Medical Management

While most cases of male infertility remain idiopathic, several known factors contribute to this condition. Fortunately, many of these causes can be effectively addressed through medical treatment, yielding high success rates. When infertility stems from idiopathic or genetic origins, medical management often involves empirical approaches.

What is Medical Management for Male Infertility?

While the majority of male infertility cases remain idiopathic, several known causes exist, with some being medically treatable with high success rates. In instances of idiopathic or genetic origins, medical management often adopts an empirical approach. A comprehensive understanding of the hypothalamic-pituitary-gonadal (HPG) axis and the implications of estrogen excess is pivotal in evaluating and treating male infertility. Medical interventions have demonstrated efficacy in enhancing sperm production or motility, primarily focusing on optimizing testosterone (T) production from Leydig cells, elevating follicle-stimulating hormone (FSH) levels to stimulate Sertoli cells and spermatogenesis, and restoring the T to estrogen ratio.

Understanding Causes and Non-Surgical Treatment Options

Approximately 15% of couples face infertility, with male factor infertility contributing to roughly 50% of cases (1). While a significant portion of male infertility remains idiopathic, characterized by unexplained abnormalities in sperm parameters or azoospermia, various known causes exist, many of which have pharmacological treatment options as first-line interventions. These treatments often yield targeted and successful outcomes. However, in cases of idiopathic or genetic male infertility, medical management tends to be empirical, aimed at optimization.

Central to testicular function is the intricate regulation of the hypothalamic-pituitary-gonadal (HPG) axis, which governs both testosterone (T) production and spermatogenesis (2). Spermatogenesis relies on elevated intratesticular T levels and follicle-stimulating hormone (FSH) stimulation of Sertoli cells. Notably, while T is vital for spermatogenesis, its administration, along with other androgens, has contraceptive properties, inhibiting luteinizing hormone (LH) stimulation of intratesticular T production and FSH stimulation of Sertoli cells, thereby exerting negative feedback on the HPG axis and should be avoided. For most known causes of male infertility, therapeutic focus lies in maintaining the reproductive axis to enhance testicular T levels. However, in cases of primary testicular failure or idiopathic male infertility, specific medical therapies may be elusive, leading to the utilization of empiric medical treatments.

This review article aims to explore non-surgical treatments available for male infertility, providing insights into their efficacy. Below is a summary table of the medications reviewed.

Hormonal treatment

Gonadotropin-releasing hormone (GnRH)

In the intricate cascade of hormonal signaling, the pulsatile release of Gonadotropin-Releasing Hormone (GnRH) from the hypothalamus serves as a vital trigger, prompting the anterior pituitary to secrete Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH). In men, the equilibrium of FSH and LH levels orchestrates spermatogenesis and sustains optimal testicular testosterone levels.

For individuals with hypogonadotropic hypogonadism (HH), characterized by deficient GnRH secretion, pulsatile GnRH therapy emerges as a pivotal intervention, particularly in cases such as Kallmann’s syndrome or idiopathic HH. By replenishing GnRH levels, this therapy restores the critical hormonal milieu necessary for spermatogenesis and Sertoli cell stimulation.

Effective administration typically involves subcutaneous delivery of GnRH at doses ranging between 5-20 µg every one to two hours, facilitated by specialized pumps or needles. Remarkably, spermatogenesis induction often manifests within four months of initiating therapy, with a success rate of approximately 85%.

Encouragingly, clinical outcomes reveal that about 60% of couples achieve pregnancy within nine months of treatment initiation, although attainment may extend up to two years. Positive predictors of treatment success include the normalization of hormonal levels, maturation of secondary sexual characteristics, and augmentation of testicular size.

However, despite its efficacy, GnRH therapy encounters limitations stemming from logistical challenges, including the need for regular subcutaneous injections and the inconvenience of pump-based administration. While GnRH stands as a cornerstone in addressing HH-related infertility, its utility in idiopathic cases remains uncertain.

Moreover, a subset of HH patients may experience spontaneous GnRH secretion recovery upon treatment cessation, offering insights into potential treatment duration optimization. Nonetheless, ongoing research endeavors seek to refine GnRH therapy, aiming to mitigate its logistical burdens while maximizing its therapeutic benefits for male infertility.

Gonadotropins

Addressing male infertility in individuals with pituitary insufficiency, whether due to conditions like pituitary adenoma or systemic diseases such as hemochromatosis and sarcoidosis, revolves around gonadotropin therapy. Traditional methods relied on urinary gonadotropins, but advancements in laboratory technology have introduced highly purified or recombinant gonadotropin products like human chorionic gonadotropin (rec-hCG), FSH (rec-hFSH), and LH (rec-hLH). These newer alternatives boast superior quality and efficacy, showing no discernible differences in safety, purity, or clinical effectiveness among various products.

The treatment typically initiates with hCG administration alone. If after several months no sperm is detected but adequate serum testosterone levels are achieved, FSH treatment is introduced. Gonadotropins are self-administered via subcutaneous injections, with dosages ranging between 75-150 IU of FSH or human menopausal gonadotropin (hMG) two to three times weekly alongside 1,500-2,500 IU of hCG twice weekly. Treatment duration may span from 6-24 months or more, continuing until sperm appears in ejaculate and/or pregnancy is achieved. Most studies indicate successful spermatogenesis induction in around 80% of treated men, with combinations like hCG and hFSH reaching up to 94% success rates. The time for sperm appearance varies, averaging around seven months, with pregnancy achieved on average within 28 months.

Side-effects are generally minimal, with proper dose adjustments optimizing testosterone levels and mitigating issues such as gynecomastia, acne, and weight gain. Factors like cryptorchidism, small testicles, elevated BMI, and severe gonadotropin insufficiency may negatively influence treatment response.

While gonadotropins have shown efficacy in hypogonadotropic hypogonadism (HH), evidence supporting their use in idiopathic infertility remains limited. Randomized controlled studies evaluating their efficacy for normogonadotropic oligoasthenoteratozoospermia (OAT) have yielded inconclusive results. However, some studies suggest improvement in seminal parameters and pregnancy rates in men with hypospermatogenesis treated with gonadotropins. The use of FSH or LH substitutes for idiopathic OAT and NOA lacks consensus and requires further placebo-controlled trials for validation.

Dopamine agonist

In cases of male infertility linked with hyperprolactinemia, it's crucial to consider prolactin-secreting pituitary adenomas as a common underlying cause. However, tumors causing stalk compression and hyperprolactinemia shouldn't be treated with dopamine agonists. Elevated prolactin levels can disrupt the pulsatile secretion of GnRH, leading to hypogonadism and infertility in men, often accompanied by headaches or visual field changes due to pituitary tumor compression. Dopamine agonists are typically prescribed to address infertility and the pituitary tumor in this scenario. While both bromocriptine and cabergoline have historically been used, evidence suggests that cabergoline is more effective in suppressing prolactin production and normalizing prolactin levels, achieving success in a significant portion of bromocriptine-resistant patients. Thus, cabergoline (at doses of 0.125-1.0 mg twice weekly) is preferred for its superior efficacy in normalizing prolactin levels and reducing prolactin-secreting tumors. In cases where patients fail to achieve normal prolactin levels despite maximum tolerated doses or experience insufficient tumor size reduction, along with continued infertility, dopamine agonist resistance may be suspected. In such instances, recommendations include escalating the medication dose or transitioning from bromocriptine to cabergoline. Patients unresponsive to these measures may be advised to undergo surgical intervention.

Aromatase inhibitor (AI) therapy

Using aromatase inhibitors (AIs) such as anastrozole (1 mg daily) or letrozole (2.5 mg daily) in the treatment of men with idiopathic oligoasthenospermia or azoospermia is an off-label practice. These medications work by increasing testosterone (T) levels, reducing estrogen levels, and inhibiting the peripheral metabolism of T. The goal is to mitigate the estrogenic impact on spermatogenesis. Elevated estrogen levels, coupled with low T levels, have been found to impede proper spermatogenesis. Moreover, heightened estrogen levels can lead to feedback inhibition of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in decreased luteinizing hormone (LH) required for T production and follicle-stimulating hormone (FSH) essential for optimal sperm production.

While a small study on high-dose testolactone didn't affect semen quality or pregnancy rates in men with idiopathic oligoasthenospermia, it didn't alter the T/E ratios either. However, another trial involving men with idiopathic infertility and low T levels (<300 ng/dL) with T/E ratios <10:1 showed improvements in hormonal profiles and semen parameters with low-dose testolactone. It's important to note that high-dose testolactone treatment may inhibit T production, potentially rendering it ineffective in improving sperm production and fertility. Candidates for aromatase inhibition typically have serum T levels <300 ng/dL and T/E ratios >10.

In a non-controlled study comparing anastrozole and testolactone in infertile men with abnormal T/E ratios, both medications led to enhancements in sperm concentration, motility, and morphology, regardless of the medication used. Anastrozole may be more effective at increasing the T to estrogen ratio compared to testolactone, with fewer side effects. Additionally, letrozole treatment in men with oligospermia or azoospermia showed significant improvements in hormonal profiles and semen parameters, leading to spontaneous pregnancy in some cases.

Overall, AIs appear effective in restoring LH, FSH, and T levels, improving semen parameters, and re-establishing fertility in men with low sperm concentration, particularly those diagnosed with non-obstructive azoospermia (NOA) or idiopathic oligoasthenospermia and presenting with low T and T/E ratios <10:1. While AI therapy is generally well-tolerated, possible side effects include nausea, decreased libido, and asymptomatic mild elevation in liver function tests. Notably, AI use may also lead to decreased bone mineral density and increased total body fat due to reduced estrogen availability.

Selective estrogen receptor modulators (SERMs)

Selective Estrogen Receptor Modulators (SERMs) are compounds that interact with the estrogen receptor, acting either as agonists or antagonists. Before the advent of intracytoplasmic sperm injection, SERMs were among the limited options available for men with idiopathic infertility. Although SERMs like clomiphene citrate (CC), tamoxifen, and toremifene have been extensively utilized in women for breast cancer and osteoporosis treatment, their application in male hypogonadism and infertility remains off-label. CC, a typical SERM, disrupts central estrogen feedback and enhances luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production, thus promoting spermatogenesis induction. Despite concerns regarding CC's estrogenic properties, studies indicate its significant positive impact on serum testosterone levels and increased pregnancy rates, particularly in hypogonadal men. Research also suggests that CC treatment, tailored to achieve a serum testosterone level of 600 ng/dL, resulted in sperm presence in the ejaculate suitable for intracytoplasmic sperm injection in a considerable percentage of men with non-obstructive azoospermia.

Tamoxifen citrate, along with similar compounds like toremifene and raloxifene, function as non-steroidal estrogen receptor antagonists, exerting effects akin to CC at the hypothalamic and pituitary levels. Clinical trials in men with oligospermia or azoospermia have demonstrated improvements in semen parameters and pregnancy rates following tamoxifen (20 mg daily) or toremifene and raloxifene (60 mg daily) treatment for three months. However, conflicting results have been reported, with some studies showing improvements in biochemical profiles without significant effects on semen parameters or fertility outcomes.

A recent meta-analysis investigating the efficacy of estrogen antagonists (CC or tamoxifen) as empirical medical therapy for idiopathic male infertility with oligo and/or asthenoteratozoospermia revealed promising results. The pooled data indicated a significant increase in pregnancy rates, sperm concentration, and sperm motility associated with estrogen antagonist use. Moreover, elevated serum follicle-stimulating hormone (FSH) and testosterone (T) levels were noted without a notable increase in adverse events compared to controls. However, other meta-analyses have not strongly supported the use of anti-estrogens in men with oligoasthenospermia, citing minimal or negligible improvements in pregnancy rates.

Antioxidant

Research suggests that high levels of reactive oxygen species (ROS) in seminal fluid may contribute to male infertility by causing sperm dysfunction and DNA damage in germ cells. While antioxidant supplements have been proposed as a treatment to counteract these effects, their efficacy remains uncertain. Clinical trials investigating antioxidant use have shown some improvement in sperm function and DNA integrity, but randomized controlled trials have yet to demonstrate a significant increase in unassisted pregnancy rates following antioxidant therapy. Additionally, the benefits of antioxidants may vary among different patient groups, and the effectiveness of specific antioxidant combinations remains inconclusive. For instance, studies on combinations like vitamin E and C have yielded mixed results, with some showing no improvement in semen parameters or pregnancy rates. However, other combinations such as vitamins A, C, E, NAC, and zinc have shown promising effects on sperm concentration. A systematic review of various antioxidant trials indicated improvements in sperm quality and pregnancy rates in a majority of cases, although the studies had limitations in terms of design and consistency. Despite these findings, there are currently no standardized recommendations for antioxidant use in treating male infertility, and their utilization remains largely empirical.

Optimizing surgical sperm extraction with hormonal manipulation

The strategy of enhancing surgical sperm extraction through medical therapy is grounded in the notion that spermatogenesis relies on elevated levels of intratesticular testosterone (T) and follicle-stimulating hormone (FSH) stimulation of Sertoli cells (2). As focal spermatogenesis is present in 60% to 70% of men with non-obstructive azoospermia (NOA), optimizing hormonal profiles in select patients may prove beneficial. Utilizing medications like clomiphene citrate (CC), aromatase inhibitors (AIs), and gonadotropins could elevate intratesticular T levels and normalize estrogen levels before sperm retrieval procedures.

A retrospective study indicated that men with Klinefelter syndrome (KS) and NOA who received AIs, CC, or human chorionic gonadotropin (hCG) before microdissection testicular sperm extraction (microTESE), and achieved a T rebound to 250 ng/dL or higher, experienced a 22% increase in sperm retrieval rates compared to those who didn't reach this threshold. Additionally, the same study suggested potential benefits for KS patients specifically using testolactone.

Another study evaluating medical therapy before sperm extraction in non-KS men with NOA and hypogonadism found that hormonal therapy often led to increased T levels, but baseline T level or response to therapy didn't significantly affect overall sperm retrieval, clinical pregnancy, or live birth rates (55).

Despite limited level one evidence, a prospective study on CC use before micro-TESE demonstrated a notable increase in favorable testis biopsy patterns and a greater likelihood of sperm extraction in patients with maturation arrest or hypospermatogenesis. However, another study involving CC treatment prior to micro-TESE didn't yield improvements in sperm retrieval or clinical pregnancy rates.

The role of gonadotropins in optimizing sperm extraction remains controversial, with uncertainty surrounding the patient population that may benefit from such treatment. Randomized controlled trials are essential for clarifying the role of medical therapy before sperm retrieval. Evidence suggests potential benefits in men with normal FSH levels and hypospermatogenesis on testicular biopsy, as well as in certain subgroups such as those who failed initial micro-TESE and underwent repeat sperm extraction, KS men before micro-TESE, and hypogonadal men who didn't normalize their T levels with CC therapy before testicular sperm extraction.

A Note from Kamakhya Andro-Uro Care & Fertility Clinic:

Comprehending the HPG axis and the implications of estrogen excess is pivotal for diagnosing and managing male infertility. The primary objective in treating infertility in such cases is to enhance LH levels to trigger testosterone production from Leydig cells, elevate FSH levels to stimulate Sertoli cells and spermatogenesis, and mitigate any estrogen surplus. Pharmacological interventions demonstrate effectiveness solely in addressing specific, well-defined causes of male infertility. However, considering existing evidence, hormonal therapies should not be employed indiscriminately for treating idiopathic male infertility due to uncertainties surrounding their efficacy and associated costs.