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

The thyroid gland, shaped like a butterfly, is an endocrine structure situated beneath the thyroid cartilage in the neck of mammals [1]. It plays a central role in hormonal regulation as part of the hypothalamic-pituitary-thyroid (HPT) axis. As part of this hormonal regulatory system, the hypothalamus releases thyrotropin-releasing hormone (TRH), which in turn signals the anterior pituitary gland to produce and release thyroid-stimulating hormone (TSH). Thyroid-stimulating hormone (TSH) activates the thyroid gland to secrete the hormones thyroxine (T4) and triiodothyronine (T3), which exist in circulation either freely (biologically active) or bound to proteins (inactive) [2] (Figure 1). Within the bloodstream, T4 is mainly transformed into the more potent T3 form through enzymatic action by type I and type II deiodinases, predominantly located in tissues such as the liver, kidneys, muscles, and thyroid [3,4]. Approximately 80% of the T3 found in circulation originates from the conversion of T4 via the process of deiodination [5]. These thyroid hormones (THs) then travel swiftly to various tissues, where they regulate energy metabolism and support essential physiological processes, including those of the reproductive system.

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.

Thyroid disorders such as hypothyroidism and hyperthyroidism are frequently encountered in clinical practice and manifest through a wide range of symptoms that are well documented. The vast majority-about 95%-of hypothyroidism cases are due to dysfunction within the thyroid gland itself, and these are typically categorized as either overt or subclinical forms. In regions where iodine consumption is sufficient, the leading cause of hypothyroidism is autoimmune thyroiditis, commonly known as Hashimoto’s thyroiditis [6]. On the other hand, hyperthyroidism arises from a broader range of causes, with Graves’ disease being the most prevalent. This autoimmune disorder results from antibodies that imitate TSH, leading to excessive stimulation of the thyroid gland [6].

Data from the U.S. National Health and Nutrition Examination Survey III report that 4.6% of individuals are affected by hypothyroidism, with 0.3% presenting with overt disease and 4.3% with subclinical hypothyroidism. Women are significantly more likely to be affected, showing prevalence rates 5 to 8 times greater than those seen in men [7]. Women are disproportionately affected, with rates 5-8 times higher than in men [7]. While overt hypothyroidism in men is rare (0.1%), subclinical hypothyroidism still has a notable prevalence of 2.8% [8]. The same national survey reported that hyperthyroidism affects approximately 1.3% of the population, with overt cases comprising 0.5% and subclinical forms 0.7%. As with hypothyroidism, women are more frequently affected than men [7].

As outlined in Table 1, the symptom profiles of both thyroid conditions are well characterized. Diagnosis typically involves measuring serum TSH alongside free T4 and/or T3. A diagnosis of hypothyroidism is confirmed by elevated TSH levels (>5.0 mU/L) and low levels of free T4 or T3 [9], while hyperthyroidism presents with low TSH (<0.4 mU/L) and elevated free thyroid hormone levels [10].

Table 1: Common clinical signs and symptoms noted in patients with hypothyroidism or hyperthyroidism [11,12].

Standard treatment for hypothyroidism involves levothyroxine (synthetic T4) replacement therapy, which usually requires 4-6 weeks to normalize hormone levels. For hyperthyroidism, treatment options include radioactive iodine therapy, antithyroid drugs, or surgical removal of the thyroid gland.

1.1 Thyroid hormones production, transport, and mechanisms of action:

Thyroid hormones (THs) are synthesized in the thyroid gland and circulate through the bloodstream; however, their tissue-specific availability is predominantly regulated by a group of enzymes known as deiodinases [13]. There are three primary forms of these enzymes: DIO1, DIO2, and DIO3. DIO2 is responsible for converting the prohormone thyroxine (T4) into the active hormone triiodothyronine (T3), while DIO3 deactivates both T3 and T4. DIO1 has a dual role-it can either activate or deactivate THs-but it exhibits lower specificity and requires high substrate concentrations to convert T4 into T3 effectively [14,15]. Although T3 and T4 are lipid-soluble, they require the assistance of specific transport proteins to enter cells. These transporters include members of the monocarboxylate transporter (MCT) family-namely MCT8/SLC16A2 and MCT10/SLC16A10-as well as organic anion transporting polypeptides (OATPs), such as SLCO1C1 and OATP1C1 [16]. In murine models, Mct8 appears more essential than Mct10, as Mct8-deficient mice exhibit altered thyroid hormone profiles and tissue-specific imbalances, unlike Mct10-deficient mice [17]. In humans, mutations in the MCT8 gene result in Allan-Herndon-Dudley syndrome, a condition characterized by profound neurological deficits [18]. Interestingly, mice lacking Mct8 do not show such severe manifestations, possibly because they can still utilize T4 via Oatp1c1, which is then locally converted to T3 [17].

The actions of thyroid hormones are primarily mediated through their interaction with nuclear thyroid hormone receptors (THRs), specifically THRα and THRβ. These receptors remain inactive until bound by THs. Upon activation, THRs bind to specific DNA sequences known as thyroid hormone response elements (TREs), typically as heterodimers with retinoid X receptors (RXRs) [19]. TREs comprise two repeated sequences (AGGT/ACA), arranged in different configurations such as direct repeats or palindromes, where RXR generally binds the 5′ site and THR the 3′ site [20]. In the absence of hormone, THRs recruit corepressors to inhibit gene transcription. Hormone binding causes a conformational change in THRs, releasing corepressors and attracting coactivators, thereby enabling gene transcription [21,22] (Figure 2). The typical configuration of DNA binding sites includes a four-base pair spacer (DR4), although variations exist. Triiodothyronine (T3) exhibits nearly tenfold greater binding affinity for thyroid hormone receptors (THRs) compared to thyroxine (T4) [21]. Beyond these genomic functions, THs also exhibit non-genomic effects, meaning they influence cellular functions without directly affecting gene transcription. These actions occur rapidly-within seconds to minutes-compared to genomic responses [26]. Initial studies showed that T3 could associate with membranes of rat erythrocytes and liver mitochondria [27]. Further investigations demonstrated that THs can modulate ATP generation, oxygen consumption, pH levels, and ion transport [28]. These rapid effects contribute to maintaining cellular homeostasis, including ionic balance and structural integrity. Evidence also suggests a dynamic interplay between genomic and non-genomic actions, indicating a complex regulatory network [23]. Although the precise molecular mechanisms of non-genomic effects remain to be fully elucidated, these effects are initiated at the plasma membrane or in the cytoplasm [25]. Some involve a membrane-associated form of THRα that targets specific membrane regions after undergoing palmitoylation.

Moreover, THs may also act through the integrin αVβ3 receptor located on the cell surface. Stimulation of this receptor can enhance the expression of genes like FGF2, HIF1α, and THRA, while suppressing genes such as CASP3 and APAF1 [24]. These responses are thought to be more strongly elicited by T4, although it remains unclear whether T3 or T4 is the primary ligand for this receptor [24]. While direct evidence for sex-specific non-genomic TH effects is lacking, the fact that THs modulate immune responses-which are themselves sex-dependent-implies potential sex-related differences [29]. For instance, THs are critical for brain development, supporting processes such as neuronal growth and cytoskeletal dynamics through non-genomic pathways [30]. T3 also appears to promote neuroprotection by activating signaling molecules like Akt and nitric oxide synthase. Future studies are necessary to understand how these pathways may contribute to sex-based variations in brain function. The regulation and production of thyroid hormones are primarily governed by the hypothalamic-pituitary-thyroid (HPT) axis. The hypothalamus, specifically the paraventricular nucleus, secretes thyrotropin-releasing hormone (TRH), which is delivered to the anterior pituitary via the portal circulation. There, TRH induces the release of thyroid-stimulating hormone (TSH). Thyroid-stimulating hormone (TSH) acts on the thyroid gland, prompting it to synthesize and release thyroid hormones. These hormones, in turn, regulate TRH and TSH secretion through a negative feedback mechanism to maintain hormonal equilibrium [31].

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).

1.2 Overview of sexual dysfunction in males and females:

Significant disturbances in the sexual health of both men and women have been linked to thyroid disease. A complex and common disorder that affects both sexes, sexual dysfunction can have several underlying causes. It typically comprises of several connected symptoms, sometimes including several different illnesses. It may be difficult to tell certain symptoms or diseases apart because they might manifest in similar ways [32]. The International Index of Erectile Function (IIEF), which was first introduced in 1997, weighs five main factors to measure male sexual health: erectile function, orgasm, sexual desire, contentment with intercourse, and overall sexual satisfaction. Despite limitations, this technique is highly validated across cultures and is regarded the baseline for measuring male sexual function (Figure 3) [33–37].

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