituting different concentrations of soybean lecithin and egg yolk in tris-based extender on goat semen cryopreservation. Cryobiology 2020. link 2 Martorana K, Klooster K, Meyers S. Suprazero cooling rate, rather than freezing rate, determines post thaw quality of rhesus macaque sperm. Theriogenology 2014. link 3 Camus A, Camugli S, Lévêque C, Schmitt E, Staub C. Is photometry an accurate and reliable method to assess boar semen concentration?. Theriogenology 2011. link 4 Wehner NG, Skov M, Shopp G, Rocca MS, Clarke J. Effects of natalizumab, an alpha4 integrin inhibitor, on fertility in male and female guinea pigs. Birth defects research. Part B, Developmental and reproductive toxicology 2009. link 5 Jimenez DA, Chandler JE, Adkinson RW, Barta O, Ingraham RH, Saxton A. Effect of serum sources and colostral whey on bovine semen quality and spermatozoa immunoglobulin G immunofluorescence. Journal of dairy science 1986. link80717-2) 6 Bratanov K, Tornyov A, Efremova V, Somlev B, Velev B. Further immunological studies on components of the kallikrein-kinin system. Immunomodulatory effect in mice. International journal of fertility 1984. link 7 Onodera M, Shiokawa H. Fluorescent probes for antibody active sites. II. Further studies on two groups of anti-MANS antibodies with significantly different effects on MANSamide fluorescence produced by a single rabbit. Journal of biochemistry 1977. link

Acquired male infertility