A Comprehensive Review of Thyroid Dysfunction: Hidden Player in Male Infertility

INTRODUCTION

Thyroid dysfunction is a medical condition that occurs when the thyroid gland, a butterfly-shaped organ located in the neck, produces an abnormal amount of thyroid hormones, which leads to multiple alterations of semen quality that include reduced volume, sperm density, sperm motility, and sperm morphology (La Vignera & Vita, 2018).

A disorder of the male reproductive system, male infertility is characterized by the inability to conceive after 12 months or more of consistent, unprotected sexual activity. It can cause significant distress, stigma, and financial hardship, affecting people’s mental and psychosocial well-being (WHO, 2023). Male infertility can be categorized as primary or secondary depending on whether the subjects have had a successful live birth previously or not (Esan et al., 2022).

It is frequently disregarded how thyroid conditions affect male reproductive health. Overall fertility, sperm quality, and sperm quantity can all be greatly impacted by this overlooked connection. Despite the growing number of reports linking thyroid dysfunction to male infertility, thyroid hormone levels are rarely assessed during laboratory work-ups for fertility tests. The purpose of this review is to emphasize the role that thyroid hormones play in controlling reproductive function, how male infertility may be caused by thyroid malfunction, and where future research on thyroid-related male infertility should go.

Prevalence of thyroid dysfunction and male infertility

An estimated 8%–12% of couples in their reproductive years’ experience infertility globally. Males are found to be solely responsible for 20%–30% of infertility cases but contribute to 50% of cases overall (Borght & Wyns, 2018). In men, the prevalence of thyroid dysfunction in patients presenting for sexual dysfunction has been estimated to be between 3.4% and 57.1% based on two studies with different cut-off values for thyroid-stimulating hormone (TSH) (Gabrielson et al., 2019). According to the U.S. National Health and Nutrition Examination Survey III, the prevalence of hypothyroidism was 4.6%, with overt and subclinical hypothyroidism being represented by 0.3% and 4.3% of the total, respectively, by screening serum TSH, thyroxine (T4), anti-thyroglobulin antibodies, and anti-thyroid peroxidase (TPO) antibodies. There is a five to eight times greater prevalence of hypothyroidism in women than in men. The frequency of overt hypothyroidism in men, however, is quite modest (0.1%). Nonetheless, clinically silent (subclinical) hypothyroidism is not rare, especially in males (2.8%). In the U.S. National Health and Nutrition Examination Survey III, hyperthyroidism was present in 1.3% of the population, with 0.5% exhibiting overt pathology and 0.7% exhibiting subclinical illness.

Out of the 150 infertile men evaluated in Benin City, Nigeria, 51.34% (77/150) had overt hypothyroidism, 7.33% (11/150) had subclinical hypothyroidism, and 41.33% (62/150) were euthyroid. Sixty-two percent (6/88) of the 88 individuals with impaired thyroid function had normozoospermia, 43% (39/88) had oligozoospermia, and 48% (43/88) had azoospermia. The authors concluded that treating possible thyroid-related causes of infertility can be facilitated by including thyroid function parameters in the investigative panel. This all-encompassing strategy guarantees careful assessment andfocusedtherapy for improved reproductive results for those who are impacted (Emokpae et al., 2024). According to a retrospective study of infertile couples in Bauchi, primary hyperthyroidism was the most prevalent biochemical pattern of thyroid dysfunction found, accounting for 10.8% of all the requests examined, whereas 80.8% of the requests showed a euthyroid pattern. In general, hypothyroidism and secondary hyperthyroidism were uncommon. There were also sporadic instances of triiodothyronine (T3) toxicosis (0.3%). In contemporary surroundings, goitres continue to be a typical manifestation of thyroid disorders. The two most prevalent types of thyroid dysfunction are primary hyperthyroidism and primary hypothyroidism (Abubakar et al., 2024).

The hidden connection between thyroid dysfunction and male infertility

A silent disruptor: While the impact of thyroid disorders on female fertility is well-established, their influence on male reproductive health is often overlooked. This unrecognized link may significantly affect sperm quality, quantity, and overall fertility. For example, hypothyroidism lowers testosterone levels, impairs sperm production and motility, and reduces libido (Grande et al., 2022). Hyperthyroidism may lead to oxidative stress, damaging sperm cells, may cause erectile dysfunction (ED), and can decrease libido (Walke et al., 2023). The silent symptoms: Many men with thyroid disorders may not experience obvious symptoms, making early diagnosis challenging. However, subtle signs such as fatigue, weight gain or loss, and changes in libido can be indicative of underlying thyroid dysfunction (Lekurwale et al., 2023).

The overlooked role of thyroid hormones in regulating male fertility

The key roles of thyroid hormones in male fertility include regulation of hormonal balance and impact on sperm quality indices such as sperm count, sperm motility, and sperm morphology, as well as sexual function. The implications of thyroid dysfunction are hypothyroidism and hyperthyroidism. Elevated thyroid hormone levels can cause oxidative stress, damaging sperm cells and affecting their motility.

The relationship between thyroid hormone levels and semen quality in humans remains in adequately understood.Thisphenomenon may arise from both direct impacts on sperm cells and indirect effects on non-germ cells. Research on thyrotoxic rats indicates a decrease in mitochondrial activity within sperm and alterations in antioxidant defenses. Furthermore, spermatogenesis is notably delayed (Romano et al., 2017). Additionally, hyperthyroid conditions have been shown to shorten the proliferative phase of neonatal Sertoli cells (La Vignera & Vita, 2018). Conversely, a deficiency in thyroid hormones has been associated with diminished sperm vitality and prolonged

transit times for sperm through the epididymis. Furthermore, both hyperthyroidism and hypothyroidism are associated with altered macroscopic characteristics of seminal fluid, such as reduced volume because of reduced secretory activity of accessory glands (La Vignera & Vita, 2018). Both thyroid hyper-and hypo-function have been linked to alterations in spermatogenesis, semen quality, sexual hormone levels, and erectile function. Nevertheless, the extent to which thyroid dysfunction contributes to male infertility remains inadequately defined (Patel & Kashanian, 2016).

Thyroid hormones may also play a role in male fertility during both prenatal and postnatal stages. Research indicates that hypothyroidism can result in hypergonadotropic hypogonadism, a condition linked to testicular involution, which subsequently leads to diminished sperm quality and changes in normal morphology. However, the mechanisms and the degree to which these factors affect fertility remain to be established. Evidence of altered semen parameters correlated with hypothyroidism has been presented in terms of sperm count, motility, and morphology (Anelli et al., 2024). However, it is important to understand that hypothyroidism can impair pulsatile secretion of GnRH by prolactin increase, leading to hypogonadotropic hypogonadism (Koyyada & Orsu, 2020). It is established that chronic hypothyroidism may lead to pituitary hyperplasia, which can be reversed through L-T4 therapy. However, men with primary hypothyroidism rarely show increased serum prolactin levels. Nonetheless, it is essential to evaluate prolactin levels in all patients with hypothyroidism to rule out the possibility of secondary hypogonadotropic hypogonadism (Poppe et al., 2018).

A potential link has been observed between thyroid hormone dysfunction and male fertility, as evidenced by studies conducted on both animal models and human subjects. Nevertheless, the specific impact on the pituitary–testicular axis, as well as on gonadal structure, function, and sexual behavior, remains inadequately understood. Indeed, certain researchers have suggested that thyroid hormones may not play a significant role in male reproductive health (Brown et al., 2023).

Research conducted on animal models indicates that thyroid dysfunction may lead to compromised sexual behavior. Numerous studies have established that hypothyroidism results in hypergonadotropic hypogonadism in rats, a condition that can be ameliorated through the administration of L-T4 therapy. The most convincing explanation suggests that hormonal and testicular impairment is due to testicular oxidative stress, DNA damage, and apoptotic activity (Asadi et al., 2017). In hypothyroid mice, reduced libido is observed along with a significant decrease of daily and total sperm production, as well as altered sperm characteristics compromising the fertilization process (Anelli et al., 2024). These data were recently confirmed by Panahandeh et al. showing that hypothyroidism directly impairs semen parameters, whereas maternal hypothyroidism has no significant effect on gonad function in offspring (Panahandeh et al., 2022). The existing evidence regarding the connection between hyperthyroidism and fertility is limited. Studies conducted on animal models indicate that thyrotoxicosis may lead to changes in gonadotropin levels and induce oxidative stress in the testes; however, the precise effects of these factors on fertility remain to be established.

IMPORTANCE OF UNDERSTANDING THE RELATIONSHIP BETWEEN THYROID DYSFUNCTION AND MALE INFERTILITY

Understanding the complex link between thyroid dysfunction and male reproduction is important for a number of reasons. Early detection of thyroid dysfunction may lead to timely treatment, improving fertility outcomes, as well as prompt intervention that may restore normal thyroid hormone levels, leading to improved sperm quality and function (Ferreira et al., 2020).

Addressing underlying thyroid issues may enhance fertility treatment. Success among subjects undergoing assisted reproductive technologies (ART) such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). This may optimize thyroid hormone levels, which is important for improving sperm quality and enhancing fertilization potential (Rao et al., 2021). Also, understanding the link between thyroid dysfunction and male infertility may facilitate better reproductive health. People can have better overall reproductive health, including more libido and sexual function, via diagnosing and treating thyroid problems (Jafleh et al., 2024). Addressing thyroid problems may enhance fetal growth and help avoid pregnancy difficulties. It may also mitigate progress in medical research and improve therapies and preventative measures that may result from increased investigation into the processes via which thyroid disease impacts male fertility. It can assist in finding certain biomarkers linked to infertility caused by the thyroid, which can be used for early diagnosis and focused treatments (Adamska et al., 2021). By knowing how often thyroid dysfunction is occurring in infertile males, screening initiatives and public health policies can be improved. Finally, couples facing infertility due to thyroid dysfunction can benefit from counseling and support to help them cope with the emotional challenges associated with this condition (Sorkhani et al., 2021).

THYROID HORMONES AND MALE REPRODUCTIVE FUNCTION

Role of thyroid hormones in regulating male reproductive hormone

Thyroid hormones have been recognized for their potential influence on male reproductive functions through various mechanisms, a topic that has garnered research interest over the past several decades. Nevertheless, the precise pathways through which thyroid hormones contribute to male infertility remain unclear (Ahmed et al., 2019). These hormones play a crucial role in regulating the reproductive system, functioning as signaling molecules that circulate in the bloodstream to target organs, thereby influencing physiological processes and their associated functions. The hormones most pertinent to the male reproductive system are those that participate in the HPG axis. In response to various stimuli, the anterior pituitary gland secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently act on testicular cells to modulate both steroidogenesis and spermatogenesis. In fact, steroidogenesis, namely the production of testosterone, is crucial for the normal occurrence of spermatogenesis and for feedback actions to the pituitary and hypothalamus (Maria & Ana, 2017).

Spermatogenesis and Sertoli cells play a crucial role in regulating the HPG axis by producing activin and inhibin B, which, in conjunction with testosterone, provide feedback to the brain. Recent research has revealed additional factors influencing male reproductive function, particularly the recognition of adipose tissue as an endocrine organ that secretes hormones potentially significant to this regulatory process. Furthermore, gut hormones, which are involved in maintaining nutrient balance, also affect the activity of testicular cells. Notably, these interactions have often been identified in the context of metabolic disorders such as hyperthyroidism, hypothyroidism, obesity, and diabetes mellitus (Maria & Ana, 2017).

The presence of thyroid hormone receptors (TRs) in the mammalian testis, particularly in Leydig cells, suggests both direct and indirect actions of thyroid hormones on testicular function (Hernandez, 2018). The regulatory functions of thyroid hormones exhibit complexity, are specific to different species, and vary according to developmental stages. Neonatal hypothyroidism was shown to impair testicular growth and sperm production in rats (de Franca et al., 1995), hamsters (Mesocricetus auratus) (Jansen et al., 2007), and juvenile teleost fish (Oreochromis niloticus) (Rodrigues et al., 2022).

Epithelial cells from various segments of the rat epididymis, specifically the caput, corpus, and cauda, exhibit the presence of TRs. Notably, these receptors differ from classical TRs as they are primarily localized in the cytoplasm of the epithelial cells within the epididymis. Both TR$\alpha$1 and TR$\beta$1 isoforms are found in all three segments. In hypothyroid rats, there is a marked increase in both the protein and mRNA levels of these TR isoforms. Additionally, TR$\beta$1 has been detected on the nuclear membrane of the PZ HPV-10 cell line, which is derived from prostatic tissue (Kumar et al., 2014).

Thyroid hormones influence semen quality through the modulation of serum testosterone levels. Additionally, these hormones play a role in regulating the components of seminal plasma, including calcium, fructose, magnesium, and zinc. By ensuring the proper levels of these constituents, thyroid hormones contribute to the regulation of various seminal characteristics, such as sperm motility, viability, and overall semen volume. Moreover, a sufficient amount of testosterone promotes spermatogenesis and maintains sperm count (Sengupta & Dutta, 2018). Testosterone, together with the seminal components, also regulates semen parameters like sperm motility and sperm morphology (Kumar et al., 2014). Thyroid hormones clearly influence the HPG axis by facilitating interactions between the HPG and the hypothalamic–pituitary–thyroid (HPT) axis. It may also directly act either individually or in combination with FSH and/or LH on male reproductive tissues to exert their modulatory actions upon gonadal development, testosterone synthesis, and spermatogenesis, thereby accentuating the semen quality (Sengupta & Dutta, 2018).

IMPACT OF HYPOTHYROIDISM AND HYPERTHYROIDISM ON TESTICULAR FUNCTION

Thyroid hormone has been identified as a crucial factor in the proliferation and functionality of Sertoli and Leydig cells, significantly impacting spermatogenesis, sperm motility, and overall fertility. Disruption of the normal euthyroid condition adversely affects both the morphological and functional maturation of the testes. Furthermore, thyroid hormone is believed to play a role in facilitating normal spermatogenesis and metabolic activities within the adult testis; however, these mechanisms remain inadequately elucidated at this time. Nevertheless, despite the gaps in our knowledge, the data herein reviewed may provide considerable evidence to conclude that thyroid hormone plays an important role in human testicular development and function (Wagner et al., 2008).

The human testes serve two primary roles: the synthesis of androgens and the process of spermatogenesis. Specifically, Leydig cells produce androgenic hormones, testosterone, androstenedione, and deidroepiandrosterone, whereas Sertoli cells promote spermatogenesis and release androgen-binding protein (ABP) under FSH stimulation (Defeudis et al., 2022).

Thyroid hormones exert their effects by binding to nuclear receptors that are present in Sertoli cells and Leydig cells, thereby influencing spermatogenesis. This influence is mediated through the regulation of gene transcription, protein synthesis, cellular proliferation, and differentiation. Under physiological conditions, T3 inhibits Sertoli cell proliferation and promotes maturation, essential for spermatogenesis (Mazzilli et al., 2023). Thyroid hormones act on the testis in multiple ways and exert their effect on different cell types, including Leydig and Sertoli cells and germ cells (La Vignera & Vita, 2018).

EFFECTS OF THYROID DYSFUNCTION ON SPERM QUALITY AND QUANTITY

Although the effects of hyperthyroidism and hypothyroidism on female reproduction are well established, the effects of thyroid disorders on male infertility have not been extensively studied, most likely because attention in thyrotoxic males is usually focused on other manifestations of the disease, and fertility status is frequently not evaluated (Ahmed et al., 2019; Emokpae et al., 2024). Thyroid hormones interfere with both androgen biosynthesis and spermatogenesis, either directly on Leydig and Sertoli cells or indirectly by modulating gonadotropin secretion (Castañeda et al., 2014).

The ideal level of intratesticular testosterone is essential for facilitating spermatogenesis. Thyrotoxicosis may lead to conditions such as oligozoospermia, asthenozoospermia, and/or teratozoospermia, in addition to a reduction in seminal volume (Rao et al., 2023). Furthermore, hypothyroidism has been linked to lower serum testosterone levels, which can result in ED, delayed ejaculation (DE), diminished sexual desire, and compromised sperm quality (Rao et al., 2023). Therefore, a comprehensive understanding of the interplay between thyroid function and sperm quality is crucial for the development of effective preventive therapeutic strategies for male infertility. Extensive research is required to reveal the role of thyroid function and its disorders in the maintenance and deterioration of male infertility and to draw more reliable conclusions that can be used in clinical practice (Rao et al., 2023).

Although smoking, obesity, and infection all reduce fertility by lowering sperm count, motility, and changing the morphology of sperm, a significant relationship between TSH and seminal volume and motility has been reported. These findings suggest that normal thyroid function is vital for good sperm quality (Rao et al., 2023).

Thyroid dysfunction results in various changes in semen quality, which encompass decreased volume, lower sperm density, diminished sperm motility, and altered sperm morphology. Particularly, concerning conventional parameters of the seminal fluid, hyperthyroidism causes hypospermia, oligozoospermia, asthenozoospermia, and teratozoospermia, whereas hypothyroidism is associated more frequently with teratozoospermia (La Vignera et al., 2017; La Vignera & Vita, 2018).

Research has shown that mitochondrial activity in sperm is diminished and the antioxidant defense system is modified in rats with thyrotoxicosis. Spermatogenesis is also delayed, while the neonatal Sertoli cell proliferative period is shortened under hyperthyroid conditions (Rijntjes et al., 2017; Romano et al., 2017). Conversely, thyroid hormone deficiency reduces sperm vitality and delays sperm transit through the epididymis (Romano et al., 2017). Furthermore, both hyperthyroidism and hypothyroidism are associated with altered macroscopic characteristics of seminal fluid, such as reduced volume because of reduced secretory activity of accessory glands (La Vignera & Vita, 2018).

MECHANISM OF THYROID-INDUCED MALE INFERTILITY: HORMONAL INTERACTIONS BETWEEN THE THYROID AND REPRODUCTIVE AXES

The regulation of male reproduction is primarily controlled by the traditional hypothalamo–hypophyseal–testicular axis, which involves the hypothalamic release of gonadotropin-releasing hormone (GnRH), the secretion of LH and FSH from the pituitary gland, and the production of gonadal steroids, with testosterone being the principal hormone involved. Thyroid hormones have been shown to exert a modulatory influence on this axis and consequently the sexual and spermatogenic function of man (Kumar et al., 2014).

Thyroid hormones have a significant impact on the development of vertebrate species, influencing nearly every biological endocrine system. Research indicates that thyrotrophins are involved in sexual differentiation and gonadal development across both mammalian and non-mammalian species. While substantial evidence suggests that the effects of thyroid hormones on reproductive development are primarily mediated through the female hormonal axis, recent studies indicate a more direct interaction between thyroid hormones and the androgen axis. These findings highlight the considerable role of thyroid hormones in the sexual development of male vertebrates, facilitated by direct interactions with specific sex-determining genes and the regulation of gonadotropin production within the HPG axis. Thyroid hormones also regulate androgen biosynthesis and signaling through direct and indirect regulation of steroidogenic enzyme expression and activity (Diana et al., 2021).

The two primary roles of the testes are the production of androgens and the process of spermatogenesis. Specifically, Leydig cells produce androgenic hormones: testosterone, androstenedione, and deidroepiandrosterone, whereas Sertoli cells promote spermatogenesis and release ABP under FSH stimulation (Defeudis and Pieralice, 2020). Thyroid hormones have their nuclear receptors expressed within the testis (Mazzilli et al., 2023).

Under normal physiological conditions, T3 acts to inhibit the proliferation of Sertoli cells while simultaneously promoting their maturation, a process that is crucial for spermatogenesis (Mazzilli et al., 2023). Specifically, TRs are located on the Sertoli cells in the seminiferous tubules, and it is believed that T3 binds directly to these receptors (Singh et al., 2011). Sertoli cells are the first somatic cells to differentiate in the testis, and they support and nurture sperm during spermatogenesis. TR on Sertoli cells can mediate the possible role, if any, of thyroid hormones in sperm production. More specifically, a particular interest has grown concerning the effects of thyroid disease such as hyperthyroidism and hypothyroidism on spermatogenesis and overall male fertility (Singh et al., 2011).

Hyperthyroidism is characterized by increased circulating T4 levels, compromised responsiveness of LH and FSH, and altered endocrine profiles, all of which result in impaired testicular functions, morphology, reduced seminiferous tubule diameter, delayed spermatogenesis, stunted sperm development, and reduced sperm motility (Ahmed et al., 2019). Disruptions in male reproductive functions due to hyperthyroidism result in reduced sperm count and compromised semen quality. The alterations in the redox status of the testes, particularly affecting Leydig cells, Sertoli cells, and germ cells, along with impaired mitochondrial function in sperm, significantly diminish sperm count, vitality, and motility, ultimately leading to a decline in semen quality (Sengupta & Dutta, 2018).

On the other hand, hypothyroidism, which is characterized by decreased levels of T3 and T4, may lead to lower concentrations of sex hormone-binding globulin (SHBG) and serum testosterone, thereby adversely affecting spermatogenesis. Prolonged thyroid insufficiency during childhood or puberty can inhibit the secretion of pituitary gonadotropins, which in turn hampers gonadal development and function, disrupts the secretory activities of accessory glands, and may contribute to ED, DE, and reduced libido, all of which further compromise semen quality. Additionally, it results in a reduction in the diameter of seminiferous tubules and the overall organ weight of the testes, epididymis, and prostate gland, leading to impaired sperm development, motility, and transport through the epididymis. Sperm vitality may also get affected in conditions of hypothyroidism owing to the induction of testicular oxidative stress (Sengupta and Dutta, 2019).

The thyroid is an integral component of the HPT axis. The anterior pituitary gland produces TSH. Thyrotropin-releasing hormone (TRH) from the hypothalamus interacts with its receptors in the pituitary gland to regulate the secretion of TSH. Subsequently, TSH attaches to the TSH receptor on the epithelial cells of the thyroid, prompting the thyroid gland to release T3 and T4 hormones. This is named as HPT axis (Singh et al., 2011). Fluctuations in the levels of circulating thyroid hormones trigger subsequent effects on the synthesis, secretion, circulation, metabolism, and physiological actions of androgen hormones. The HPG axis plays a crucial role in regulating androgen signaling and biosynthesis. Originating from the hypothalamus, GnRH regulates the biosynthesis and secretion of the gonadotropins: LH and FSH, which are largely responsible for gonadal formation and maintenance of the gonadal (Diana et al., 2014). The neuron responsible for releasing TRH is strategically situated to assimilate data regarding environmental conditions and circulating levels of thyroid hormones, thereby influencing metabolism in reaction to these physiological alterations.

OXIDATIVE STRESS AND THYROID DYSFUNCTION

The physiological function of reactive oxygen species (ROS) in the synthesis of thyroid hormones is well established. However, dysregulation of ROS levels is observed in both hyperthyroidism and hypothyroidism, presenting potential pharmaceutical targets for various medications. Additionally, an overproduction of ROS, stemming from either decreased elimination or increased generation, may play a significant role in the carcinogenesis of thyroid cancer by activating numerous signaling pathways. The molecular mechanisms linked to ROS-related thyroid disorders have been thoroughly summarized. Several risk factors, such as radiation exposure in the development of thyroid cancer, are associated with ROS generation (Periyasamy et al., 2022).

ROS are crucial for the proper functioning of the thyroid gland. Thyroid cells produce oxidases that facilitate the generation of ROS (Kochman et al., 2021). Additionally, inositols contribute to the synthesis of thyroid hormones and the maintenance of normal thyroid activity by initiating a series of processes. These processes include the regulation of TSH-dependent signaling, acting as a transmitter for TSH, and the production of hydrogen peroxide (H₂O₂), which is essential for the iodination and coupling of iodotyrosine and iodothyronine. Inositol deficiency or impairment of inositol cascades may result in insufficient synthesis of thyroid hormones, leading to hypothyroidism, which may be further compounded by an increased need for inositols in response to high TSH levels (Kochman et al., 2021). Myo-inositol supplementation in individuals with hypothyroidism significantly reduces TSH levels. Its effect has been demonstrated in combination with metformin and selenium compared to treatment without inositol (Morgante et al., 2013; Pace et al., 2020).

The synthesis of T4 and T3 catalyzed by TPO in thyroid follicles is a very complex process involving ROS, notably, H₂O₂ (Thana et al., 2020). ROS are already essential in the initial stages of thyroid hormone production, during iodide oxidation (Kochman et al., 2021). Additionally, thyroid hormones perform a metabolic regulatory function by affecting mitochondrial activity (Venditti et al., 2003).

Because of the reliance on ROS in its function, the thyroid is particularly exposed to oxidative damage (Singh et al., 2011). Therefore, the antioxidant defense system of the thyroid must effectively regulate ROS production and scavenging (Ameziane et al., 2020; Rostami et al., 2013). THs are associated with oxidative stress and antioxidant status due to their capacity to accelerate the basal metabolism and change respiratory rate in mitochondria (Sepasi et al., 2018). However, thyroid hormones are related to oxidative stress not only by their stimulation of metabolism but also by their effects on antioxidant mechanisms (Angela et al., 2015). These regulate proteins, vitamins, and antioxidant enzymes synthesis and degradation, as well as oxygen consumption and mitochondria energy metabolism, playing an important role in free radical production (Torun et al., 2009).

It has been suggested that variations of thyroid hormone levels can be one of the main physiological modulators of in vivo cellular oxidative stress (Campos et al., 2016; Kochman et al., 2021). Redox homeostasis requires an equilibrium of ROS production and scavenging (Irazabal et al., 2020). Even though the concept of oxidative stress was introduced in the 1980s, its definition and scope of research have been continually elaborated and expanded (Sies et al., 2015).

Thyroid hormones exhibit a pro-oxidant effect, leading to an increase in lipid peroxidation. This process is highly detrimental and is associated with numerous diseases, potentially serving as a causative factor for the diverse systemic manifestations of hyperthyroidism, such as myopathy and myocardial insufficiency. The functions of antioxidant scavenging enzymes, including erythrocyte superoxide dismutase, catalase, and glutathione peroxidase, which play a crucial role in preventing lipid peroxidation, are significantly influenced by both hyperthyroidism and hypothyroidism. Additionally, various studies have indicated that hypothyroidism induces alterations in free radical scavenging enzymes that are contrary to those seen in hyperthyroidism. Consequently, oxidative injury is intensified in the context of thyroid dysfunction.

CLINICAL MANIFESTATION OF THYROID DYSFUNCTION IN MEN

Symptoms of hypothyroidism and hyperthyroidism in men

Hypothyroidism is characterized by a range of symptoms, which may include weight gain, fatigue, constipation, intolerance to cold, cognitive impairment, dry skin, swelling, muscle pain, and irregular menstrual cycles. Conversely, hyperthyroidism manifests in both males and females through symptoms such as increased appetite accompanied by weight loss, intolerance to heat, tremors, palpitations, emotional instability, and anxiety. The severity of these conditions can vary, spanning from subclinical presentations to overt disease, including acute thyrotoxicosis. Infertility, gynecomastia, and/or ED should also prompt an investigation into thyroid abnormalities (Cripps et al., 2024). Hyperthyroidism is characterized by elevated levels of total thyroxine (T4), which correlates with an increase in the circulation of SHBG and a reduction in the metabolic clearance rate of testosterone.

In males with hyperthyroidism, bioavailable testosterone levels are often found to be below normal, accompanied by heightened levels of circulating estradiol (E2). This condition may lead to gynecomastia, diminished libido, and ED. Additionally, research has indicated that the responses of LH and FSH to GnRH administration are significantly amplified in hyperthyroid males. Altered reproductive hormone levels affect sperm production and maturation, thus altering semen quality (Sengupta & Dutta, 2018). Hyperthyroidism is associated with an increase in SHBG levels and increased bound testosterone, along with decreased free testosterone in blood due to the fact that most of the testosterone is bound to binding molecules (Ahmed et al., 2019).

Men diagnosed with thyrotoxicosis exhibit elevated levels of SHBG and total testosterone, while maintaining normal levels of free testosterone. Additionally, there is a decrease in the testosterone clearance rate and the ratio of free testosterone to estradiol, attributed to increased concentrations of both total and free estradiol. Hyperthyroidism predominantly affects the metabolism of androgens and estrogens. It is characterized by increased circulating T4 levels, compromised responsiveness of LH and FSH, and altered endocrine profile, all of which result in impaired testicular functions, morphology, reduced seminiferous tubule diameter, delayed spermatogenesis, stunted sperm development, and reduced sperm motility (Ahmed et al., 2019).

Conversely, hyperthyroidism leads to the inhibition of Sertoli cell proliferation, adversely affecting spermatogenesis and resulting in a decrease in testicular volume. Additionally, hyperthyroidism is linked to a decline in seminal volume, motility, and morphology, along with a reduction in semen volume. Various studies have documented the impact of hyperthyroidism on semen parameters (Mazzilli et al., 2023).

Hyperthyroidism is characterized by increased circulating T4 levels, compromised responsiveness of LH and FSH, and altered endocrine profile, all of which result in impaired testicular functions, morphology, reduced seminiferous tubule diameter, delayed spermatogenesis, stunted sperm development, and reduced sperm motility (Ahmed et al., 2019). These disruptions in male reproductive functions cause low sperm count and deteriorated semen quality in hyperthyroid men. Hyperthyroidism-induced changes in the redox status of the testis, in the Leydig cells, Sertoli cells, and germ cells, as well as impaired sperm mitochondrial activities, severely affect sperm count, vitality, and motility, thereby deteriorating semen concentration (Sengupta & Dutta, 2018). Additionally, elevated levels of thyroid hormones may lead to sperm DNA damage and infertility. In fact, increased concentrations of T3 and T4 are associated with a rise in ROS, which in turn contributes to oxidative stress (Mazzilli et al., 2023).

In humans, the excess of circulating thyroid hormones that are found during thyrotoxicosis is reported to result in asthenozoospermia in more than half of patients (La Vignera & Vita, 2018). Approximately 40% of patients exhibit oligozoospermia and teratozoospermia. These abnormalities are frequently associated with a reduced seminal volume thus, reduced sperm density, motility, and morphology, together with an overall decrease in sperm concentration, are the main semen alterations of thyrotoxic male patients (La Vignera & Vita, 2018).

IMPACT OF THYROID DYSFUNCTION ON SEXUAL FUNCTION AND LIBIDO

The ejaculatory process is controlled by thyroid hormones as well as a number of other metabolic hormones. As a result, hypothyroidism has been linked to DE. Conversely, hyperthyroidism is linked to premature ejaculation (PE) (Corona et al., 2012). Hypoactive sexual desire, ED, and DE were shown to be more common in hypothyroid individuals (64.3%) in a multicenter study to determine the incidence of sexual dysfunctions in patients with thyroid diseases. Compared to their hypothyroid counterparts (7.1%), hyperthyroid individuals had a greater rate of PE (50.0%). Subsequent normalization of the thyroid hormone levels in hyperthyroid patients, PE was declined to 15%, while DE was improved in half of the treated hypothyroid male patients (Ahmed et al., 2019). A significant difference between patients and controls was found in another survey that used the Sexual Health Inventory for Males (SHIM) to examine the effects of thyroid dysfunctions on male sexual health. 78.9% of patients with thyroid dysfunctions scored 21 or lower (normal SHIM: 22–25), compared to 33.8% of controls. However, both hyperthyroid and hypothyroid patients showed a substantial rise in SHIM ratings after therapy ($P<0.0001$). Also, a high prevalence of ED was noted in patients with hyperthyroid and hyperthyroid patients, compared to controls (Krasses et al., 2008).

Sperm motility and morphology may be impacted by hypothyroidism, which might raise the incidence of the teratozoospermia index. Sperm count, sperm motility, and morphology, and the longitudinal diameters of seminal vesicles were shown to differ significantly among patients with hypothyroidism. Reduced sperm production, viable spermatozoa in the epididymis, and testicular germ cell count were seen in rodent models of induced hypothyroidism. It also reduces gonadal androgen receptor expression (sperm motility, fertilizing capacity, and epididymal secretory activity) (Ahmed et al., 2019).

Furthermore, it may affect the mitochondria, such as alteration of mitochondrial lipid peroxidation apoptotic changes in epididymal mitochondria, reduction in acrosome integrity, and mitochondrial activity (Mazzilli et al., 2023). Moreover, an increase in the expression of thyroid hormone receptors (Thra1) and a decrease in the expression of deiodinases (Dio3) were associated with hypothyroidism, suggesting a critical metabolic role of thyroid hormones in spermatogenesis (Romano et al., 2017).

Hypothyroidism and hyperthyroidism have been reported to impair libido in men and women; however, evidence of the impact of hypothyroidism on male libido is mixed (Gabrielson et al., 2019). Significant disruptions in both male and female sexual dysfunction (FSD) have been linked to thyroid issues. Male sexual dysfunction is a very common and complex problem with several underlying causes. From a male viewpoint, sexual dysfunction may be divided into three categories: reduced libido, ejaculatory abnormalities, which include PE and DE, and ED. PE is the most prevalent male sexual disorder, that occurs in 20%–30% of men during their lifetime. ED is another common male sexual dysfunction, which is a highly age-dependent issue, reported to be 18% for the age range of 50–59 years, increasing up to 37% for ages 70–75 years (Cripps et al., 2024). An estimated 5%–15% of men experience diminished libido, many of whom reported concomitant deterioration in other domains of sexual functioning (Gabrielson et al., 2019).

DIAGNOSIS AND MANAGEMENT OF THYROID DYSFUNCTION IN MEN WITH INFERTILITY

Diagnostic tests for thyroid dysfunction

Serum TSH levels are usually measured as part of a diagnostic workup, coupled with free T4 and/or T3. Low free T4 and/or T3 plus a high serum TSH ($>5.0$mU/L) can confirm a probable diagnosis of hypothyroidism. TSH is usually repressed ($<0.4$mU/L) while free T4 and/or T3 are elevated in hyperthyroidism. Findings from a physical examination might also be useful in determining the cause of a patient’s thyroid condition. Note that abnormal increases or reductions in blood TSH without corresponding changes in free T4 or T3 levels might indicate subclinical thyroid dysfunction. Subclinical thyroid dysfunction can still have a detrimental effect on sexual function in patients, and as such, sexual medicine clinicians may consider screening for thyroid disease in otherwise asymptomatic patients presenting with sexual symptoms (Gabrielson et al., 2019).

Blood levels of T3, T4, and TSH are measured by thyroid function testing. They are essential for both identifying thyroid issues and distinguishing between the primary and secondary causes of thyroid illness. A secondary issue arising in the anterior pituitary is indicated by a change in TSH that coincides with variations in T3 and T4. In contrast, a TSH change that follows the opposite direction of T3 and T4 suggests a problem in the thyroid gland itself (Calsolaro et al., 2019).

Treatment options for thyroid dysfunction

Guidelines for treating thyroid illness are clear. Synthetic T4 replacement therapy is the main treatment for hypothyroidism until the patient is euthyroid, which may take up to 4–6 weeks before changes in hormone levels become apparent. Modalities for treatment of hyperthyroidism include radioactive iodine, various anti-thyroid medications, and thyroidectomy (Gabrielson et al., 2019). Although treating a patient’s thyroid condition may also help with their sexual dysfunction, a number of the aforementioned studies found that sexual dysfunction is a substantial burden among individuals with thyroid dysfunction. Prompt treatment of a patient’s thyroid disease may reduce or eliminate the need for therapies targeting sexual dysfunction (Cripps et al., 2024).

Impact of thyroid treatment on male infertility

Several options exist to treat hyperthyroidism: radioiodine ablation (RAI), surgical thyroidectomy, or antithyroid drug (ATD) therapy (Alexander et al., 2017). There is limited evidence linking the treatment of hypo-and hyperthyroidism to an improvement in testis function. What is currently well established is that treatment of hyperthyroidism, restoring normal or high normal level of T4, improves seminal parameters (Mintziori et al., 2016).

FUTURE DIRECTIONS IN THYROID DYSFUNCTION AND MALE REPRODUCTIVE HEALTH

Significant advancements have been achieved in elucidating the connection between thyroid dysfunction and male reproductive health; however, four primary domains necessitate further exploration. These domains encompass comprehensive molecular investigations, clinical applications alongside personalized medicine, the influence of environmental factors and lifestyle changes, and the development of innovative therapeutic strategies. A more profound examination of the molecular mechanisms that govern the effects of thyroid hormones on testicular function, sperm maturation, and hormonal regulation is needed. Additionally, it is important to investigate the distinct roles of various TR isoforms within the male reproductive system.

The potential epigenetic ramifications of thyroid dysfunction on male reproductive health also merit thorough investigation. There is a need for the creation of sensitive biomarkers and diagnostic instruments aimed at the early identification of thyroid dysfunction in men experiencing fertility challenges, alongside the formulation of customized treatment strategies. It is advisable to implement personalized treatment regimens that take into account individual patient characteristics, including genetic predispositions and specific thyroid hormone profiles. Furthermore, conducting longitudinal studies to evaluate the enduring effects of thyroid hormone replacement therapy on male reproductive health is of paramount importance.

The influence of environmental factors and lifestyle modifications warrants careful examination. Investigating how environmental pollutants affect thyroid function and male reproductive health could illuminate factors that exacerbate thyroid dysfunction in men. Additionally, the potential advantages of specific dietary interventions, such as iodine supplementation and diets rich in antioxidants, should be assessed in relation to enhancing male reproductive health amid thyroid dysfunction. The impact of lifestyle elements, including stress, sleep patterns, and physical activity, on thyroid function and male fertility also requires thorough evaluation.

Lastly, the exploration of novel therapeutic approaches, including targeted therapies, combination therapies, and stem cell treatments, should be prioritized. The development of targeted therapies that specifically address the underlying mechanisms of thyroid dysfunction in the context of male reproductive health is essential.

CONCLUSION

Thyroid function significantly influences the development of the testes, spermatogenesis, and male fertility, indicating that an abnormal thyroid profile can adversely affect semen quality and potentially result in infertility. Optimal male sexual function necessitates a normal libido, a fully functional HPG axis, adequate neurovascular supply to the genital region, and appropriate levels of sex hormones. Recent studies, including those reviewed here, indicate that dysregulation of the thyroid axis is a critical factor in sexual dysfunction, which warrants serious consideration. Unfortunately, there is a lack of well-structured research that elucidates the prevalence, pathophysiological mechanisms, and outcomes for patients experiencing sexual dysfunction due to thyroid disorders.

Various studies have documented the impact of both hypothyroidism and hyperthyroidism on semen quality and quantity. Notably, treatment for thyroid dysfunction has been shown to enhance both semen quality and fertility outcomes. Evidence indicates a correlation between teratozoospermia and free T4 levels, with improvements in sperm morphology observed following replacement therapy. Therefore, it is essential to monitor thyroid function in both males and females within couples attempting to conceive naturally or through ART, as timely treatment is likely to enhance the likelihood of successful outcomes.

CONFLICT OF INTEREST

None declared.

ORCID

Mathias Abiodun Emokpae  https://orcid.org/0000-0002-6266-1774

Elizabeth Moyinoluwa Babatunde  https://orcid.org/0009-0001-9511-4224