Thyroid Hormones and It's Effects on Sexual Health of Males and Females

Abstract

Thyroid hormones play a crucial role in regulating numerous physiological processes, yet their impact on reproductive and sexual health is often underestimated. Recent research suggests that imbalances in thyroid function-whether due to hypothyroidism or hyperthyroidism-can negatively affect the hypothalamic-pituitary-gonadal (HPG) axis, resulting in altered sex hormone levels, impaired gamete development, and reduced libido in both males and females. This article reviews recent clinical and experimental data to examine how thyroid imbalances contribute to infertility and sexual dysfunction, which affect millions worldwide. In men, thyroid dysfunction is frequently linked to lower testosterone levels, reduced sperm production, erectile difficulties, and issues with ejaculation. In women, thyroid hormone imbalances influence the development of ovarian follicles, menstrual cycle consistency, the receptivity of the endometrium, and pregnancy outcomes. Autoimmune thyroid conditions like Hashimoto’s thyroiditis and Graves’ disease add further complexity, particularly in women undergoing assisted reproductive treatments (ART). Fortunately, many of these reproductive and sexual symptoms can be reversed with timely correction of thyroid hormone levels, highlighting the importance of early diagnosis and management. In addition to their traditional hormonal roles, thyroid hormones act through both genomic and non-genomic pathways in reproductive tissues and interact with other hormonal signals such as leptin, prolactin, and insulin-like growth factors. These mechanisms offer potential pathways for developing novel diagnostic and treatment approaches. By integrating insights from both endocrinology and reproductive medicine, this review emphasizes the importance of evaluating thyroid function in individuals experiencing infertility or

Keywords

Introduction

Figure 1: Illustration outlining the functional hypothalamic-pituitary-thyroid (HPT) axis, including the physiological effects of circulating and protein-bound forms of tri-iodothyronine (T3) and thyroxine (T4) throughout the body. Abbreviations: TBG– thyroxine-binding globulin; TRH– thyrotropin-releasing hormone; TSH– thyroid-stimulating hormone.

Subclinical thyroid dysfunction, characterized by abnormal TSH levels with normal T4 and T3, can still exert significant physiological effects [10]. As elaborated later in this review, such dysfunctions may adversely affect sexual health in both men and women.

Figure 2: Depiction of the intracellular signaling mechanism of thyroid hormones (TH). Cellular uptake of TH is facilitated by specific transport proteins. Once inside the cell, T4 may be converted to T3 by the enzyme DIO2. Although not depicted, DIO1 also plays a role in this conversion. T3 and T4 interact with thyroid hormone receptors (THRs), which are primarily bound to retinoid X receptors (RXRs). This binding induces a structural change in the THRs, resulting in the release of corepressors and the recruitment of coactivators, thereby initiating the transcription of genes located downstream of thyroid hormone response elements (TREs).

Figure 3: Overview of how thyroid hormone imbalances influence male sexual function.

The Figure 4 shows how sexual desire, arousal/lubrication, orgasm, overall satisfaction, and pain experienced during sexual intercourse are the criteria used to classify female sexual dysfunction [35,38].

Figure 4: Overview of how thyroid hormone imbalances affect female sexual function.

1. Thyroid hormones and sexual function in males:

Numerous environmental and lifestyle factors interact intricately to cause internal physiological changes that result in male infertility or subfertility [39].  The thyroid hormone profile, which serves a variety of biological functions [40] and is essential for preserving a healthy male reproductive capacity, is one of the major variables affecting reproductive health.  Semen parameters and reproductive potential have been demonstrated to be adversely affected by changes in thyroid hormone levels [41].  Thyroid hormones' function in controlling male reproduction has been the subject of numerous studies [42], although little is known about the precise mechanisms by which thyroid abnormalities affect fertility indicators [43].

1. 1. Genomic and non-genomic impacts of thyroid hormones on male reproduction:

Transcriptional regulatory mechanisms are the main way that thyroid hormones affect the body. Sertoli cells in both foetuses and adults have been found to contain nuclear receptors for these hormones [44]. Activating gene expression and protein production, triiodothyronine (T3) stimulates Sertoli cell proliferation and differentiation when it attaches to its receptors within testicular cells [45]. Conversely, thyroid hormones can have non-genomic effects by interacting with receptors outside the nucleus, which may change the structure, metabolism, and proliferation of cells. There is still much to learn about the precise differences between genomic and non-genomic pathways [46]. Research indicates that cyclic adenosine monophosphate (cAMP) synthesis, calcium release, and sperm motility can all be improved by non-nuclear binding of thyroid hormones. Significantly, supplementing semen samples with thyroxine (T4) resulted in increased sperm hypermotility within 20 minutes [47]. Furthermore, by interacting with the mitochondria or cytoskeletal components of sperm cells, iodinated thyroid chemicals may have unknown non-genomic effects on them [46]. Thyroid hormones help maintain antioxidant defences and regulate oxidative equilibrium [48]. Neonatal hypothyroidism, for example, has been associated with increased oxidative stress, which interferes with the control of glucose in the testes and ultimately affects the survival, proliferation, and expression of proliferating cell nuclear antigen in germ cells [49]. Protein carbonyls and other indicators of oxidative stress rise in transitory hypothyroidism, although antioxidants such as catalase, glutathione reductase, glutathione peroxidase, and superoxide dismutase (SOD) fall. Only catalase and SOD levels, however, seem to increase in chronic hypothyroidism [50].

1. Effect of hypothyroidism on semen parameters and sex hormones:

Reduced blood testosterone concentrations have been demonstrated to be positively correlated with lower thyroid hormone levels [51]. Erectile dysfunction, delayed ejaculation, decreased sexual drive, and poor semen quality are some of the male reproductive issues associated with this hormonal imbalance. The exact processes by which hypothyroidism influences semen qualities are still unclear, despite the fact that numerous studies have linked it to male infertility [51].

• Men are less likely than women to have hypothyroidism, according to several human research [52]. Its emergence in males is frequently linked to extended exposure to substances that affect hormones. Sex hormone-binding globulin (SHBG) and free testosterone levels have been shown to be somewhat lower in hypothyroidism than in euthyroid males [52]. Additionally, the gonadotropic cells in the anterior pituitary may lose their sensitivity to gonadotropin-releasing hormone (GnRH), which would change the release of luteinizing hormone (LH) and upset the hypothalamic-pituitary-testicular axis' hormonal balance [52]. It has been documented that T4 treatment helps hypothyroid males regain their plasma testosterone levels. However, it seems that subclinical hypothyroidism has little impact on semen characteristics including sperm motility, morphology, and concentration [53]. However, decreased sperm motility, decreased secretions from accessory sex glands, and decreased semen volume have all been associated with short-term hypothyroidism that develops after puberty [51, 52]. Six men with childhood or pubertal-onset hypothyroidism had histological abnormalities in their testes, according to De la Balze et al. [54]. This suggests that a prolonged thyroid hormone deficiency during these times may suppress pituitary gonadotropin release and negatively impact testicular structure and function. Moreover, hypothyroid guys were often found to have lower serum testosterone and SHBG levels. Short-term post-pubertal hypothyroidism did not improve semen quality or substantially change testicular function, according to Corrales et al. [51]. Semen quality improved during hormone restoration, according to a study by Jaya Kumar et al. that tracked eight men from a hypothyroid to a euthyroid condition using T4 medication [55].  Similarly, hypothyroidism has a detrimental effect on spermatogenesis, according to Rassas et al., who noted noticeable changes in sperm motility and morphology [56].
• Studies on animals utilizing rat models have demonstrated that antithyroid medications that inhibit thyroid hormone production can result in lower seminal volume, smaller seminiferous tubules, halted spermatogenesis, and decreased testicular, epididymal, and prostate weights.  Additionally, hypothyroid rats showed decreased accessory gland secretions, a delayed epididymal transit time, and worse progressive sperm motility.  Furthermore, this condition seems to impair the acrosomal and mitochondrial activity of sperm [57].  Both temporary and long-term hypothyroid rats showed a significant decrease in viable testicular germ cells, most likely as a result of impaired antioxidant defense systems and elevated oxidative stress in the testes [61]. Congenital hypothyroidism in rodents has been demonstrated to result in unregulated Sertoli cell proliferation and delayed differentiation, leading to abnormally large testes and dysregulated sperm production, given the significance of thyroid hormones in Sertoli cell regulation [60].

The fundamental process entails a drop in circulating T3 and T4 levels, which lowers testosterone and SHBG and ultimately interferes with spermatogenesis. Sexual dysfunctions like erectile dysfunction, delayed ejaculation, decreased libido, and poor semen quality can result from a prolonged thyroid hormone deficiency during childhood or puberty that suppresses the pituitary's release of gonadotropin, which in turn affects testicular development, function, and accessory gland secretions. Furthermore, it results in decreased testicular, epididymal, and prostate weights as well as lower seminiferous tubule widths, all of which hinder sperm production, motility, and passage through the male reproductive system. Oxidative stress brought on by hypothyroidism may further reduce sperm viability [58].

2. Effect of hyperthyroidism on semen parameters and sex hormones:

Excessive blood levels of sex hormone-binding globulin (SHBG) and a slower metabolic clearance of serum testosterone are associated with hyperthyroidism, which is characterized by excessive serum total T4 levels, according to human studies [59].  Men with hyperthyroidism frequently exhibit higher amounts of circulating estrogen and lower levels of bioavailable testosterone. Symptoms including erectile dysfunction, decreased sexual desire, and gynecomastia can be exacerbated by these hormonal abnormalities.  Furthermore, men with hyperthyroidism exhibit heightened luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses to external gonadotropin-releasing hormone (GnRH) treatment.  Testicular function is subsequently compromised, and semen quality is impacted by these hormonal changes.

Despite these results, hyperthyroidism and semen quality have only been directly associated in a small number of clinical studies.  For instance, two of the three hyperthyroid male participants in a research by Clyde et al. exhibited oligozoospermia along with decreased sperm motility, and the third individual had both low sperm count and impaired motility [62].  Similarly, Kidd et al. found that hyperthyroid individuals had sperm concentrations less than 40×10?/mL [60]. A 1992 research by Hudson and Edwards with 16 hyperthyroid men reported similar results [63]. 9 of the 21 hyperthyroid males in a different study by Abalovich et al. had lower sperm counts, 18 had poor sperm motility, and 13 had abnormalities in progressive motility [61]. Krassas et al. assessed semen parameters in 23 hyperthyroid men and 15 euthyroid controls in a prospective research. The individuals' semen was examined both before and after receiving methimazole treatment, either by alone or in combination with radioiodine. Comparing the results to the control group, there were slight decreases in sperm density, alterations in sperm morphology, and a notable drop in motility. Crucially, following therapy, sperm motility and concentration increased [64]. The conditions asthenozoospermia, oligozoospermia, and teratozoospermia have all been closely linked to thyrotoxicosis, which results in high amounts of thyroid hormones in the blood. Hypoposia, or decreased semen volume, may also be a result of elevated thyroid hormone levels [61].

On the other hand, little is known about the relationship between hyperthyroidism and semen quality in animal models. Nonetheless, the research that is now available indicates that hyperthyroid rats might have smaller seminiferous tubule widths, decreased mitochondrial efficiency, and a delayed initiation of spermatogenesis. According to one study, hyperthyroidism in mice raised catalase activity while lowering glutathione peroxidase activity [57].

• The fundamental mechanism is a disturbed hormonal balance brought on by increased levels of circulating T4 and decreased reactivity of LH and FSH. Testicular structure and function are adversely affected by these alterations, which result in decreased motility, delayed sperm production, poor sperm development, and smaller seminiferous tubule diameter. As a result, hyperthyroid males see a decrease in sperm count and overall semen quality. Furthermore, sperm viability and motility are severely compromised by changes in testicular redox balance that impact Leydig, Sertoli, and germ cells as well as decreased mitochondrial activity within sperm cells, which ultimately lowers semen quality [58].

2.2 Thyroid disorders and reproductive dysfunctions in males:

1. Levels of Serum SHBG and androgen binding protein (ABP):

Thyroid dysfunction affects the production of androgen-binding protein (ABP) in Sertoli cells and sex hormone-binding globulin (SHBG) in the liver, both of which are involved in the transportation of testosterone. Increased levels of SHBG and testosterone are seen in thyrotoxicosis patients, most likely as a result of decreased metabolic clearance. Nevertheless, in vitro research revealed that Sertoli cells produced less ABP when exogenous T3 was added [65].

2. Sexual dysfunction: libido and erectile dysfunction:

Ejaculation is regulated in part by thyroid hormones and other metabolic regulators. Hypothyroidism has been associated with delayed ejaculation, but hyperthyroidism is more commonly associated with premature ejaculation. Male hypothyroids had greater rates of decreased libido, erectile dysfunction, and delayed ejaculation (64.3%), according to a multi-center study assessing sexual dysfunction in people with thyroid diseases. In contrast, only 7.1% of men with hypothyroidism reported premature ejaculation, whereas 50.0% of men with hyperthyroidism did. About half of the hypothyroid respondents experienced an improvement in delayed ejaculation, while the incidence of premature ejaculation decreased to 15% once thyroid hormone levels were stabilized in hyperthyroid patients [66]. An additional survey that used the Sexual Health Inventory for Males (SHIM) revealed a significant disparity in sexual function scores between thyroid dysfunction patients and healthy controls: 78.9% of those with thyroid dysfunction scored 21 or lower, which is indicative of dysfunction, while only 33.8% of the control group did the same. Both hyperthyroid and hypothyroid males showed significant improvements in their SHIM scores after treatment (P<0.0001). Furthermore, compared to control groups, a significantly greater prevalence of erectile dysfunction was noted in people with thyroid problems [56].

3. Spermatogenesis and semen parameters:

Thyroid hormones may have a direct impact on spermatogenesis and are essential for testicular growth and function. Thyroid hormone excess or insufficiency, as well as variations in thyroid levels, may have a variety of effects on male reproductive physiology, according to clinical and experimental research, especially in male rats and humans. For instance, larger testes have been linked to temporary hypothyroidism in rats during the neonatal stage [67]. When compared to euthyroid controls, hyperthyroid men have clinically demonstrated decreased sperm motility and conditions including asthenozoospermia, oligozoospermia, and teratozoospermia. Higher free T3 levels have recently been associated with higher serum fructose concentrations and ejaculate volume [68]. It has been demonstrated that hypothyroidism affects sperm motility and morphology, which raises teratozoospermia indices. Sperm count, motility, morphology, and seminal vesicle size were all considerably impacted in hypothyroid individuals. In mouse models of hypothyroidism, there was a drop in testicular germ cell populations, a reduction in sperm production, and a decrease in viable epididymal spermatozoa [57]. Other effects include decreased sperm motility and fertilization potential, impaired secretory function of the epididymis, and decreased expression of androgen receptors in the gonads. Reduced acrosome integrity, altered lipid peroxidation, mitochondrial apoptosis, and general mitochondrial activity are all indicators of compromised mitochondrial function [50,57]. The crucial metabolic involvement of thyroid hormones in sperm generation is shown by hypothyroidism's increased expression of thyroid hormone receptor alpha-1 (Thra1) and decreased expression of the deiodinase enzyme Dio3 [57]. Conversely, hyperthyroid rat models have been found to exhibit impaired mitochondrial activity and oxidative balance, delayed spermatogenesis, inhibited maturation, Leydig cell hyperplasia, and narrowing of seminiferous tubules. Additionally, elevated expression of solute carrier family 16 member 2 and monocarboxylate transporter 8 (MCT8), both essential for plasma membrane integrity, was linked to hyperthyroid conditions [56].

2.3 Thyroid disorders and testicular oxidative stress:

1. Hyperthyroidism and testicular oxidative stress:

It appears that hyperthyroidism makes the tissues more susceptible to oxidative injury. Given that thyroid hormones frequently activate physiological processes, hyperthyroidism is bound to overstimulate metabolic states and increase the production of excess free radicals, which can lead to oxidative damage and lipid peroxidation in various tissues [69]. In comparison to other tissues, the testis is far more vulnerable to oxidative damage due to its high content of unsaturated fatty acids, strong machinery that produces reactive oxygen species, and low antioxidant capacity. According to studies, different thyroid hormone isomers may cause variable amounts of oxidative stress when hyperthyroidism is induced. As evidenced by increasing amounts of malondialdehyde, thiobarbituric acid reactive compounds, lipid hydroperoxide, protein carbonyl contents, or hydrogen peroxide, it has been proposed that hyperthyroidism causes a significant rise in testicular oxidative stress [69]. When hypothyroid patients received short-term L-thyroxine treatment, changes in antioxidant defense measures, such as elevated testicular glutathione (GSH) concentrations, were noted. Following three days of T3 administration, oxidized glutathione disulfide levels rose and GSH levels fell, resulting in a drop in the ratio of reduced to oxidized glutathione in the testis. Testicular GSH levels in both mitochondrial and post-mitochondrial fractions increased after five days of T3 administration, as did testicular ascorbic acid levels [69]. The "reduced to oxidized" glutathione ratio was elevated in both the mitochondrial and post-mitochondrial portions of hyperthyroidism caused by L-thyroxine or T3 [50,69]. There have been reports linking acute hyperthyroidism to elevated testicular catalase (CAT), glutathione peroxidase (GPx), and glucose-6-phosphate dehydrogenase activity and decreased testicular SOD [50,69]. L-thyroxine has been demonstrated to cause a multifold rise in GPx in the testis' mitochondrial and post-mitochondrial fractions [70]. T3 treatment increased seleno-independent GPx activity only in the testicular mitochondrial fraction [70]. These increased seleno-dependent and/or independent GPx levels, which are reactions to hyperthyroidism induced by L-thyroxine [70] or T3 [69], could be viewed as an adaptive reaction to counteract the harmful effects of hydrogen peroxide on the testicles. Male fertility is impacted by changes in oxidative stress parameters and testicular antioxidant defense systems brought on by hyperthyroidism, which result in a decrease in the number of viable and total sperm [50,69].

2. Hypothyroidism and testicular oxidative stress:

Likewise, because of a depressed metabolic state, hypothyroidism impairs antioxidant capacity, raises the production of reactive molecules, and upsets testicular redox equilibrium. Variations in the antioxidant defense system during testicular development and maturation have been linked to both temporary and chronic forms of hypothyroidism. Decreased levels of malondialdehyde, increased hydrogen peroxide, increased protein carbonyls, and increased mitochondrial lipid peroxidation are all indicators of oxidative stress in hypothyroid rats. In such situations, testicular mitochondrial protein carbonylation is frequently employed as an indication of oxidative stress [70]. Additionally, the ratio of reduced to oxidized glutathione in the testes is lowered in hypothyroid rats due to decreased GSH levels and increased oxidized glutathione.

It has been demonstrated that in immature rat testes, persistent hypothyroidism disrupts proper redox homeostasis [70]. There have been reports of decreased glutathione-S-transferase activity, elevated GPx, and decreased SOD and CAT activities. Nonetheless, some research indicates that chronic hypothyroidism may decrease glutathione reductase and GPx levels while increasing SOD and CAT activity [50]. Reduced levels of seleno-dependent and seleno-independent GPx are another effect of chronic hypothyroidism [70], suggesting that SOD and CAT have a greater role in controlling oxidative stress in these circumstances.

Because testosterone's metabolism necessitates protection from peroxidative damage, the decrease in GPx activity has a detrimental effect on testosterone production. Reduced semen quality results from lower serum testosterone levels, which also impair spermatogenesis, increase germ cell death, and decrease testicular germ cell populations [69, 70]. In terms of morphology, hypothyroidism causes the diameter of seminiferous tubules to decrease. These alterations in testicular function brought on by hypothyroidism may eventually show up as decreased adult fertility, with signs of low-quality semen, decreased germ cell viability, and decreased sperm counts [69, 70].

2.4 Crosstalk of thyroid hormones with growth factors and other hormones in regulation of male reproductive functions:

1. Prolactin:

Prolactin at physiological quantities has been demonstrated to directly activate Sertoli cells, increasing the synthesis of androgen-binding protein (ABP), a crucial component of Sertoli cell proliferation and metabolism. Koivisto et al. found that a single intravenous dosage of thyroxine dramatically increased prolactin levels in a model of metoclopramide-induced short-term hyperprolactinemia in male Beagle dogs. Semen parameters, luteinizing hormone (LH), and testosterone levels, however, did not show any appreciable alterations. Significantly greater prolactin levels were seen in hypothyroidism patients than in control subjects (P<0.001) [71].

2. Growth hormone:

Evidence suggests that thyroid malfunction may be linked to illnesses like acromegaly and increased growth hormone levels. 42.1% of the 57 acromegaly patients had erectile dysfunction, particularly those with a longer history of the condition [72].

3. Insulin-like growth factor (IGF)-1:

IGF-1 and thyroid hormone (T3) seem to work in concert to promote the growth and differentiation of type A undifferentiated spermatogonia by boosting IGF-1 bioactivity via blocking IGF-binding proteins [72].

4. Leptin:

Obesity and weight gain are common side effects of hypothyroid disorders, and they are linked to increased adipose tissue production of leptin. Leptin has both central and peripheral effects on reproductive function. Leptin's regulating role in male reproductive health is demonstrated by the discovery of leptin receptors in seminal vesicles, the prostate, and Leydig cells. Although leptin also has indirect effects that may impact GnRH signaling, it has been demonstrated to directly reduce testicular testosterone synthesis. Reduced testicular weight, volume, seminiferous tubule diameter, and spermatocyte count can result from hyperleptinemia, which can also stimulate cytokine signaling-3 and decrease the expression of phosphorylated STAT-3. Leptin and thyroid hormones also interact; research has shown that body mass index, leptin, and serum thyroid-stimulating hormone (TSH) are positively correlated. Elevated leptin levels may be a compensatory mechanism for weight gain brought on by hypothyroidism in hypothyroid people [73].

3. Thyroid hormones and sexual function in females:
   1. Thyrotoxicosis:

Thyrotoxicosis, a clinical condition caused by excessive exposure to thyroid hormones, is most commonly caused by hyperthyroidism, which is most often caused by Graves' disease (GD), an autoimmune ailment, during the reproductive years. About 0.2% of women experience GD during pregnancy, and 0.4% to 1.0% do so before [74]. It is crucial to distinguish GD from hyperemesis gravidarum, which affects 0.3–1% of pregnancies and is a more prevalent illness. Subacute thyroiditis, toxic adenoma, and toxic multinodular goiter are less common causes, but additional etiologies are extremely uncommon. For the right treatment to be administered, the underlying cause must be accurately identified. Compared to GD, gestational transitory thyrotoxicosis is more prevalent. TSH receptor gene abnormalities that cause increased sensitivity to hCG are an uncommon cause of hyperthyroidism during pregnancy. Maternal TSH levels frequently decrease throughout the first trimester, particularly around the hCG peak between weeks 7 and 11 of pregnancy, since hCG can trigger TSH receptors. By week 11, up to 5% of pregnant women may have TSH levels as low as 0.1 mU/L [75].

• Effect on natural conception: Serum levels of sex hormone-binding globulin (SHBG) are high in thyrotoxicosis, mostly because of elevated estradiol concentrations and decreased metabolic clearance of estradiol. Because of increased synthesis, women with hyperthyroidism have higher amounts of androstenedione and testosterone. Furthermore, there is an increase in the conversion rates of testosterone to estradiol and androstenedione to estrone [76]. Menstrual abnormalities, which occur at a rate 2.5 times greater than in the general population [76], are a result of these hormonal changes (Figure 5). According to the metabolic condition of the liver, hepatocyte nuclear factor-4 alpha (HNF-4α) further regulates the generation of SHBG, which is stimulated by thyroid hormones [77]. Thyroid hormones affect the production of other binding proteins, including thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG), in addition to SHBG. These proteins together operate as markers of thyroid activity in the liver [78]. Severe hyperthyroidism may result in hypocortisolemia symptoms. Prolonged hyperthyroidism can potentially harm the liver directly, impairing hepatic function and hepatocyte oxygen deprivation.It has been discovered that luteinizing hormone (LH) output is higher in patients with Graves' disease (GD) than in euthyroid people. Additionally, some research indicates that ovarian reserve may be adversely affected by radioactive iodine (RAI) treatment [79].

Figure 5: Representation of how thyroid dysfunction impacts reproductive physiology in both males and females.

• Effect on ART outcomes: As of right now, no research has been done to directly evaluate how hyperthyroidism affects the results of in vitro fertilization (IVF). The suggestion that individuals with hyperthyroidism postpone using assisted reproductive technologies until their thyroid function has stabilized may be the cause of this [79].
• Effect on pregnancy and obstetric outcomes: Numerous difficulties for both the mother and the unborn child have been connected to hyperthyroidism during pregnancy. Maternal complications from thyrotoxicosis include placental abruption, preterm birth, maternal heart failure, preeclampsia, recurrent miscarriage (three or more consecutive pregnancy losses), and miscarriage (pregnancy loss before 20 weeks, usually within the first 10 weeks). Adverse fetal outcomes, such as low birth weight, intrauterine growth restriction (IUGR), and stillbirth, have also been linked to excessive maternal thyroid hormone exposure. Additionally, the illness may raise the child's chance of neurological and behavioral issues, such as seizures [80].
  2. Hypothyroidism:

In the general population, the overall prevalence of overt and subclinical hypothyroidism is between 0.3-0.4% and 4.3-8.5%, respectively. The primary causes of these events are drug usage, autoimmune illnesses, radiation exposure, and thyroidectomy. Prevalence estimates for overt and subclinical hypothyroidism during pregnancy are 0.3-0.5% and 2-3%, respectively, with the latter occasionally reaching 5% [75]. The primary causes of hypothyroidism during pregnancy in iodine-sufficient regions are endemic iodine deficiency and autoimmune thyroiditis [81]. Although there is ample evidence linking overt hypothyroidism to infertility and unfavorable pregnancy outcomes, the effects of subclinical hypothyroidism are less clear. There is significant discussion and critical evaluation about the proper reference ranges for thyroid-stimulating hormone (TSH) levels in connection to assisted reproduction, pregnancy, and fertility.

• Effect on natural conception: Hormonal alterations involving androgens and estrogens have been observed in hypothyroid patients. These result from enhanced peripheral aromatization and impaired metabolic clearance of androstenedione and estrone. Lower SHBG levels result in lower total hormone concentrations, even though free testosterone and estradiol levels may be higher. Furthermore, increased thyrotropin-releasing hormone (TRH) release from the hypothalamus may cause prolactin levels to rise in tandem with TSH [76]. Consequently, menstrual irregularities are experienced by almost 80% of women with hypothyroidism [76]. TSH levels have been linked to poor ovarian reserve, which is indicated by elevated day-3 FSH (>14 IU/L), low antral follicle count (<5), or a suboptimal response to previous ovarian stimulation. Two times as many women with unexplained infertility had TSH levels > 2.5 mIU/L as those with male factor infertility, according to a study of 239 infertile women [82].
• Effect on ART outcomes: Since these individuals are usually treated prior to starting ART, there isn't any published research that particularly looks at how overt hypothyroidism affects the results of in vitro fertilization (IVF). Subclinical hypothyroidism, on the other hand, has been studied in greater detail. Women having IVF/ICSI with TSH ≤ 2.5 mIU/L had greater pregnancy rates than those with TSH > 2.5 mIU/L (22.3% vs. 8.9%), according to Fumarola et al. [83]. These results haven't been widely confirmed, though. Several studies demonstrate similar results whether a TSH cutoff of <2.5 mIU/L or <4.0 mIU/L is used. When comparing the two thresholds, a major retrospective study evaluating initial IVF cycles found no discernible changes in clinical pregnancy, delivery, or miscarriage rates. Similarly, Chai et al. used TSH cutoffs of 2.5 mIU/L and 4.5 mIU/L and found no changes in live birth or miscarriage rates [84]. Using TSH criteria of 2.5 mIU/L versus 5.0 mIU/L, Unuane et al. conducted another retrospective analysis and discovered no discernible difference in cumulative live birth rates following six IVF/ICSI cycles [85].

Karmon et al. observed that preconception TSH levels between 2.5 and 4.9 mIU/L did not correspond with unfavorable clinical or obstetric outcomes, such as a lower live birth or a higher rate of miscarriage, when assessing the results of intrauterine insemination (IUI) [86]. Additionally, groups with TSH values between 2.5 and 5.0 mIU/L and those with TSH values below 2.5 mIU/L did not differ statistically significantly in live birth, pregnancy, or miscarriage rates, according to Unuane et al. [87]. It's critical to acknowledge the significant variation across current research. The main cause of this is the changing definitions of "normal thyroid function" and "subclinical hypothyroidism," which have an impact on study interpretations and treatment choices. Conclusions are made more difficult by discrepancies in study design, outcome definitions, and reporting guidelines. A patient's age, body mass index, history of IVF, and cause of infertility all have a big impact on the results. Results may also be impacted by the particular IVF procedures and fertilization techniques (such as ICSI for male factor infertility) and the quantity of embryos transferred. When taken as a whole, these factors make it challenging to develop consistent clinical recommendations.

• Effect on pregnancy and obstetric outcomes: Preterm birth, postpartum hemorrhage, low birth weight, newborn respiratory distress, stillbirth, placental abruption, miscarriage, gestational hypertension, and postpartum hemorrhage are among the negative outcomes that are associated with overt hypothyroidism during pregnancy. Overt hypothyroidism is thought to represent a 60% risk of foetal loss if treatment is not received [88]. Additionally, intrauterine growth and neurodevelopment may be hampered by inadequate thyroid hormone during pregnancy. Early-stage thyroid dysfunction during pregnancy can cause behavioral issues, delayed motor development, cognitive impairments, and a reduction in the offspring's intellectual potential [88].
  3. Autoimmune thyroiditis:

According to a number of studies, a subclinical form of hypothyroidism may be associated with an increased risk of miscarriage, preterm birth, preeclampsia, increased fetal mortality, and developmental delays in children's neuropsychological functions and vision, depending on the threshold for TSH used to define the condition [82]. Furthermore, studies have shown that women with TSH levels less than 2.5 mU/L have much reduced miscarriage rates than those with levels greater than 2.5. In a large research of 17,298 pregnant women, Casey et al. established a relationship between subclinical hypothyroidism (TSH > 3) and an increased risk of premature birth (before 34 weeks) [89]. Cleary-Goldman et al., however, did not support these findings, finding no connection between high TSH and preterm delivery (before 37 weeks) [90].

• Effect on natural conception: TPO expression on mature granulosa cells was discovered by Dosiou et al. [91]. The relationship between thyroid autoimmunity (TAI) and infertility problems has been explained by three primary theories. According to the first, TAI is a reflection of a larger autoimmune activity that increases natural cytotoxicity; the second implies that TAI directly affects ovarian tissue; and the third links decreased fertility to the development of overt hypothyroidism as a result of TAI. Dosiou et al. have suggested a fourth mechanism: autoimmunity attacks the ovaries in the early stages, when levothyroxine is useless but inositol, antioxidants, and immunomodulators may be helpful [91]. A vicious loop is created when TAI progresses because the thyroid's reaction to hCG stimulation becomes less, leading to thyroid malfunction that is unable to meet the needs of pregnancy [91]. TAI has been linked to infertility that cannot be explained and may be a factor in decreased ovarian reserve, regardless of thyroid function. This is corroborated by the fact that women with infertility that cannot be explained frequently have low antral follicle numbers and increased TPOAb levels.
• Effects on ART outcomes: The impact of TAI on the results of assisted reproductive technology (ART) has been examined in a number of original studies and systematic reviews, while the results are still mixed. According to a meta-analysis of 1,098 IVF-treated subfertile women (141 with and 957 without TAI), the addition of TAI quadrupled the probability of miscarriage without appreciably altering clinical pregnancy or live delivery rates. These results were supported by larger and more recent meta-analyses, which found lower live birth rates [93] and higher preterm birth rates [92]. Busnelli et al. found an odds ratio (OR) of 1.44 [93], while Thangaratinam et al. reported an OR of 3.15 [92] for miscarriage. Notably, there was no discernible variation in ART outcomes in the most recent meta-analyses [94]. Poppe et al. (2018) analyzed four studies with 1,855 cycles (290 with TAI) and looked at the effect of TAI on pregnancy outcomes in infertile women undergoing ICSI (apart from IVF and IUI). No elevated risk of early miscarriage was identified [95]. Levothyroxine did not improve miscarriage rates in TAI-positive women on ART, according to another meta-analysis, although it did lower miscarriages in those who also had subclinical hypothyroidism, which may be dangerous on its own [75]. However, due in large part to a dearth of randomized controlled trials, little is known about the relationship between thyroid function and controlled ovarian hyperstimulation (COH).
• Effect on pregnancy and obstetric outcomes: Thyroid autoimmunity and pregnancy loss were originally linked by Stagnaro-Green, who found that patients with TAI had a twofold higher risk [96]. Later, numerous research and meta-analyses backed this up. With some publications indicating ORs as high as 2.9, even euthyroid women who test positive for TPOAb or TgAb seem to have a noticeably increased risk of premature birth [92]. Three sizable, recent prospective cohort studies, however, failed to discover a meaningful connection between TAI and preterm birth [97]. Placental abruption, postpartum depression, and an elevated risk of perinatal death are additional issues noted in women with TAI [97]. The neurodevelopment of children born to mothers with TAI has also been evaluated in a number of research; results have included sensorineural hearing loss and decreased motor and cognitive development. Williams et al. observed that children of TgAb-positive mothers had poorer motor and perceptual scores [98], and TgAb-positive cord blood was associated with lower perceptual scores. It is still up for dispute whether levothyroxine medication can lessen difficulties for both the mother and the fetus. A major experiment that used a set 50 mcg dose before conception found no substantial improvement in live birth rates, despite two randomized studies reporting a notable decrease in miscarriage with therapy [99]. However, a research indicated that thyroid hormone therapy decreased both miscarriage and preterm birth in euthyroid women with TAI [99], while another study reported a 69% decrease in preterm birth [92]. Interestingly, considering that ART did not lower miscarriage rates, these advantages might only apply to women who conceive naturally.

4. Management considerations:

1. Hypothyroidism:

Levothyroxine (L-T4) was used to treat biochemical hypothyroidism in 44 men in a research by Krassas et al. The SHIM questionnaire was used both before and one year after the patients reached a euthyroid condition. Originally seen in 84.1% (37 out of 44), a SHIM score of 21 or below indicated a degree of erectile dysfunction (ED). 29.5%, were still in this range. Following treatment, there was a significant improvement in SHIM scores (mean score increased from 17.0 to 24.0; P < 0.0001). A year later, treated patients' SHIM ratings did not change statistically from those of healthy controls [100]. L-T4 was used in a similar manner by Carani et al. to restore euthyroidism in 14 hypothyroid men. Significant decreases in intravaginal ejaculation latency time (IELT) were observed in half of the participants, along with a resolution of delayed ejaculation (DE). Interestingly, IELT dropped after therapy whether or not DE existed at baseline. The prevalence of ED dropped from 64.3% (9 out of 14) to 21.4% (3 out of 14). Intercourse satisfaction was the only individual dimension with a statistically significant change, despite the fact that IIEF ratings improved significantly. Following treatment, patients with hypoactive sexual desire disorder (HSDD) also reported significant symptom alleviation [66]. Sexual function in women was similarly positively impacted by thyroid hormone supplementation. According to Oppo et al., hypothyroid women who received treatment to attain euthyroidism saw complete normalization in the FSFI domains of pain, desire, and satisfaction, but only slight changes in the arousal and orgasm domains [101].

2. Hyperthyroidism:

Additionally, 27 hyperthyroid individuals on antithyroid medications such methimazole were examined by Krassas et al. Following treatment, the number of patients with SHIM scores indicating ED (≤21) decreased to 25.9% (7 of 27), down from 70.4% (19 of 27) prior to treatment. After reaching euthyroidism, SHIM scores significantly increased (mean score increased from 14.5 to 23.0; P<0.0001) [100]. After thyroid function returned to normal, 34 hyperthyroid males participated in another trial that shown significant improvements in IIEF scores, especially in the areas of erectile function and intercourse satisfaction. Premature ejaculation (PE) prevalence decreased from 50% to 15%, which is the predicted rate in the general population. The majority of subjects in the study also showed improvement or resolution of both DE and HSDD [66]. Thyroid hormone normalization dramatically decreased the prevalence of severe ED from 28.6% to 0%, according to additional research by Corona et al. [102]. Cihan et al. treated 24 hyperthyroid men with radioiodine (n = 7), thyroidectomy (n = 7), or antithyroid medication alone (n = 10). After treatment, the percentage of patients having definite PE, as determined by IELT, decreased from 66% (16 of 24) before to 25% (6 of 24). After therapy, the IELT also increased dramatically, going from 75.8 ± 99.3 seconds to 123 ± 96.4 seconds. All IIEF domains showed improvements as well, with the exception of intercourse satisfaction [103]. Similar to hypothyroidism, hyperthyroid women's sexual function improved in a number of ways after their thyroid levels returned to normal. Returning to a euthyroid condition considerably enhanced FSFI dimensions like desire, arousal, lubrication, satisfaction, and pain in a study involving 22 women; however, the orgasm domain showed no discernible changes. Interestingly, pain scores were still greater than those of healthy euthyroid controls even after improvements [101].

5. Conclusion and future perspectives:

The intricate relationship between thyroid function and human reproductive health underscores the essential role of thyroid hormones in maintaining sexual function and fertility across both sexes. Dysregulation of thyroid hormones-manifesting as either hypothyroidism or hyperthyroidism-has been consistently associated with a range of reproductive abnormalities. In men, thyroid dysfunction alters spermatogenesis, affects seminal parameters, and contributes to erectile and ejaculatory dysfunction. In women, thyroid disorders influence menstrual regularity, ovarian reserve, and contribute to infertility, miscarriage, and adverse pregnancy outcomes. Both genomic and non-genomic pathways mediate these effects, involving thyroid hormone receptors, transport proteins, and a network of endocrine and paracrine signals that interact with the hypothalamic-pituitary-gonadal axis.

Despite the accumulating evidence, several gaps persist. For instance, while the physiological influence of thyroid hormones on reproductive tissues is well described, the precise molecular mechanisms-especially those underpinning sex-specific effects-remain poorly elucidated. Furthermore, the threshold levels at which thyroid hormone deviations begin to significantly impair fertility parameters are not yet well standardized, especially in subclinical cases. Additionally, psychological and metabolic confounders, often present in thyroid disorders, are frequently overlooked when assessing sexual dysfunction.

Future research must focus on large-scale, longitudinal studies to clarify the temporal relationship between thyroid dysfunction and reproductive outcomes. There is also a need for integrative models that can delineate the interplay between thyroid hormones, other metabolic regulators (e.g., leptin, insulin), and inflammatory mediators in the context of reproductive dysfunction. The development of more precise biomarkers to predict reproductive risk in thyroid disease patients could enhance early intervention strategies.

Clinically, a multidisciplinary approach integrating endocrinology, andrology, gynecology, and mental health services is essential for optimal management. Early screening for thyroid dysfunction in individuals presenting with idiopathic infertility or unexplained sexual dysfunction may uncover reversible causes and improve therapeutic outcomes. Finally, future guidelines should aim to stratify risk based on thyroid hormone levels and reproductive profiles, thereby moving toward more personalized medicine in reproductive endocrinology.

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