Comprehensive Review of the Biological Causes of Male Infertility and Therapeutic Approaches for Treatment

Abstract

Male infertility is the reason for half of the 8-12% couple suffering from infertility. Male infertility increases from time to time and it is one of the concern people facing nowadays. Biologically, it is caused by genetics, anatomical and hormonal. In this review biological causes of male infertility like varicocele, infection, ejaculation, Anti-sperm antibodies (ASA), Undescended testis or Cryptorchidism, Gonadotropin-releasing hormone (GnRH) are explained in details and the treatment such as assisted reproductive technologies (ART) like intracytoplasmic sperm injection (ICSI) surgical interventions and hormonal therapies. Lifestyle modifications also can help to improve the sperm quality.

Keywords

Introduction

A couple is considered infertile if they are unable to conceive after a year of frequent, unprotected sexual activity. It impacts at least 180 million couples globally and 15% of all couples in the US¹. A male's inability to conceive a fertile female after at least a year of consistent, unprotected sexual activity is known as male infertility, according to the World Health Organization (WHO)². About 20% of infertility cases are exclusively the male's fault³.

Biological causes of infertility in men

1. 1. Varicocele

The negative impact of varicocele on spermatogenesis arises from several factors, including elevated testicular temperature, increased pressure, hypoxia from reduced blood flow, and hormonal abnormalities⁴. Varicocele leads to warmer scrotal temperatures due to warm blood reflux, primarily from insufficient internal spermatic vein valves. Surgical repair can normalize temperature. Although the exact mechanism linking temperature to spermatogenesis is unclear, it may involve thermal damage to DNA in spermatic tubule cells⁵. Additionally, increased venous pressure reduces arterial flow, affecting testicular blood circulation. Varicocele is associated with lower testosterone levels in older men, possibly due to Leydig cell dysfunction, but it doesnot cause clinical hypogonadism. Oxidative stress, related to varicocele, leads to sperm DNA damage and affects sperm quality, resulting in increased germ cell apoptosis⁶. While the relationship between varicocele and infertility is complex, many men with varicocele remain fertile, suggesting it may be a response to testicular dysfunction rather than a direct cause of infertility. Varicocele is notably more prevalent in men attending infertility clinics, with rates 2-3 times higher than in the general population⁷. Studies show varying prevalence rates of varicocele in the general population (4% to 30%) and among infertile men (17% to 41%), suggesting diagnostic subjectivity. A WHO study indicated that varicocele frequency in infertile couples varied geographically from 6% to 47%⁸.

Research continues to debate the extent to which varicocele affects semen parameters, typically ranging from normal to mild/moderate abnormalities⁹. While initial sperm concentration may not be significantly impacted, motility and quality can decline over time, leading to rare cases of azoospermia¹⁰. Some studies report slightly elevated serum FSH levels in infertile men with varicocele, but overall semen parameters may not differ significantly from those without the condition¹¹.The hypothesis that varicocele progressively damages testicular function is supported by its higher incidence in men with secondary infertility. Surgical repair has shown mixed results; while some studies indicate improvements in semen parameters, controlled trials often fail to demonstrate increased pregnancy rates post-surgery¹². Azoospermia in men with varicocele raises questions about the necessity of surgical intervention, especially when primary testicular failure coexists¹³.Subclinical varicocele, detectable only via imaging techniques, is generally not an indication for surgery, as studies have not shown increased pregnancy rates postoperatively¹⁴.With the advent of ICSI, questions arise about whether to treat varicocele before pursuing assisted reproductive technologies. Successful varicocele repair may allow for natural conception and is cost-effective, provided specific criteria are met, including persistent infertility, palpable varicocele, and normal testicular size¹⁵.

Treatment: Various surgical techniques are available for treating varicocele, including embolization, open non-microsurgical methods, laparoscopic approaches, and microsurgical techniques¹⁶. Each method has documented advantages and disadvantages, making it crucial to determine the most effective option based on factors like pregnancy rates and postoperative complications¹⁷. Routine evaluations for infertile men with varicocele should include a thorough medical history, physical examination, and semen analyses. Treatment indications generally include palpable varicocele and abnormal semen quality¹⁸.

Microsurgical techniques demonstrate the highest pregnancy rates (up to 41.97%) and the lowest recurrence (0-1.05%) and hydrocele formation rates (0.44%). Laparoscopic approaches yield moderate success, while open techniques like Palomo have higher recurrence rates¹⁹. Research indicates that varicocele repair enhances sperm parameters and may improve testosterone levels, though these factors are often overlooked in analyses²⁰.

The latest EAU guidelines recommend considering varicocele treatment in cases of infertility lasting two years or more, but not in men with normal semen analysis. Future studies should focus on defining the role of varicocelectomy and identifying which patients are most likely to benefit from surgical intervention. Overall, the effectiveness of microsurgical repair positions it as a preferred option²¹.

1. 2.  Infection

Healthy fertility is crucial for species survival, yet reports indicate declining male fertility globally. Infertility affects millions of couples, with male factors accounting for about 50% of cases. Key contributors include genetic defects, hormonal disorders, and infections²². The prevalence of infertility varies significantly between developed and developing regions, influenced by sanitary conditions and lifestyle²³. Pathogenic bacteria, such as Chlamydia trachomatis and Neisseria gonorrhoeae, can infect the male reproductive system, causing inflammation and impairing fertility through oxidative stress and autophagy²⁴. Understanding these mechanisms is vital for addressing male infertility linked to bacterial infections²⁵.

Bacterial infections can impair spermatogenesis and lead to sperm apoptosis, contributing to male infertility²⁶. Such infections cause significant sperm damage, including chromosome breakage and mitochondrial dysfunction. The integrity of sperm DNA is crucial for fertility, with studies linking DNA damage to infertility²⁷. Chlamydia, for instance, has been shown to cause chromosome breakage. Sertoli cells support sperm development but can also become infected, disrupting spermatogenesis. Leydig cells, essential for testosterone production, can also be affected by inflammation, impacting male reproduction. Additionally, some bacteria may infect the male reproductive system without directly impairing male fertility, potentially affecting female fertility instead²⁸.

Treatment: Treating male infertility often involves addressing underlying microbial infections that disrupt the genital microbiota, and while targeted antimicrobial therapies can be effective, they should be used judiciously to avoid exacerbating microbiota imbalances; interventions like probiotics, prebiotics, and synbiotics can help restore microbial balance and improve reproductive outcomes, with precision medicine potentially leveraging molecular biomarkers and inflammatory mediators to enhance reproductive health²⁹. Antibiotics tailored to specific infections are commonly employed to tackle bacterial issues in the genital microbiota, but indiscriminate use can disrupt beneficial commensal bacteria, leading to further dysbiosis; effective antibiotics, such as quinolones and tetracyclines, have been shown to improve semen parameters and fertility outcomes in infected males, while antifungal and antiviral agents target infections from Candida and viruses like HSV and HPV, both of which are associated with infertility, though some antibiotics may pose risks of testicular or sperm toxicity, necessitating careful consideration³⁰. Probiotics play a crucial role in promoting a balanced genital microbiome by supporting beneficial bacteria and inhibiting harmful strains, with oral probiotics, particularly Lactobacillus, influencing both gut and genital microbiota and potentially enhancing semen quality, while topical probiotics applied directly to the vaginal tract may also contribute to fertility by maintaining a healthy microbial environment. Prebiotics, which are non-digestible fibers, foster the growth of beneficial bacteria and are vital for restoring microbial equilibrium, found in whole grains and vegetables; they help produce short-chain fatty acids that maintain microbiota balance and may enhance sperm quality while modulating the immune response. Fecal microbiota transplantation (FMT), which involves transferring healthy donor fecal matter to restore gut and potentially genital microbiota, is primarily used for treating Clostridioides difficile infections but shows promise for other conditions linked to dysbiosis, including male infertility, although more research is needed to confirm its safety and efficacy. In summary, targeted antimicrobial therapies, probiotics, prebiotics, and FMT represent promising strategies for improving male fertility by modulating the genital microbiota, highlighting the need for ongoing research to refine these approaches and integrate them into personalized medicine for optimal patient care^{31, 32, 33, 34, 35, 36, 37, 38, 39, 40}.

1. 3.  Ejaculation problems:

Normal antegrade ejaculation involves two key phases: emission and expulsion, regulated by a complex network of nerve fibres. During emission, ejaculate enters the posterior urethra through smooth muscle contractions, primarily controlled by sympathetic nerves⁴¹. The expulsion phase follows, characterized by rhythmic contractions of the bulbo cavernosum and pelvic floor muscles, ensuring semen is propelled through the urethra while preventing retrograde flow into the bladder via coordinated bladder neck closure and urinary sphincter relaxation⁴². Central and peripheral nervous systems, particularly serotonin (5-HT) and dopamine systems, play significant roles in the ejaculatory reflex, with serotonin generally having an inhibitory effect on ejaculation⁴³. Disorders such as premature ejaculation (PE), delayed ejaculation (DE), retrograde ejaculation (RE), and anejaculation (AE) can disrupt this process⁴⁴. PE is defined by a rapid ejaculatory response causing distress, while DE is characterized by persistent difficulty achieving orgasm⁴⁵. RE occurs when semen flows backward into the bladder, often due to nerve damage or surgeries affecting the bladder neck. Effective treatments for ejaculatory dysfunction-related infertility include pharmacotherapy, assisted ejaculation techniques like penile vibratory stimulation and electroejaculation, and surgical sperm retrieval when necessary, highlighting the importance of addressing these disorders in men wishing to conceive⁴⁶.

Treatment: Testosterone solutions, applied at a 2% concentration once daily in the morning, can correct hypogonadism but may cause side effects such as pain, redness, swelling, gum irritation, breast pain, and cough⁴⁷. Cabergoline, a dopamine agonist administered at 0.5 mg twice a week at bedtime, can activate specific receptors but may lead to nausea, drowsiness, and risks of cardiac valve regurgitation^{48, 49}. Bupropion, a dopamine and norepinephrine reuptake inhibitor taken in doses of 150–300 mg daily in the morning, can cause palpitations and blurred vision among other effects^{50, 51}. Amantadine, which facilitates dopamine release, is taken as needed, typically 100–400 mg daily, with side effects that include nausea and dizziness^{52, 53, 54}. Cyproheptadine, an antiserotonergic, is dosed at 2–16 mg one to two hours before sexual activity and can result in sedation and impaired concentration. Midodrine, an ?1-adrenergic receptor agonist taken as needed in doses of 7.5–30 mg before sex, may cause dysuria and pruritus⁵⁵. Other medications like imipramine, ephedrine, and pseudoephedrine, all acting on adrenergic receptors, have specific dosing instructions and potential side effects ranging from dry mouth to insomnia. Yohimbine, an ?2-adrenergic antagonist, is used in doses of 20–50 mg one hour before sex, but may result in tachycardia and hyperglycemia. Buspirone, which has effects on 5HT1A receptors, is taken twice daily at 20–60 mg and may cause dizziness and headache^{56, 57, 58}. Oxytocin can be administered intranasally during sex at doses of 16–24 IU but might lead to nausea and hypertension, while bethanechol, a muscarinic receptor agonist, can be taken as needed at varying doses, potentially causing abdominal pain and diarrhea^{59, 60}.

1. 4.  Anti-sperm antibodies (ASA)

Anti-sperm antibodies (ASA), discovered in the context of male infertility, arise when mature spermatozoa are exposed to the immune system, typically due to damage to the blood-testis barrier^{61, 62}. This exposure can occur from various factors such as testicular injury, infections, or surgical interventions^{63, 64, 65}. Although ASA can impair sperm function, their presence alone does not diagnose immunological infertility, which is confirmed only when sperm functional capacity is affected. The prevalence of ASA in infertile men ranges from 3.9% to 15.6%, significantly higher than in fertile men, yet the clinical significance of ASA detection remains debated^{66, 67, 68}.

Testing for ASA, recommended by the WHO, involves methods like mixed anti-globulin reactions and immunobead binding tests^{69, 70}. However, guidelines from the American Society for Reproductive Medicine suggest that ASA testing is not a first-line evaluation for male infertility^{71, 72, 73}. Additionally, while sperm agglutination may indicate ASA, its correlation is not definitive⁷⁴. Management strategies vary based on the underlying cause and clinical practices^{75, 76}. This review summarizes the causes of ASA, the role of testing, and presents findings from a global survey on clinical management practices regarding immunological male infertility^{77, 78}.

Treatment: Various treatment methods have been explored to address antisperm antibodies (ASA)-mediated infertility in males, including strategies to reduce ASA production, remove ASA from sperm, and utilize assisted reproductive technologies (ART). Systemic corticosteroids have shown limited effectiveness, benefiting only about 20% of patients^{79, 80}. While simple sperm washing fails to adequately remove ASA, direct ejaculation into a washing buffer has proven beneficial for sperm recovery and minimizing ASA coating^{81, 82, 83}. Intrauterine insemination (IUI) can be helpful; one study noted a 64% pregnancy rate when using ejaculate collected in sterile medium from men with high ASA levels⁸⁴. In cases where IUI is ineffective, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) offer promising alternatives^{85, 86, 87}. IVF helps overcome the issue of reduced sperm transport, and some studies indicate high fertilization rates, while others suggest ASA negatively impacts fertilization, especially when bound to the sperm head^{88, 89, 90}. ICSI has been effective in bypassing autoimmune-related fertilization failures, showing comparable outcomes to ASA-negative males^{91, 92}.

To systematically diagnose and treat ASA-related infertility, a routine test like the D-IBT can identify ASA presence, followed by postcoital tests (PCT) and hemizona assays (HZA) to evaluate sperm function and fertilization potential⁹³. In a study involving 509 semen samples, 3.54% tested positive for ASA, with notable impairments in sperm penetration and fertilizing ability observed⁹⁴. The overall pregnancy rate among treated patients was 62.5?. A proposed strategy involves using D-IBT for initial screening, followed by PCT and HZA to guide treatment decisions, such as opting for ICSI when abnormal results are found⁹⁵. Although routine ASA testing is debated, it is crucial for managing unexplained infertility in cases of treatment failure⁹⁶.

1. 5.  Tumour induced male infertility

Prostate cancer is the most common malignant neoplasm in men, significantly impacting fertility due to various treatment modalities⁹⁷. Many patients, particularly those under 55, express interest in paternity, yet only a small percentage receive fertility counseling before treatment⁹⁸. Radical prostatectomy can cause permanent obstructive azoospermia, while erectile dysfunction can further complicate fertility⁹⁹. Radiotherapy and hormone therapies also negatively affect testosterone levels and spermatogenesis, leading to azoospermia or severe oligospermia¹⁰⁰.

In the context of muscle-invasive bladder cancer, treatments like radical cystoprostatectomy similarly result in azoospermia and erectile dysfunction¹⁰¹. Neoadjuvant chemotherapy can also impair fertility, though to a lesser extent than older regimens¹⁰². Invasive penile cancer treatments, such as penile amputation, hinder the ability to engage in natural intercourse, although new surgical techniques aim to preserve erectile function and penile length^{103, 104}.

Fertility preservation strategies include cryopreservation of sperm, yet only a small percentage of patients utilize this option^105,106. Psychological barriers, costs, and lack of information contribute to the low rates of sperm banking¹⁰⁷. Emerging hormonal treatments aim to protect spermatogenesis during cancer therapies, but results are inconsistent¹⁰⁸.

Innovative approaches like germ cell auto transplantation have shown promise in animal models but face ethical and safety concerns in humans¹⁰⁹. Overall, advancements in fertility preservation techniques are crucial for improving reproductive outcomes in men undergoing treatment for genitourinary cancers¹¹⁰. Further research is needed to refine these methods and address the psychological and financial barriers patients face¹¹¹.

Testicular cancer, the most common cancer in males aged 14 to 44, affects seven out of every 100,000 men and has seen rising incidence rates in Western countries^{112, 113, 114.} With early diagnosis and improved treatments, the overall survival rate exceeds 95%. However, testicular tumors significantly impact male fertility due to their location and the necessary functioning of the testicular, hormonal, and ejaculatory systems^{115, 116, 117.} Factors contributing to reduced sperm count and motility include the tumor's volumetric destruction of healthy tissue, increased scrotal temperature, and changes in blood flow¹¹⁸. Many patients also have testicular dysgenesis and related risk factors^119. Tumors can produce gonadotropins like beta-hCG, leading to hormonal imbalances that decrease sperm production and testosterone levels, resulting in hypogonadism and erectile dysfunction¹²⁰. Additionally, autoimmune responses with anti-sperm antibodies can cause further tissue damage^{121, 123}.

Surgical interventions for testicular cancer, particularly orchiectomy, significantly affect male fertility, with unilateral orchiectomy leading to reduced sperm count; studies show that 40% of patients become azoospermic or oligospermic shortly after the procedure^{124, 125, 126}. Although normal spermatogenesis often resumes within 2–3 years due to an increase in follicle-stimulating hormone (FSH) levels, and the restoration of sperm production is notably better when pre-surgery FSH levels are low, while partial orchiectomy has emerged as a potential option to preserve testicular function, especially in cases of benign tumors, though its application in germ cell tumors is contentious due to the likelihood of multifocality and local recurrence, and although some guidelines recommend this procedure for small masses (up to 2 cm), it necessitates careful intraoperative assessment to avoid missing concurrent malignancies, with postoperative radiotherapy potentially reducing tumor relapse but further compromising fertility; additionally, retroperitoneal lymphadenectomy (RPLND) carries a risk of retrograde ejaculation or anejaculation due to potential nerve damage, and while the incidence of these complications has decreased with advancements in surgical techniques, they still pose significant challenges to fertility, with modified RPLND approaches, including nerve-sparing techniques, shown to improve postoperative sexual function, though the standard of care for residual retroperitoneal masses remains RPLND, and radiation therapy is another critical factor influencing fertility, given the radiosensitivity of the germinal epithelium, as even low doses can cause considerable damage and fertility recovery post-radiation is gradual, often requiring 9–18 months, with higher doses leading to a risk of permanent azoospermia, and the extent of the irradiated area also plays a role in fertility outcomes; chemotherapy, particularly regimens involving cisplatin, etoposide, and bleomycin (PEB), has notable effects on spermatogenesis, with cisplatin being particularly associated with oligospermia and recovery rates highly variable depending on pre-treatment fertility and the number of cycles administered, generally presenting a relatively low risk of permanent infertility with fewer treatment cycles; given the potential impact of oncological treatments on fertility, various preservation methods are available, with semen cryopreservation remaining the most common approach, although a significant number of patients do not utilize this option, and innovative hormonal treatments and surgical techniques like partial orchiectomy can help mitigate fertility risks, highlighting the need for thorough discussions about fertility preservation strategies in light of the complex challenges posed by surgical treatment for testicular cancer^{127, 128, 129, 130, 131, 132}.

1. 6.  Undescended testis, or cryptorchidism

Undescended testis, or cryptorchidism, affects 1 to 4% of full-term and up to 30% of preterm male neonates, leading to potential long-term complications like impaired spermatogenesis and increased testicular cancer risk^{133, 134}. Fertility is notably impaired in these patients; around 90% with untreated bilateral cryptorchidism develop azoospermia, compared to only 0.4-0.5% in the general population. Even with treatment, azoospermia rates remain high, particularly in bilateral cases^{135, 136}.

The fertility issues stem from reduced germ cell numbers and defective maturation processes¹³⁷. Primitive germ cells present at birth undergo critical transformations involving hormonal surges during early infancy, which are often compromised in cryptorchidism¹³⁸. This disruption affects the maturation of gonocytes into adult spermatogonia, leading to a delayed establishment of the adult stem cell pool necessary for normal spermatogenesis^{139, 140}.

Factors contributing to infertility include the age at surgical correction and the duration of undescended testis. Testicular biopsies have shown lower germ cell counts in cryptorchid boys, with significant correlations between the presence of adult spermatogonia and post-pubertal sperm counts. Additionally, hormonal deficiencies during the neonatal period contribute to abnormal testicular development^{141, 142}.

Research indicates that gene expression related to spermatogenesis is disrupted in boys at risk of azoospermia, with specific genes critical for meiosis being under-expressed in those with cryptorchidism. Elevated transposon activity, leading to genomic instability, may also play a role in reduced germ cell counts¹⁴³.

Overall, cryptorchidism poses significant challenges for male fertility, necessitating timely intervention and ongoing research to better understand its impacts and potential treatments¹⁴⁴.

The American Urological Association (AUA) advises against hormonal therapy to induce testicular descent due to low efficacy and lack of long-term success, aligning with recommendations from several medical organizations, including the European Society for Pediatric Urology and the Canadian Urological Association, while the American Pediatric Association supports using hormones, specifically hCG, in patients with undescended testes linked to Prader-Willi syndrome to potentially avoid surgical intervention in high-risk infants, with the success rate for hCG treatment varying from 5% to 50% and also stimulating penile growth by increasing testosterone levels^{145, 146, 147}. Despite its cost-effectiveness and minimal complications, recent meta-analyses show no greater efficacy than placebo, and the AUA recommends surgery for congenital undescended testes between 6 and 18 months of age, with many specialists advocating for intervention as early as 6 months to enhance testicular growth and fertility, although 70% of affected boys undergo surgery later than recommended due to factors such as secondary cryptorchidism and reliance on family caregivers for referrals, leading to decreased fertility and increased risks of testicular malignancy, while for premature infants, corrected age is used to determine surgical timing, and for bilateral undescended testes, adults are often infertile, although some pregnancies via assisted reproduction have been reported, with surgery also indicated for acquired undescended testes and for retractile testes, which require annual monitoring due to the risk of transitioning to undescended status; for palpable undescended testes, inguinal or scrotal orchiopexy is recommended, involving various incision types and careful dissection to separate the hernia sac from surrounding structures, while the testis can be secured in a sub-dartos pouch using sutures or left unsutured, and for nonpalpable testes, laparoscopic exploratory surgery is advised with techniques including laparoscopic orchiopexy that preserves the gonadal vessels, 1-stage Fowler-Stephens orchiopexy that divides gonadal vessels to bring the testis down, 2-stage Fowler-Stephens orchiopexy where gonadal vessels are clipped and relocation is deferred for 6 months, and 2-stage traction-orchidopexy (Shehata technique) that fixes the testis for 3 months before relocation while preserving vasculature; the Shehata technique has shown high success rates ranging from 84% to 100% and lower atrophy risks, with the choice of technique depending on surgeon preference and experience, favoring the Shehata method when the ischemia test indicates adequate collateral blood supply, and in cases where no testis is found during laparoscopy, surgeons assess for blind-ending vessels or a testicular nubbin to confirm the absence of a testis, and if vessels are seen at the internal ring, scrotal exploration is necessary to locate any residual tissue^{148, 149, 150}.

1. 7.  Gonadotropin-releasing hormone (GnRH)

Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH)¹⁵¹. FSH promotes spermatogenesis via Sertoli cells, while LH stimulates testosterone production in Leydig cells; normal spermatogenesis requires intratesticular testosterone levels to be significantly higher than those in serum¹⁵². Endocrinopathies can negatively impact male fertility and are categorized based on hormone deficiency or excess¹⁵³. Hypogonadotropic hypogonadism (HH) can be congenital, such as in Kallmann syndrome, or acquired, leading to delayed puberty and infertility¹⁵⁴. Management often involves gonadotropin therapy (hCG and hMG or rFSH), which can restore fertility in a significant percentage of patients, although treatment may take 6-12 months¹⁵⁵. Hypergonadotropic hypogonadism results from impaired testicular function, leading to elevated gonadotropins and insufficient testosterone. Treatment strategies include gonadotropins, selective estrogen receptor modulators (SERMs), and aromatase inhibitors, especially in conditions like Klinefelter syndrome, where surgical sperm extraction may also be considered¹⁵⁶. Androgen excess, arising from exogenous sources such as anabolic steroid use or endogenous production, leads to suppressed gonadotropins and reduced spermatogenesis; discontinuation of exogenous sources can restore normal spermatogenesis within months, though recovery may vary¹⁵⁷. Future research is crucial for understanding endocrine disorders affecting male fertility and developing evidence-based treatment protocols, particularly focusing on the relationship between hormonal levels, testicular size, and treatment outcomes. Elevated estrogen levels can inhibit the hypothalamic-pituitary-gonadal (HPG) axis, contributing to reduced fertility in both men and women, with obesity playing a significant role in increasing estrogen levels, thereby lowering the testosterone-to-estradiol ratio, which is crucial for fertility¹⁵⁸. Aromatase inhibitors like testolactone and anastrozole have shown effectiveness in improving sperm quality by increasing testosterone levels and enhancing sperm concentration and motility in men with low testosterone-to-estradiol ratios¹⁵⁹. Hypothyroidism also impacts male fertility by reducing sexual desire and is linked to infertility, as it results in decreased levels of sex-hormone-binding globulin (SHBG) and testosterone, leading to diminished LH and FSH levels that affect sperm maturation¹⁶⁰. Animal studies indicate that correcting hypothyroidism can improve sperm parameters, highlighting the link between thyroid function and reproductive health¹⁶¹. In contrast, hyperthyroidism adversely affects sperm quality, characterized by lower motility and ejaculate volume, with hormonal changes leading to increased SHBG and LH levels but lower free testosterone. Hyperprolactinemia, defined by elevated prolactin levels, can inhibit GnRH release and reduce testosterone production, resulting in symptoms like diminished sexual desire and erectile dysfunction¹⁶². Dopamine agonists such as cabergoline and bromocriptine are effective treatments that can improve sperm parameters¹⁶³. Diabetes further complicates male reproduction by reducing libido and causing various sexual dysfunctions due to insulin insufficiency disrupting hormonal feedback loops¹⁶⁴. Obesity is also a significant factor, disrupting the HPG axis and causing lower testosterone and higher estrogen levels due to increased aromatase activity¹⁶⁵. The interplay of leptin and adipokines produced by adipose tissue further regulates reproductive hormones, with increased estrogen levels inhibiting gonadotropin release and impairing spermatogenesis¹⁶⁶. Additionally, oxidative stress can damage reproductive tissues, affecting sperm quality and hormone production, although antioxidants like selenium and coenzyme Q10 may help mitigate oxidative damage in the testes¹⁶⁷. Overall, the complex relationships between diabetes, obesity, and hormonal disruptions emphasize the need for comprehensive approaches to address male infertility, with future research crucial for unraveling these mechanisms and developing targeted therapies to enhance reproductive health in affected individuals¹⁶⁸.

GnRH (gonadotropin-releasing hormone), specifically GnRH-I, is produced by hypothalamic neurosecretory cells and released in pulses into the hypothalamo-hypophyseal portal circulation, stimulating the anterior pituitary to produce LH (luteinizing hormone) and FSH (follicle-stimulating hormone), which regulate gonadal functions¹⁶⁹. It also acts in extrapituitary tissues such as the ovary and immune system. Numerous GnRH-I analogues have been developed, showing effectiveness in treating reproductive endocrinopathies¹⁷⁰. However, a study of sustained GnRH treatment in idiopathic oligoasthenoteratozoospermia found no significant impact on circulating gonadotropins or semen parameters¹⁷¹. Pulsatile GnRH therapy has been implemented via a portable pump, showing promise in cases of hypothalamic deficiencies, while its efficacy in pituitary dysfunction remains uncertain due to potential antibody formation and the inconvenience of the device¹⁷².

LH and FSH, produced by the anterior pituitary under GnRH influence, are crucial for spermatogenesis, with hCG (human chorionic gonadotropin) also playing a role¹⁷³. Mixed gonadotropin therapy involves administering hCG and hMG (human menopausal gonadotropin) to stimulate spermatogenesis, leading to increased sperm counts and pregnancies, especially in patients with hypogonadotropic hypogonadism¹⁷⁴.

FSH therapy enhances androgen-binding protein production by Sertoli cells and is vital for spermatogenesis. However, studies have shown mixed results regarding its efficacy in improving pregnancy rates. Generally, FSH alone has limited effectiveness, as LH is also necessary for spermatogenesis. Further research with well-defined patient groups is needed to clarify FSH’s role in treating infertility. Overall, both GnRH and gonadotropin therapies offer potential for certain infertility cases, but their effectiveness can vary significantly based on underlying conditions¹⁷⁵.

Testosterone and dihydrotestosterone are the primary male sex hormones, essential for male sexual differentiation and function, but testosterone replacement therapy (TRT) can decrease sperm count due to negative feedback on the hypothalamus and pituitary, making TRT unsuitable for treating male infertility. Although testosterone therapies have been explored in infertile men, results are mixed, with studies showing no significant improvement in pregnancy rates; however, combinations like testosterone undecanoate and tamoxifen have shown promise in enhancing sperm parameters. Growth hormone (GH) plays a critical role in sexual differentiation and spermatogenesis, and GH deficiency correlates with infertility, but while GH has shown some benefit as an adjunct treatment, its efficacy remains uncertain. Antiestrogens like tamoxifen, a nonsteroidal estrogen antagonist, have been studied for male infertility, showing variable success in improving sperm count and motility, particularly in cases of oligozoospermia. Combination therapies, such as tamoxifen with kallikrein or testosterone, have also yielded better results, but studies are limited in scope¹⁷⁶. Clomiphene citrate, which enhances gonadotropin secretion, has demonstrated significant improvements in sperm motility and count, showing promise with pregnancy rates up to 50%. Additionally, thyroid hormones are essential for overall development, and while their role in spermatogenesis is debated, evidence suggests that thyroid dysfunction negatively affects fertility. Studies indicate that treating hypothyroidism may improve semen parameters, suggesting that thyroid hormone treatment could benefit men whose infertility is linked to thyroid issues. In summary, while various hormonal therapies exist, their effectiveness in treating male infertility varies, and further research is needed to establish optimal treatment protocols¹⁷⁷.

CONCLUSION

In conclusion by the above comprehensive review, we get to know that, male infertility is a multifactorial condition influenced by various factors that disrupt spermatogenesis and reproductive health. Conditions like varicocele, bacterial infections, ejaculatory dysfunctions, anti-sperm antibodies, cancer treatments, cryptorchidism, and hormonal imbalances contribute to fertility challenges. Varicocele, a leading cause, affects testicular function through mechanisms such as increased temperature and oxidative stress, with surgical intervention often showing variable results. Bacterial infections and ejaculatory dysfunctions also impair sperm function, with timely diagnosis and appropriate treatments being essential for restoring fertility. Emerging therapies, such as probiotics and fecal microbiota transplantation, show potential in improving reproductive health by addressing microbial imbalances.

Despite the availability of treatments like assisted reproductive technologies (ART), hormone therapies, and microsurgical procedures, there remains a need for ongoing research to refine diagnostic methods, improve treatment protocols, and enhance fertility outcomes. A more personalized and comprehensive approach—incorporating genetic, immunological, and hormonal insights—is crucial for optimizing care and providing tailored solutions for men experiencing infertility. By further advancing fertility preservation techniques and expanding knowledge on the underlying causes of male infertility, we can better support individuals in their journey toward improved reproductive health and outcomes.

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