Endocrine and Molecular Mechanisms Linking Thyroid Dysfunction to Male and Female Infertility

Infertility is a significant global reproductive health concern, affecting approximately 8–12% of couples, with male factors contributing to nearly 50% of cases overall^[2]. Increasing evidence highlights the strong association between infertility and endocrine disorders, among which thyroid dysfunction is one of the most common and clinically relevant abnormalities in both women and men.^[¹?³^]

Thyroid hormones play a crucial role in regulating reproductive physiology through their interaction with the hypothalamic–pituitary–ovarian (HPO) axis in females and the hypothalamic–pituitary–gonadal (HPG) axis in males. They influence key processes such as menstrual cyclicity, follicular development, ovulation, endometrial receptivity, spermatogenesis, and steroidogenesis.^[6,3] Thyroid dysfunction—both hypothyroidism and hyperthyroidism—can disrupt these processes, leading to impaired fertility outcomes in both sexes.The burden of thyroid abnormalities among infertile individuals is considerable. In women, thyroid dysfunction is reported in 15–25% of infertile cases in Asian populations, with prevalence in India ranging from 20–26%, predominantly hypothyroidism.^{[3,4,8 ]}Autoimmune thyroid disease, particularly Hashimoto’s thyroiditis, is also common and has been associated with unexplained infertility, recurrent pregnancy loss, and reduced success rates of assisted reproductive technologies.^[2,8,33] In men, thyroid dysfunction has been linked to alterations in semen parameters, including reduced sperm concentration, motility, and abnormal morphology [1], with prevalence among men with sexual dysfunction ranging from 3.4% to 57.1% ^4].Emerging evidence suggests that oxidative stress may serve as a key unifying mechanism linking thyroid dysfunction and infertility. Thyroid hormone imbalance disrupts cellular metabolism and mitochondrial function, leading to excessive production of reactive oxygen species (ROS), which adversely affect oocyte quality, spermatogenesis, embryo development, and endometrial receptivity.^[5,6]This review aims to synthesize current evidence on thyroid dysfunction and infertility, focusing on its epidemiology, clinical impact, and therapeutic implications. It emphasizes the importance of early diagnosis and appropriate management of thyroid disorders to improve reproductive outcomes in both females and males.

Physiology of Thyroid Hormones and Their Role in Reproduction

Hypothalamic–Pituitary–Thyroid Axis: Basic Physiology

The hypothalamic–pituitary–thyroid (HPT) axis is a multi-level regulatory system responsible for maintaining metabolic homeostasis and energy balance. The axis begins at the hypothalamus, which secretes thyrotropin-releasing hormone (TRH) in response to metabolic and energy-sensing signals such as leptin, neuropeptide Y, and agouti-related peptide.⁹TRH stimulates thyrotropic cells in the anterior pituitary gland to release thyroid-stimulating hormone (TSH). TSH then acts on the thyroid gland to stimulate the synthesis and secretion of the thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4).¹⁰Once released into circulation, T3 and T4 are transported bound to plasma proteins, mainly thyroxine-binding globulin, transthyretin, and albumin. Although T4 is produced in larger quantities by the thyroid gland, it is considered a prohormone and must be converted into the biologically active hormone T3 within peripheral tissues. This conversion occurs through the action of deiodinase enzymes type 1 and type 2.¹¹(figure 1) Alternatively, T4 may be converted into reverse T3, an inactive metabolite, by deiodinase type 3. This peripheral conversion provides fine regulation of thyroid hormone action and prevents excessive T3 activity.¹¹At the cellular level, thyroid hormones enter target cells through specific transporters such as monocarboxylate transporter 8 and monocarboxylate transporter 10, or by passive diffusion. Inside the cell, T3 binds to thyroid hormone receptors located in the nucleus. These receptors form a heterodimer with the retinoid X receptor and regulate gene transcription by interacting with coactivator proteins. In the absence of T3, the thyroid hormone receptor–retinoid X receptor complex binds to corepressor proteins, suppressing gene transcription. T3 and T4 also exert negative feedback control at the hypothalamic and pituitary levels, inhibiting further release of TRH and TSH, thereby maintaining hormonal balance.¹²

Thyroid Hormones and Female Reproductive Physiology

Interaction Between the Thyroid Axis and the Hypothalamic–Pituitary–Gonadal Axis

Reproductive function is regulated by the hypothalamic–pituitary–gonadal (HPG) axis, which integrates signals related to energy balance, stress, and homeostasis. The central reproductive system receives input from metabolic signals such as glucose, insulin, insulin-like growth factor-1, and leptin; stress-related mediators such as glucocorticoids and corticotropin-releasing hormone; and thyroid hormones.¹³

Many of these signals are processed by kisspeptin–neurokinin B–dynorphin neurons, which play a critical role in initiating reproductive hormone secretion. These neurons release kisspeptin, which stimulates pulsatile secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons. GnRH then triggers the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. LH and FSH act on the theca and granulosa cells of the ovary to regulate folliculogenesis and the synthesis of sex steroids and peptides.¹³Thyroid hormones and related hormones such as TRH, TSH, T3, and T4 exert facilitatory and modulatory effects at multiple levels of the HPG axis.¹²

Role of Thyrotropin-Releasing Hormone in Reproduction

Thyrotropin-releasing hormone primarily regulates the HPT axis but also indirectly influences reproductive function.¹⁴ In primary hypothyroidism, increased TRH secretion leads to elevated prolactin levels because TRH is a potent stimulator of prolactin release.¹⁵Prolactin plays an essential role in mammary gland development and lactation, but elevated prolactin levels inhibit reproductive function.¹⁶Prolactin suppresses hypothalamic GnRH secretion both directly and indirectly. It reduces the expression of kisspeptin messenger RNA, leading to decreased GnRH release.¹⁷Additionally, increased prolactin stimulates dopamine secretion, which further inhibits GnRH release and alters kisspeptin signaling.¹⁸

Prolactin and dopamine also reduce pituitary responsiveness to GnRH. ¹⁹Furthermore, prolactin can stimulate progesterone secretion from the corpus luteum, potentially prolonging its lifespan and contributing to menstrual irregularities observed in hypothyroidism.²⁰

Role of Thyroid-Stimulating Hormone in Reproduction

Thyroid-stimulating hormone is a glycoprotein hormone that shares a common alpha subunit with luteinizing hormone and follicle-stimulating hormone. Elevated TSH levels have been implicated in precocious puberty, particularly in Van Wyk–Grumbach syndrome, due to cross-reactivity with follicle-stimulating hormone receptors.²¹

TSH receptors are expressed in ovarian follicular cells, Leydig cells, and endometrial tissue, indicating a direct role for TSH in reproductive tissues.²²TSH has also been shown to promote endometrial proliferation, particularly in women with endometriosis.²³Additionally, TSH interacts closely with leptin, a hormone secreted by adipocytes that signals energy sufficiency to the reproductive axis. TSH promotes adipocyte proliferation and leptin secretion, thereby indirectly influencing kisspeptin neurons. In hypothyroid states, elevated TSH levels are associated with increased leptin levels, which normalize following levothyroxine therapy. Conversely, leptin also regulates TSH secretion by influencing TRH production in the hypothalamus, highlighting a bidirectional relationship between TSH and leptin in reproductive regulation.²⁴

Role of Triiodothyronine and Tetraiodothyronine in Reproductive Regulation

The precise mechanisms by which triiodothyronine and tetraiodothyronine regulate gonadotropin secretion are not fully understood. However, animal studies have demonstrated that thyroid hormone administration increases the expression of kisspeptin and gonadotropin-releasing hormone genes, whereas hypothyroid states reduce kisspeptin expression.²⁵

Thyroid hormones may exert their reproductive effects indirectly through interactions with other regulatory systems, including gonadotropin-inhibiting hormone, insulin, glucocorticoids, and neuropeptide Y. ²⁶Thyroid hormone receptors have been identified on kisspeptin–neurokinin B–dynorphin neurons in several mammalian species, suggesting a direct regulatory role.²⁵

Thyroid hormones also influence metabolic pathways that affect reproductive function. They enhance hypothalamic insulin signaling, which promotes GnRH secretion by suppressing neuropeptide Y, an inhibitory regulator of GnRH neurons. Hypothyroid states impair insulin secretion and signaling, further contributing to reproductive dysfunction.^26,27

Stress-related pathways also interact with thyroid hormones. Glucocorticoids suppress thyroid hormone production and conversion, while thyroid hormones influence glucocorticoid receptor expression and responsiveness.²⁸ Additionally, thyroid hormone-mediated increases in estradiol levels enhance luteinizing hormone feedback mechanisms, indicating complex interactions between thyroid hormones, stress hormones, and sex steroids.²⁹

Recent evidence suggests that gonadotropin-inhibiting hormone, also known as RFamide-related peptide-3 in humans, may serve as an additional pathway through which thyroid hormones regulate reproductive function. Hypothyroidism has been shown to increase gonadotropin-inhibiting hormone expression and delay puberty in animal models, effects that are reversed when this pathway is disrupted. Given the presence of gonadotropin-inhibiting hormone in the human hypothalamus, a similar mechanism may contribute to reproductive dysfunction in hyothyroid individuals.^30-32

PATHOLOGY -

1. HYPOTHYROIDISM IN FEMALE REPRODUCTION

1.Neuroendocrine Dysregulation of the Hypothalamic–Pituitary–Ovarian Axis :

Hypothyroidism results in reduced circulating T3 and T4 levels, leading to loss of negative feedback at the hypothalamic–pituitary axis. This causes increased secretion of thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH).⁶Elevated TRH also stimulates prolactin release, resulting in hyperprolactinemia. Increased prolactin suppresses pulsatile gonadotropin-releasing hormone (GnRH) secretion. Consequently, luteinizing hormone (LH) pulsatility is disrupted and follicle-stimulating hormone (FSH) dynamics are altered. Although LH and FSH levels may remain within normal limits, their abnormal secretion impairs follicular maturation and ovulation. This leads to anovulatory cycles, luteal phase defects, menstrual irregularities, and infertility in hypothyroid women.³³

Table no 1: Evidence Supporting Neuroendocrine Disruption in Hypothyroidism

2 Ovarian and Peripheral Hormonal Effects of Thyroid Hormone Deficiency:

Thyroid hormone receptors are present in ovarian granulosa cells and oocytes, indicating a direct role in follicular development. Under normal conditions, thyroid hormones enhance granulosa cell responsiveness to FSH and support estradiol production.⁶ In hypothyroidism, reduced thyroid hormone signaling decreases follicular sensitivity to gonadotropins, leading to impaired follicle maturation, poor steroidogenesis, and reduced oocyte quality. Clinically, this may present as diminished ovarian reserve, reflected by reduced antral follicle count and elevated early follicular phase FSH levels.³³

Additionally, hypothyroidism alters peripheral sex steroid metabolism. Reduced thyroid hormone levels decrease hepatic production of sex hormone–binding globulin (SHBG), lowering total circulating estrogen and androgen levels. Altered androgen metabolism and increased peripheral aromatization further disturb estrogen balance. This hormonal imbalance contributes to endometrial dysfunction and a high prevalence of menstrual abnormalities, including oligomenorrhea, amenorrhea, anovulatory bleeding, and menorrhagia.³⁷

Table 2: Evidence Supporting Ovarian and Peripheral Hormonal Effects of Thyroid Hormone Deficiency

3. Impact on Fertility, Pregnancy, and Fetal Development

Hypothyroidism impairs female fertility by causing anovulation, luteal phase defects, poor oocyte quality, and reduced endometrial receptivity. Elevated TSH levels are more frequently observed in women with unexplained infertility. During early pregnancy, fetal development depends entirely on maternal thyroid hormone supply.⁴⁰ Overt hypothyroidism increases the risk of miscarriage, preeclampsia, placental abruption, preterm delivery, postpartum hemorrhage, low birth weight, and stillbirth. In inadequately treated cases, fetal loss rates may reach 60%. Thyroid hormones are essential for fetal brain development, regulating neuronal migration, myelination, and synapse formation. Maternal hypothyroidism, especially in the first trimester, can lead to long-term neurodevelopmental impairment in offspring.⁴¹

Table 3: Evidence Supporting Impact of Maternal Hypothyroidism on Fertility, Pregnancy Outcomes, and Fetal Neurodevelopment

2. HYPERTHYROIDISM IN FEMALE REPRODUCTION

1. Neuroendocrine Dysregulation of the Hypothalamic–Pituitary–Ovarian Axis:

Hyperthyroidism, often caused by Graves’ disease, toxic multinodular goiter, or thyroid nodules, leads to excessive T3 and T4 and suppressed TSH. In Graves’ disease, autoantibodies overstimulate the thyroid, disrupting hypothalamic–pituitary feedback.⁶ This alters GnRH, LH, and FSH secretion, causing menstrual irregularities, most commonly oligomenorrhea and amenorrhea, and ovulatory dysfunction. Metabolic and adrenergic effects of thyroid excess further impair reproductive hormone coordination. Overall, hyperthyroidism dysregulates the endocrine network, negatively affecting reproductive hormone rhythms and contr

Table 4: Evidence Supporting Central (HPO Axis) Dysregulation in Hyperthyroidism and Its Impact on Fertilityibuting to subfertility and cycle disturbances.⁴³

2. Ovarian and Peripheral Hormonal Effects of Thyroid Hormone Excess:

Excess thyroid hormones affect ovarian and peripheral reproductive physiology both directly and indirectly. Thyroid hormone receptors in ovarian tissue increase metabolic activity in granulosa cells and oocytes, altering follicular growth.⁴⁷ Peripherally, hyperthyroidism raises sex hormone-binding globulin (SHBG), increasing total estrogen and testosterone but often reducing free active fractions. It also enhances peripheral conversion of androgens to estrogens. These changes disrupt the estrogen–progesterone balance, impairing follicular development, luteal function, and endometrial stability, leading to irregular cycles, hypomenorrhea, ovulatory dysfunction, and reduced fertility.⁴⁸

Table 5: Evidence for Ovarian and Peripheral Hormonal Effects of Thyroid Hormone Excess

3. Impact on Fertility, Pregnancy, and Fetal Development:

Hyperthyroidism can impair fertility by causing irregular ovulation and altered luteal phase support, although evidence is less consistent than for hypothyroidism. During pregnancy, uncontrolled hyperthyroidism increases the risk of miscarriage, preterm delivery, preeclampsia, and maternal cardiac complications.⁴⁰ In Graves’ disease, thyroid-stimulating antibodies (TRAbs) can cross the placenta, potentially causing fetal or neonatal thyrotoxicosis, which may result in tachycardia, intrauterine growth restriction, hydrops fetalis, or stillbirth if untreated. Effective maternal thyroid control improves outcomes, but antithyroid therapy must be carefully managed to balance maternal euthyroidism with fetal safety.⁴³

Table 6: Evidence Linking Maternal Hyperthyroidism to Adverse Pregnancy and Fetal Outcomes

• AUTO-IMMUNE THYROID DISEASE :

1. Neuroendocrine Dysregulation of the Hypothalamic–Pituitary–Ovarian Axis

Autoimmune thyroid disease (AITD) is characterized by thyroid peroxidase (TPOAb) and thyroglobulin antibodies (TgAb) and is common in reproductive-age women. Reproductive impairment may occur even in euthyroid women, indicating immune-mediated effects beyond hormone deficiency.³³ Thyroid autoimmunity alters hypothalamic–pituitary–ovarian (HPO) axis regulation. Subtle changes in GnRH pulsatility disturb LH and FSH secretion patterns. This disrupts coordinated follicular development and ovulation.⁵¹ AITD frequently coexists with subclinical hypothyroidism due to reduced thyroid reserve. During pregnancy or increased thyroid demand, this impaired adaptive capacity worsens endocrine balance. Overall, immune dysregulation contributes to reproductive dysfunction independent of overt hypothyroidism.⁵³

2. Ovarian and Peripheral Hormonal Effects

AITD is associated with reduced ovarian reserve even when thyroid hormone levels are normal. Women with positive thyroid autoantibodies show lower anti-Müllerian hormone (AMH) levels. ³³ A reduced antral follicle count indicates compromised follicular quantity. Immune-mediated mechanisms, including inflammatory cytokines, may impair follicular quality. Autoimmune cross-reactivity may directly affect ovarian tissue.⁵²Thyroid autoimmunity can disturb the follicular microenvironment. Subtle alterations in estrogen–progesterone signaling may occur. These changes impair endometrial receptivity and luteal phase adequacy, reducing implantation potential.⁵⁴

3. Impact on Fertility, Assisted Reproductive Technology, and Pregnancy

Women with AITD have a higher risk of infertility and early pregnancy loss, even if euthyroid. The increased miscarriage risk is strongly linked to thyroid autoantibody positivity. ⁵¹ In assisted reproductive technology (IVF/ICSI), miscarriage rates are higher in antibody-positive women. Effects on implantation and clinical pregnancy rates are less consistent.⁵² Levothyroxine does not uniformly improve ART outcomes in euthyroid women. However, it may reduce miscarriage risk when subclinical hypothyroidism is present. During pregnancy, AITD is associated with miscarriage, preterm delivery, and placental dysfunction. Some studies suggest possible adverse neuro-developmental outcomes in offspring.^[54]

Table 7: Clinical Implications of Differential Thyroid Dysfunction on Female Fertility

Spermatogenesis.

Spermatogenesis is a highly regulated biological process governed by the coordinated activity of the hypothalamic–pituitary–gonadal (HPG) axis. The initiation of this axis begins at the level of the hypothalamus, which integrates multiple internal and external signals to regulate male reproductive function. Neural inputs related to circadian rhythm, nutritional status, stress, and sexual maturation converge on specialized hypothalamic neurons. During puberty and adulthood, these neurons acquire sensitivity to metabolic and neuroendocrine cues, resulting in the pulsatile release of gonadotropin-releasing hormone (GnRH). This pulsatility is critical, as continuous GnRH secretion leads to down regulation of pituitary gonadotropin release.

GnRH is transported via the hypophyseal portal circulation to the anterior pituitary gland, where it binds to GnRH receptors on gonadotroph cells. This interaction stimulates the synthesis and episodic secretion of two key gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The frequency and amplitude of GnRH pulses influence the relative secretion of these hormones, thereby fine-tuning testicular function.

LH primarily targets the Leydig cells located in the interstitial tissue of the testes. Upon LH stimulation, Leydig cells synthesize and secrete testosterone, the principal androgen responsible for male reproductive development. Testosterone diffuses locally into the seminiferous tubules and also enters systemic circulation. Within the tubules, testosterone plays a crucial paracrine role in supporting germ cell development.

FSH acts on Sertoli cells, which line the seminiferous tubules and provide structural and metabolic support to developing germ cells. Under FSH stimulation, Sertoli cells produce androgen-binding protein (ABP), which binds testosterone and maintains a high intratubular androgen concentration. Sertoli cells also form the blood–testis barrier, secrete growth factors, and regulate the microenvironment required for germ cell maturation. Additionally, they release inhibin B, which provides negative feedback to the pituitary to regulate FSH secretion.

The combined action of testosterone and Sertoli cell support creates an optimal intratubular environment for spermatogenesis. Within the seminiferous tubules, spermatogonia undergo mitotic proliferation, followed by meiotic division to form haploid spermatids. These spermatids then undergo spermiogenesis, a differentiation process that results in the formation of mature spermatozoa. Thus, spermatogenesis represents the final outcome of precise neuroendocrine signaling initiated at the hypothalamic level and executed within the seminiferous tubules.

Role of thyroid hormones on spermatogenesis genomically and non-genomically: GENOMICALLY

Thyroid hormones, principally 3,5,3′-triiodothyronine (T3) and thyroxine (T4), play an important regulatory role in testicular development and function through both genomic and non-genomic mechanisms^[7]. Among these, genomic actions represent a key pathway through which thyroid hormones influence spermatogenesis and testicular cell maturation.

Genomic effects are primarily mediated by T3, the biologically active form of thyroid hormone, which enters target cells and binds to thyroid hormone receptors (TRs) located within the nucleus of Sertoli and Leydig cells^[58,59]. Upon binding, the T3–TR complex interacts with specific DNA sequences known as thyroid hormone response elements (TREs), leading to activation or repression of target gene transcription and subsequent protein synthesis^[59]. Through this mechanism, thyroid hormones exert long-term effects on cellular growth, differentiation, and functional activity within the testis.

Thyroid hormone receptors are encoded by two genes, TRα and TRβ, which give rise to five receptor isoforms—TRα1, TRα2, TRα3, TRβ1, and TRβ2—through alternative splicing. Among these, TRα1, TRβ1, and TRβ2 are functional receptors capable of binding T3, whereas TRα2 and TRα3 lack a hormone-binding domain. These non-binding isoforms can still attach to TREs and act as dominant negative regulators by competing with T3-bound receptors, thereby suppressing thyroid hormone–dependent gene transcription^[6].

Within the testis, TRα1 is the predominant receptor isoform expressed in germ cells, particularly from intermediate spermatogonia to pachytene spermatocytes, as well as in Sertoli cells. Sertoli cell development and function are further modulated by TRβ1 and TRβ2, highlighting the importance of thyroid hormone signaling in shaping the seminiferous epithelium^[58]. Rather than acting directly on germ cells, T3 primarily influences spermatogenesis indirectly by regulating the proliferation, differentiation, and functional maturation of non-germ cells.

NON-GENOMICALLY:

In addition to their genomic actions, thyroid hormones exert rapid nongenomic effects that directly influence sperm function. These effects are mediated through binding to nonnuclear receptors located on the plasma membrane, cytoplasm, cytoskeleton, and mitochondria of spermatozoa. Activation of these extranuclear pathways triggers intracellular signaling cascades, particularly increased cyclic adenosine monophosphate (cAMP) production and calcium (Ca²?) mobilization, which together enhance flagellar activity and sperm motility^[7,60].

Thyroxine(T4) has been shown to rapidly stimulate sperm hyper-motility by increasing flagellar movement, resulting in improved recovery of motile sperm during swim-up procedures^[60]. In comparative observations, exposure to T4 enabled all treated sperm samples to reach the minimum motile sperm threshold required for intrauterine insemination, outperforming pentoxifylline, a phosphodiesterase inhibitor commonly used to increase cAMP levels^[7]. These findings suggest a potential role for thyroid hormones in improving sperm preparation outcomes in assisted reproductive techniques.

Besides T3 and T4, other iodothyronines may also act through nongenomic mechanisms. Reverse triiodothyronine (rT3) has been reported to interact with cytoskeletal elements, while diiodothyronine (T2) preferentially targets mitochondria^[61]. However, their specific effects on spermatozoa remain insufficiently studied and warrant further investigation.

Thyroid hormones also play an important role in maintaining the redox balance of the testis, which is essential for sperm viability and motility^[60]. The sperm mid piece is rich in glutathione peroxidase (GPx), a selenium-dependent enzyme that protects against oxidative stress and inhibits apoptosis^[62]. Selenium is a key micronutrient for thyroid hormone metabolism, as it is required for iodothyronines deiodinases that convert T4 to the active hormone T3. In selenium-deficient men, supplementation has been associated with improved sperm motility as well as better thyroid immune status^[63].

Additional antioxidant systems in the testis include superoxide dismutase, γ-glutamyl transferase, catalase, glutathione-S-transferase, cytochrome c, melatonin, vitamins C and E, and zinc^[7]. Thyroid hormones modulate these defenses by enhancing γ-glutamyl transferase and catalase expression while downregulating GPx and cytochrome c, thereby contributing to optimal sperm function^[64,65]

HYPERTHYROIDISM:

Hyperthyroidism is consistently associated with adverse effects on spermatogenesis and semen quality. Excess circulating thyroid hormones negatively influence germ cell development and sperm function, leading to reductions in sperm concentration, motility, and normal morphology, along with a decrease in semen volume. Histological and functional studies indicate that hyperthyroid states may delay spermatogenic progression, often resulting in maturation arrest. Structural changes such as reduced seminiferous tubule diameter, absence of pachytene spermatocytes, impaired mitochondrial activity, and decreased lipid content within germ cells further contribute to compromised sperm development^[65].linically, thyrotoxicosis is frequently associated with asthenozoospermia, affecting more than half of hyperthyroid men. Oligozoospermia and teratozoospermia are reported in approximately 40% of patients and are often accompanied by hypospermia^[66]. Together, these abnormalities result in a marked reduction in overall semen quality, characterized by decreased sperm density, motility, and morphological integrity.

Several clinical studies support these observations. Early work by Hudson and Edwards demonstrated reduced progressive sperm motility in 16 adult men with Graves’ disease compared with euthyroid controls^[67]. Subsequent studies confirmed these findings, with Krassas and colleagues reporting significantly lower sperm motility in hyperthyroid men. Importantly, treatment of thyrotoxicosis has been shown to improve sperm motility, although changes in sperm concentration and morphology appear to be less consistent, suggesting differential sensitivity of semen parameters to thyroid hormone normalization^[68].Beyond conventional semen parameters, high levels of thyroid hormones—particularly FT3 and FT4—have been implicated in sperm DNA damage and reduced fertility potential. Elevated T3 and T4 increase the production of reactive oxygen species (ROS), leading to oxidative stress, which adversely affects sperm chromatin integrity, mitochondrial function, and membrane stability^[69,72].

ecent investigations have highlighted the relevance of thyroid hormones within seminal plasma. Seminal FT4 levels have been detected at measurable concentrations, and in vitro studies have shown that incubation of semen with low, physiological concentrations of levothyroxine reduces sperm necrosis and lipid per oxidation while improving chromatin compactness. These findings suggest that an optimal balance of thyroid hormones within seminal plasma may be necessary for maintaining sperm bio functional integrity. Although these observations open new perspectives for clinical applications in idiopathic male infertility, further studies are required to define physiological reference ranges for seminal FT3 and FT4^[70,72].

What is well established is that treatment of hyperthyroidism, restoring euthyroid or high-normal FT4 levels, leads to improvement in semen quality, reinforcing the concept that thyroid hormone–related sperm dysfunction is largely reversible.

THYROTOXICOSIS:

Men with thyrotoxicosis exhibit distinct alterations in sex hormone balance that significantly affect testicular function. Hyperthyroidism is associated with increased concentrations of sex hormone–binding globulin (SHBG) and total testosterone, while free testosterone levels typically remain within the normal range. However, despite normal free testosterone, testosterone bioavailability is functionally reduced due to a decreased testosterone clearance rate and a lower free testosterone–to–estradiol ratio. This imbalance arises from elevated circulating levels of both total and free estradiol, reflecting enhanced estrogenic activity in hyperthyroid states^{[6,44,63,65,73,74-76]}.

Thyroid hormone excess also promotes the peripheral conversion of androgens to estrogens, further contributing to estrogen predominance. This shift in the androgen–estrogen balance plays an important role in impairing male reproductive function^[6,44]. Experimental studies suggest that thyrotoxicosis affects Leydig cell physiology by delaying their maturation and inducing spermatogenic disturbances, even though Leydig cell proliferation may be increased. These findings indicate that an increase in cell number does not necessarily translate into improved functional capacity^[7,78]. It also negatively affects Sertoli cells, which are essential for supporting germ cell development. Excess thyroid hormones inhibit Sertoli cell proliferation, leading to impaired spermatogenic support. This reduction in Sertoli cell number and function contributes to defective spermatogenesis and is associated with a decrease in overall testicular volume^[55,77]. Collectively, these hormonal and cellular alterations explain the detrimental effects of hyperthyroidism on male fertility, despite elevated circulating androgen levels.^[55]

HYPOTHYROIDISM:

Primary hypothyroidism has significant effects on testicular development and function, primarily through its impact on Sertoli and Leydig cells. In hypothyroid patients, Sertoli cell maturation is delayed, resulting in impaired support of germ cell development^[78-80]. It also adversely affects Leydig cell function. Reduced thyroid hormone levels impair Leydig cell maturation and decrease their responsiveness to human chorionic gonadotropin (hCG), leading to diminished androgen synthesis^[79,81]. As a consequence, circulating concentrations of sex hormone–binding globulin (SHBG), total testosterone, and free testosterone are reduced. This androgen deficiency further compromises spermatogenesis and overall testicular function^[6].

In addition to hormonal disturbances, hypothyroidism is associated with qualitative abnormalities in spermatozoa^[6,7]. Alterations in sperm morphology are frequently observed, with hypothyroid men exhibiting a higher percentage of atypical sperm compared to euthyroid individuals. Clinical studies have demonstrated a significant association between teratozoospermia and reduced free thyroxine (fT4) levels, suggesting a direct relationship between thyroid hormone deficiency and abnormal sperm structure. Encouragingly, sperm morphology has been shown to improve following thyroid hormone replacement therapy^[82].

Hypothyroidism may also negatively affect quantitative semen parameters. Reduced total sperm count and impaired sperm motility have been reported in affected individuals. At the cellular level, thyroid hormone deficiency can compromise acrosomal integrity and mitochondrial activity, both of which are essential for sperm motility, fertilization capacity, and energy production^[83]. Consistent with other reproductive alterations seen in hypothyroidism, improvements in sperm motility and functional parameters are commonly observed after restoration of normal thyroid hormone levels^[77,84].

Overall, these findings highlight that hypothyroidism exerts a multifaceted yet largely reversible impact on male fertility by disrupting testicular cell maturation, androgen production, and sperm quality.

Table. 8 Clinical evidence linking thyroid disorders to male infertility