Hypothyroidism is a clinical condition characterized by inadequate secretion of thyroid hormones—thyroxine (T₄) and triiodothyronine (T₃)—from the thyroid gland, leading to a generalized slowing of metabolic processes. It affects nearly 5% of the global population, with a striking female predominance; women are five to eight times more likely to develop hypothyroidism compared to men [1]. The higher prevalence among females can be attributed to a complex interplay of hormonal, genetic, immunological, and environmental factors. The disorder manifests through varied symptoms such as fatigue, weight gain, cold intolerance, cognitive dysfunction, and menstrual irregularities, significantly impacting quality of life and reproductive health [2,3].

Thyroid hormones control metabolism, heart function, reproduction, and brain development itself. Further, these hormones regulate many important body processes. As per medical knowledge, the thyroid gland sits in the front part of the neck and makes T₄ and T₃ hormones when the TSH hormone from the brain tells it to do so. Regarding its function, TSH comes from the front part of the pituitary gland in the brain. This process is actually controlled by the hypothalamic-pituitary-thyroid (HPT) axis [4]. The HPT system definitely regulates these functions. As per medical studies, any problem in this system can cause hypothyroidism, regarding issues from body attacking the gland to treatment-related causes.

Epidemiology and Gender Disparity

As per global data, hypothyroidism happens more in areas with low iodine and among older women. Regarding age and location, these two factors show higher rates of this thyroid problem. Studies actually show that 10-12% of women over 60 years definitely have some thyroid hormone problems [5]. In India, hypothyroidism actually affects 11% to 16% of women, making it definitely one of the most common hormone problems [6].

Thyroid disorders surely affect women more than men, and this gender difference is well-known. Moreover, doctors and researchers have clearly established this bias through many studies. Estrogen controls immune tolerance and can further increase autoimmune thyroid disease itself. Also, further, genetic factors linked to the X chromosome and differences in immune cells themselves contribute to this disparity [7].

Pregnancy and menopause are actually critical times when hormones definitely change how the thyroid works in the body. During pregnancy, estrogen actually increases a protein that binds thyroid hormones, so total hormone levels go up, but free hormones definitely drop for some time. Also, as per research, menopause changes the balance between estrogen and progesterone hormones, which increases the risk for autoimmune diseases that can cause hypothyroidism. Regarding this hormonal change, women may develop thyroid problems more easily after menopause [8].

Pathophysiology and Thyroid Hormone Regulation

The thyroid gland utilizes iodine to synthesize T₄ and T₃ via iodination and coupling reactions catalyzed by thyroid peroxidase (TPO) [9]. Autoimmune destruction of thyroid follicles, as seen in Hashimoto’s thyroiditis, impairs this process. In iodine-deficient conditions, synthesis is hindered, resulting in compensatory TSH elevation and goiter formation.

Thyroid hormone secretion is tightly controlled through a negative feedback mechanism. Low levels of circulating thyroid hormones stimulate thyrotropin-releasing hormone (TRH) from the hypothalamus and TSH from the pituitary, enhancing thyroid stimulation [10]. In primary hypothyroidism, the thyroid gland fails to respond adequately to TSH; in secondary or tertiary hypothyroidism, the defect lies in the pituitary or hypothalamus.

Autoimmune Etiology in Females

Autoimmune thyroiditis (Hashimoto’s disease) is the leading cause of hypothyroidism in iodine-sufficient populations. It is characterized by the presence of TPO and thyroglobulin antibodies (TgAb), lymphocytic infiltration of the gland, and gradual destruction of thyroid follicles [11]. The disorder often coexists with other autoimmune diseases such as type 1 diabetes, celiac disease, or systemic lupus erythematosus [12].

Females are more predisposed due to stronger humoral and cellular immune responses influenced by estrogen and X-linked immune regulatory genes [13]. Studies demonstrate that estrogen enhances B-cell survival and promotes the production of autoreactive antibodies, explaining the higher incidence in women [14]. Furthermore, pregnancy-induced immunomodulation can trigger postpartum thyroiditis, a transient but significant contributor to hypothyroidism in young mothers [15].

Iodine Deficiency and Environmental Factors

Iodine deficiency is actually the main cause of hypothyroidism which can definitely be prevented around the world. The thyroid itself needs about 150 µg of iodine daily for normal hormone production, and further research confirms this requirement [16]. In areas where people are not getting enough iodine in their food, we are seeing that thyroid hormone production goes down, which makes TSH levels go up and causes goiter to form. Universal salt iodization has reduced endemic goiter in many countries; however, iodine deficiency persists in certain rural areas and developing nations [17].

Environmental goitrogens—such as perchlorate, thiocyanate, and nitrate—found in contaminated water or food can interfere with iodine uptake by the sodium-iodide symporter (NIS) [18]. Basically, exposure to heavy metals like cadmium and lead, plus chemicals like bisphenol A and polychlorinated biphenyls (PCBs), causes the same thyroid problems in women [19]. These pollutants surely act like estrogen or work against thyroid function, and they change how our body accepts foreign substances. Moreover, they also disturb the pathways that make important hormones in our body.

Iatrogenic and Drug-Induced Causes

A considerable proportion of hypothyroidism cases in women arises from iatrogenic factors, particularly following treatment for hyperthyroidism, thyroid carcinoma, or neck irradiation [20]. We are seeing that radioiodine treatment works well for thyrotoxicosis, but it only destroys normal thyroid tissue and causes permanent hypothyroidism. As per surgical procedures, thyroidectomy also causes hormone shortage when a complete or nearly complete removal of the thyroid gland happens.

Several drugs can precipitate hypothyroidism, including amiodarone, lithium carbonate, interferon-α, and tyrosine kinase inhibitors [21]. Amiodarone, rich in iodine, can induce a "Wolff–Chaikoff effect," suppressing thyroid hormone synthesis. Lithium interferes with iodine organification and hormone release. These mechanisms are particularly concerning in women with pre-existing autoimmune susceptibility [22].

Genetic and Epigenetic Influences

Genetic predisposition plays a central role in hypothyroidism, especially autoimmune forms. Studies have identified associations between HLA-DR3, DR5, CTLA-4, PTPN22, and FOXP3 gene polymorphisms with Hashimoto’s thyroiditis [23]. Familial clustering suggests heritable susceptibility, though environmental triggers are necessary for disease expression.

Emerging evidence points to epigenetic modifications—DNA methylation, histone acetylation, and microRNA expression—as regulators of thyroid autoimmunity [24]. Chronic stress, infections, and exposure to endocrine disruptors can induce these changes, altering immune tolerance in genetically predisposed women.

Hormonal Modulation and Reproductive Health

We are seeing that female hormones and thyroid work together in both directions, where each one affects the other only. Basically, estrogen affects the liver, making TBG, changes how thyroid hormones work, and does the same with immune system control. Hypothyroidism further affects reproductive health by disturbing ovulation and causing irregular periods, which in itself increases the risk of infertility [25]. During pregnancy, untreated thyroid problems actually cause miscarriage and high blood pressure, and definitely affect the baby's brain development. As per these findings, regular thyroid check-ups are needed for women who can have babies. This shows the importance of thyroid screening for all women of childbearing age.

Rationale for the Present Review

Basically, hypothyroidism affects many women and has the same serious impact on their physical, emotional, and reproductive health, so understanding all the causes is crucial. Earlier studies actually looked at only one risk factor at a time—like iodine deficiency or autoimmunity—without considering others. These studies definitely examined each cause separately. Current evidence shows that genetic, hormonal, environmental, and psychosocial factors work together to determine when the disease starts and how it progresses further. The disease development itself depends on the dynamic interaction of these multiple factors. We are seeing that this review only wants to bring together different insights into one framework that shows risk factors specific to women's body functioning, helping to guide prevention and early detection methods that are sensitive to gender differences.

Hypothyroidism is a clinical condition characterized by inadequate secretion of thyroid hormones—thyroxine (T₄) and triiodothyronine (T₃)—from the thyroid gland, leading to a generalized slowing of metabolic processes. It affects nearly 5% of the global population, with a striking female predominance; women are five to eight times more likely to develop hypothyroidism compared to men [1]. The higher prevalence among females can be attributed to a complex interplay of hormonal, genetic, immunological, and environmental factors. The disorder manifests through varied symptoms such as fatigue, weight gain, cold intolerance, cognitive dysfunction, and menstrual irregularities, significantly impacting quality of life and reproductive health [2,3].

Thyroid hormones control metabolism, heart function, reproduction, and brain development itself. Further, these hormones regulate many important body processes. As per medical knowledge, the thyroid gland sits in the front part of the neck and makes T₄ and T₃ hormones when the TSH hormone from the brain tells it to do so. Regarding its function, TSH comes from the front part of the pituitary gland in the brain. This process is actually controlled by the hypothalamic-pituitary-thyroid (HPT) axis [4]. The HPT system definitely regulates these functions. As per medical studies, any problem in this system can cause hypothyroidism, regarding issues from body attacking the gland to treatment-related causes.

Epidemiology and Gender Disparity

As per global data, hypothyroidism happens more in areas with low iodine and among older women. Regarding age and location, these two factors show higher rates of this thyroid problem. Studies actually show that 10-12% of women over 60 years definitely have some thyroid hormone problems [5]. In India, hypothyroidism actually affects 11% to 16% of women, making it definitely one of the most common hormone problems [6].

Thyroid disorders surely affect women more than men, and this gender difference is well-known. Moreover, doctors and researchers have clearly established this bias through many studies. Estrogen controls immune tolerance and can further increase autoimmune thyroid disease itself. Also, further, genetic factors linked to the X chromosome and differences in immune cells themselves contribute to this disparity [7].

Pregnancy and menopause are actually critical times when hormones definitely change how the thyroid works in the body. During pregnancy, estrogen actually increases a protein that binds thyroid hormones, so total hormone levels go up, but free hormones definitely drop for some time. Also, as per research, menopause changes the balance between estrogen and progesterone hormones, which increases the risk for autoimmune diseases that can cause hypothyroidism. Regarding this hormonal change, women may develop thyroid problems more easily after menopause [8].

Pathophysiology and Thyroid Hormone Regulation

The thyroid gland utilizes iodine to synthesize T₄ and T₃ via iodination and coupling reactions catalyzed by thyroid peroxidase (TPO) [9]. Autoimmune destruction of thyroid follicles, as seen in Hashimoto’s thyroiditis, impairs this process. In iodine-deficient conditions, synthesis is hindered, resulting in compensatory TSH elevation and goiter formation.

Thyroid hormone secretion is tightly controlled through a negative feedback mechanism. Low levels of circulating thyroid hormones stimulate thyrotropin-releasing hormone (TRH) from the hypothalamus and TSH from the pituitary, enhancing thyroid stimulation [10]. In primary hypothyroidism, the thyroid gland fails to respond adequately to TSH; in secondary or tertiary hypothyroidism, the defect lies in the pituitary or hypothalamus.

Autoimmune Etiology in Females

Autoimmune thyroiditis (Hashimoto’s disease) is the leading cause of hypothyroidism in iodine-sufficient populations. It is characterized by the presence of TPO and thyroglobulin antibodies (TgAb), lymphocytic infiltration of the gland, and gradual destruction of thyroid follicles [11]. The disorder often coexists with other autoimmune diseases such as type 1 diabetes, celiac disease, or systemic lupus erythematosus [12].

Females are more predisposed due to stronger humoral and cellular immune responses influenced by estrogen and X-linked immune regulatory genes [13]. Studies demonstrate that estrogen enhances B-cell survival and promotes the production of autoreactive antibodies, explaining the higher incidence in women [14]. Furthermore, pregnancy-induced immunomodulation can trigger postpartum thyroiditis, a transient but significant contributor to hypothyroidism in young mothers [15].

Iodine Deficiency and Environmental Factors

Iodine deficiency is actually the main cause of hypothyroidism which can definitely be prevented around the world. The thyroid itself needs about 150 µg of iodine daily for normal hormone production, and further research confirms this requirement [16]. In areas where people are not getting enough iodine in their food, we are seeing that thyroid hormone production goes down, which makes TSH levels go up and causes goiter to form. Universal salt iodization has reduced endemic goiter in many countries; however, iodine deficiency persists in certain rural areas and developing nations [17].

Environmental goitrogens—such as perchlorate, thiocyanate, and nitrate—found in contaminated water or food can interfere with iodine uptake by the sodium-iodide symporter (NIS) [18]. Basically, exposure to heavy metals like cadmium and lead, plus chemicals like bisphenol A and polychlorinated biphenyls (PCBs), causes the same thyroid problems in women [19]. These pollutants surely act like estrogen or work against thyroid function, and they change how our body accepts foreign substances. Moreover, they also disturb the pathways that make important hormones in our body.

Iatrogenic and Drug-Induced Causes

A considerable proportion of hypothyroidism cases in women arises from iatrogenic factors, particularly following treatment for hyperthyroidism, thyroid carcinoma, or neck irradiation [20]. We are seeing that radioiodine treatment works well for thyrotoxicosis, but it only destroys normal thyroid tissue and causes permanent hypothyroidism. As per surgical procedures, thyroidectomy also causes hormone shortage when a complete or nearly complete removal of the thyroid gland happens.

Several drugs can precipitate hypothyroidism, including amiodarone, lithium carbonate, interferon-α, and tyrosine kinase inhibitors [21]. Amiodarone, rich in iodine, can induce a "Wolff–Chaikoff effect," suppressing thyroid hormone synthesis. Lithium interferes with iodine organification and hormone release. These mechanisms are particularly concerning in women with pre-existing autoimmune susceptibility [22].

Genetic and Epigenetic Influences

Genetic predisposition plays a central role in hypothyroidism, especially autoimmune forms. Studies have identified associations between HLA-DR3, DR5, CTLA-4, PTPN22, and FOXP3 gene polymorphisms with Hashimoto’s thyroiditis [23]. Familial clustering suggests heritable susceptibility, though environmental triggers are necessary for disease expression.

Emerging evidence points to epigenetic modifications—DNA methylation, histone acetylation, and microRNA expression—as regulators of thyroid autoimmunity [24]. Chronic stress, infections, and exposure to endocrine disruptors can induce these changes, altering immune tolerance in genetically predisposed women.

Hormonal Modulation and Reproductive Health

We are seeing that female hormones and thyroid work together in both directions, where each one affects the other only. Basically, estrogen affects the liver, making TBG, changes how thyroid hormones work, and does the same with immune system control. Hypothyroidism further affects reproductive health by disturbing ovulation and causing irregular periods, which in itself increases the risk of infertility [25]. During pregnancy, untreated thyroid problems actually cause miscarriage and high blood pressure, and definitely affect the baby's brain development. As per these findings, regular thyroid check-ups are needed for women who can have babies. This shows the importance of thyroid screening for all women of childbearing age.

Rationale for the Present Review

Basically, hypothyroidism affects many women and has the same serious impact on their physical, emotional, and reproductive health, so understanding all the causes is crucial. Earlier studies actually looked at only one risk factor at a time—like iodine deficiency or autoimmunity—without considering others. These studies definitely examined each cause separately. Current evidence shows that genetic, hormonal, environmental, and psychosocial factors work together to determine when the disease starts and how it progresses further. The disease development itself depends on the dynamic interaction of these multiple factors. We are seeing that this review only wants to bring together different insights into one framework that shows risk factors specific to women's body functioning, helping to guide prevention and early detection methods that are sensitive to gender differences.

Ethical Considerations

This review was based exclusively on previously published data; therefore, ethical approval was not required. However, the review adhered to ethical research principles by ensuring accurate citation of all primary sources, transparent reporting, and unbiased interpretation of evidence.

Overview of Included Studies [36,37]

A total of 58 studies were included in the final qualitative synthesis, representing diverse geographical regions—North America (n=16), Europe (n=13), Asia (n=19), Africa (n=6), and Latin America (n=4). The studies included randomized trials, observational cohorts, and population-based surveys published between 2000 and 2024. Collectively, they encompassed data from over 145,000 female participants aged 18 to 80 years.

Most studies reported primary hypothyroidism (82%), with secondary and subclinical forms comprising 12% and 6%, respectively. The highest prevalence was observed in peri-menopausal and post-menopausal women. Overall, autoimmune thyroiditis accounted for 55–65% of all female hypothyroidism cases, followed by iodine deficiency (20%), iatrogenic causes (10%), genetic factors (3%), and environmental exposures (2%) [36,37].

Autoimmune Etiology [38–40]

Autoimmune thyroiditis, primarily Hashimoto’s disease, emerged as the most dominant cause of hypothyroidism among women across all regions. Studies consistently reported elevated titers of thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb) in affected individuals [38]. The pathophysiology involves lymphocytic infiltration and progressive destruction of thyroid follicles mediated by cytotoxic T-cells.

Female predominance was evident, with a female-to-male ratio averaging 8:1. Genetic predisposition (HLA-DR3, DR5, CTLA-4, PTPN22 polymorphisms) and hormonal factors (estrogen-driven immune activation) were key contributors [39]. Postpartum thyroiditis accounted for up to 15% of cases in younger women, particularly within six months after delivery, underscoring the immune rebound phenomenon following pregnancy-induced immunosuppression [40].

Iodine Deficiency and Nutritional Factors [41,42]

In developing regions, iodine deficiency continues to represent a significant yet preventable cause of hypothyroidism. Among the 58 included studies, 12 highlighted the correlation between low urinary iodine levels and elevated TSH among rural women. Despite universal salt iodization programs, moderate deficiency persists due to inconsistent intake or consumption of non-iodized salt [41].

As per the research, micronutrient problems like lack of selenium, iron, and zinc were found in many cases along with iodine issues [42]. These deficiencies were commonly seen regarding thyroid health problems. Basically, selenium helps important enzymes work properly, and when selenium is low, the body cannot convert T₄ to T₃ the same way, which causes low thyroid hormone levels. Basically, iron deficiency anemia is the same problem that reduces thyroid peroxidase activity, especially in women during their periods and after childbirth. Further, studies showed that taking iodine and selenium together gave better results for thyroid function than taking iodine itself. Further research indicated this combination was more effective than iodine alone.

Iatrogenic and Drug-Induced Hypothyroidism [43,44]

A subset of studies highlighted iatrogenic hypothyroidism following treatment for hyperthyroidism, thyroid carcinoma, or neck malignancy. Radioiodine ablation was surely the most common cause mentioned in studies. Moreover, this treatment led to permanent thyroid damage in 70–90% of women who received it [43]. Surgical thyroidectomy also contributed significantly, especially where total or near-total resections were performed without postoperative hormone replacement.

Basically, medicines like amiodarone, lithium, interferon-α, and tyrosine kinase inhibitors can cause the same problem of low thyroid function [44]. Amiodarone-induced hypothyroidism was prevalent in iodine-sufficient regions (Europe, North America), whereas lithium-induced cases were more common among psychiatric patients receiving chronic therapy. We are seeing that the process stops iodine from working properly in the thyroid, reduces T₄ hormone release, and only triggers immune system problems in women who already have genetic risk factors.

Genetic and Epigenetic Influences [45,46]

Genetic analyses in multiple studies identified polymorphisms in immune-regulatory genes (e.g., HLA-DRB1, CTLA-4, FOXP3, PTPN22) as strong susceptibility markers for autoimmune thyroid disease in women [45]. Twin studies estimated heritability between 60–70%, indicating substantial genetic contribution.

Emerging research has emphasized epigenetic mechanisms—DNA methylation, histone modification, and microRNA dysregulation—as critical modulators of thyroid autoimmunity [46]. Environmental stressors such as viral infections, heavy metal exposure, and dietary toxins can trigger these epigenetic alterations, leading to aberrant immune activation against thyroid tissue. Such findings bridge the gap between genetic predisposition and environmental triggers, providing insight into why certain women develop hypothyroidism while others with similar genetics do not.

Environmental and Lifestyle Determinants [47,48]

Environmental pollutants are increasingly recognized as non-traditional causes of thyroid dysfunction. Studies revealed associations between hypothyroidism and exposure to endocrine-disrupting chemicals (EDCs) such as bisphenol A (BPA), phthalates, perchlorates, and polychlorinated biphenyls (PCBs) [47]. These compounds interfere with iodine uptake, thyroglobulin iodination, and thyroid hormone receptor signaling.

Lifestyle factors also play a role. Chronic psychological stress, poor sleep, obesity, and sedentary behavior were linked to altered hypothalamic-pituitary-thyroid (HPT) axis activity [48]. Stress-induced cortisol elevation suppresses TSH secretion and affects peripheral T₄ to T₃ conversion. Smoking, paradoxically, showed both protective and harmful associations in different populations—protective against autoimmune thyroiditis but detrimental in terms of thyrotoxicosis transition.

Hormonal and Reproductive Influences [49,50]

Reproductive physiology profoundly influences thyroid homeostasis in women. Studies showed that estrogen dominance, prevalent during pregnancy or from exogenous hormone use, increases thyroxine-binding globulin (TBG) levels, leading to transient changes in free hormone concentration [49].

Pregnancy represents a unique physiological stress test for the thyroid gland. Maternal hypothyroidism—especially in the first trimester—is associated with miscarriage, preeclampsia, and impaired neurodevelopment in offspring. Postpartum thyroiditis, a self-limiting inflammatory condition, affects 5–10% of women within six months of delivery and often progresses to permanent hypothyroidism.

Menopause, on the other hand, coincides with increased autoantibody titers and higher susceptibility to thyroid dysfunction due to the decline in estrogen’s immunomodulatory effects [50]. These hormonal transitions illustrate how female reproductive milestones—menarche, pregnancy, and menopause—form biological checkpoints that influence the onset and progression of hypothyroidism.

Key Etiological Factors of Hypothyroidism in Females

Summary of Findings

In summary, the etiology of hypothyroidism in females is multifactorial, with autoimmune thyroiditis remaining the predominant cause worldwide. However, regional and individual variations exist, influenced by iodine nutrition, genetic makeup, reproductive status, and environmental exposures. The review also highlights critical intersections—such as the interaction between hormonal status and immune regulation—that make women uniquely vulnerable to thyroid dysfunction.

The synthesis of 58 studies indicates that early-life exposures, dietary patterns, and hormonal fluctuations across the lifespan contribute synergistically to thyroid failure. Collectively, the findings underline the importance of comprehensive screening programs for women, integrating endocrine, nutritional, and reproductive assessments for timely intervention.

The findings of this systematic review reveal that the etiology of hypothyroidism in females is multifactorial, reflecting a complex interplay of genetic, hormonal, environmental, and immunological factors. Across the 58 included studies, autoimmune thyroiditis remained the predominant cause, followed by nutritional deficiencies, iatrogenic interventions, drug-induced mechanisms, and hormonal transitions related to pregnancy and menopause.

Global Patterns and Autoimmune Predominance [51,52]

Autoimmune thyroiditis, particularly Hashimoto’s disease, continues to be the leading cause of hypothyroidism in women worldwide. Its predominance across ethnic and geographical lines underscores the universal nature of autoimmune dysregulation influenced by female-specific immunomodulatory factors [51]. The higher incidence in women has been attributed to the immunoenhancing role of estrogen, which promotes B-cell activation and antibody synthesis while inhibiting T-cell suppression [52].

As per medical standards, (TPO) and thyroglobulin antibodies (TgAb) in blood tests confirm autoimmune hypothyroidism. Regarding diagnosis, these antibodies are the main markers doctors use to identify this thyroid condition. Some forms actually don't have antibodies, which definitely shows that other ways, like T-cells and cell death, also destroy the thyroid. Many studies show that antibody levels strongly relate to how severe the disease is and how it progresses further, especially during the postpartum and menopausal transitions.

Nutritional and Micronutrient Determinants [53,54]

Further, autoimmune causes surely dominate in rich countries; moreover, nutritional problems remain the main issue in poor regions. Iodine deficiency itself continues in rural and poor populations, despite global fortification programs being further implemented [53]. As per this deficiency, hormone production gets damaged, leading to high TSH and goiter formation. Regarding the process, the lack of proper hormone production causes these health problems. As per the study, selenium and iron deficiency were often seen as co-contributing factors regarding this condition. Selenium actually helps convert T₄ hormone to T₃ hormone in the body. When selenium levels are low, this conversion process definitely becomes less efficient.

Several studies further show that iron deficiency anemia itself makes hypothyroidism worse, especially in women who menstruate. We are seeing that low hemoglobin only makes it harder for body tissues to get oxygen, and this makes the thyroid problem symptoms worse. These results surely show that fixing micronutrient deficiency can be a simple but powerful way to prevent or reduce hypothyroidism [53]. Moreover, this approach offers an effective treatment strategy that is easy to implement.

Iatrogenic and Drug-Induced Hypothyroidism [55,56]

Iatrogenic hypothyroidism has emerged as a predictable but often under-monitored outcome of thyroid ablation therapies and oncological interventions. Post-radioiodine therapy and total thyroidectomy, most women develop permanent hormone dependency within a year [55].

Drug-induced thyroid dysfunction is another growing concern. Agents such as amiodarone, lithium, interferon-α, and tyrosine kinase inhibitors alter thyroid hormone synthesis or release, disrupt iodine metabolism, or provoke autoimmune responses [56]. Chronic exposure often leads to either reversible or permanent hypothyroidism depending on genetic predisposition and baseline thyroid reserve. Monitoring thyroid function in women undergoing long-term therapy with these medications is crucial for early intervention.

Genetic and Epigenetic Influences [57,58]

The review identifies significant genetic predispositions underlying female hypothyroidism, with variants in HLA-DR3, CTLA-4, PTPN22, and FOXP3 genes frequently associated with increased autoimmune susceptibility [57]. Twin studies reveal heritability estimates between 60–70%, confirming a strong genetic basis. However, genetics alone cannot explain the recent global rise in hypothyroidism prevalence, implying an interaction with environmental and hormonal modulators.

Emerging epigenetic research has added new depth to this understanding. DNA methylation and histone modification patterns, particularly in immune-regulatory genes, have been shown to differ markedly between women with and without hypothyroidism [58]. These epigenetic imprints are shaped by lifestyle, diet, and environmental toxins, explaining why hypothyroidism disproportionately affects women in urban and industrialized environments.

Environmental Triggers and Endocrine Disruptors [59]

The exposure of women to endocrine-disrupting chemicals (EDCs)—such as bisphenol A, perchlorates, and polychlorinated biphenyls—was repeatedly associated with altered thyroid function [59]. These compounds mimic or block natural hormones, interfere with iodine uptake, and disrupt thyroglobulin iodination. Long-term exposure, especially during reproductive years, compounds the risk for both subclinical and overt hypothyroidism.

Moreover, heavy metal toxicity (mercury, cadmium, lead) and smoking were identified as modifiers of thyroid autoimmunity. Interestingly, some studies reported paradoxical effects of smoking—reduced autoimmune activity but increased goitrogenic effects—highlighting the complexity of environmental interactions in thyroid physiology.

Hormonal and Reproductive Dimensions [60,61]

The intimate relationship between thyroid and reproductive function forms one of the most unique aspects of female endocrinology. Pregnancy, postpartum, and menopause represent critical windows of vulnerability for thyroid dysfunction [60]. During pregnancy, increased thyroxine-binding globulin (TBG) and heightened metabolic demand can unmask latent hypothyroidism. Postpartum, immune rebound triggers postpartum thyroiditis in up to 10% of women, often progressing to permanent hypothyroidism.

At menopause, declining estrogen levels contribute to immune dysregulation and increased autoantibody production, explaining the midlife surge in hypothyroidism prevalence [61]. This link underscores the need for proactive thyroid monitoring during reproductive transitions, particularly for women with family histories of thyroid disease or autoimmune disorders.

Integrative Pathophysiology and Cross-Mechanisms [62]

An integrative understanding of female hypothyroidism reveals intersecting biological axes:

• Immune axis: Estrogen amplifies B-cell activation; progesterone and testosterone act as immunosuppressants.
• Nutritional axis: Micronutrient deficiencies modulate enzyme and antioxidant pathways.
• Environmental axis: Chronic low-dose exposure to toxins alters thyroid receptor signaling.
• Neuroendocrine axis: Stress-induced cortisol elevation suppresses hypothalamic TSH release.

This interconnected framework suggests that hypothyroidism in women cannot be understood solely as a glandular disease—it reflects a systemic dysregulation influenced by lifestyle, hormonal balance, and immune adaptation.

Comparison with Global Epidemiological Data [63,64]

Globally, the prevalence of hypothyroidism among women ranges between 5% and 15%, with higher rates in South Asia, the Middle East, and parts of Europe [63]. Autoimmune thyroiditis dominates in iodine-sufficient areas, while nutritional deficiencies remain the leading cause in iodine-deficient populations.

Socioeconomic factors also influence disease burden. Women in low-income groups face compounded risks from poor diet, limited healthcare access, and delayed diagnosis. Contrastingly, in high-income countries, hypothyroidism often arises as a byproduct of overtreatment or chronic medication use. This dichotomy illustrates that while biological predisposition remains constant, contextual determinants significantly shape disease expression [64].

Clinical Implications and Public Health Perspectives [65]

This review surely shows that we need prevention strategies for many different factors. Moreover, a single approach will not work effectively for complete prevention. We are seeing that women who have just had babies and those going through menopause only need regular thyroid check-ups as part of their normal healthcare visits. We are seeing that giving people iodine and selenium can only help reduce thyroid problems in areas where many people have this disease.

Basically, doctors must recognize that commonly prescribed drugs can cause thyroid problems and ensure they monitor thyroid function at regular intervals using the same monitoring approach. Doctors should actually check thyroid levels before pregnancy and after delivery to definitely prevent hormone problems and brain development issues in mothers and babies.

This systematic review underscores that hypothyroidism in females is not a single-pathway disorder but a multifactorial condition shaped by genetics, hormonal regulation, nutrition, environment, and medical interventions. Across the 58 studies reviewed, autoimmune thyroiditis consistently emerged as the leading cause, reflecting the unique immunological susceptibility conferred by estrogen and X-linked genetic variations [66]. Nutritional deficiencies, particularly of iodine, selenium, and iron, remain persistent contributors in resource-limited settings, highlighting the interplay between endocrine and nutritional health [67].

The evidence reveals that women experience distinct life-stage vulnerabilities—notably during pregnancy, postpartum, and menopause—where fluctuating estrogen levels modulate immune tolerance and thyroid metabolism [68]. Moreover, widespread exposure to endocrine-disrupting chemicals, stress, and lifestyle transitions compound the risk in modern societies. Iatrogenic and drug-induced hypothyroidism continue to rise with the growing use of radioiodine therapy, lithium, and amiodarone, emphasizing the need for vigilant endocrine monitoring in therapeutic protocols [69].

The findings show that we need a combined approach with regular thyroid tests, better nutrition programs, and healthcare policies that consider gender differences. This strategy itself will further help improve both clinical care and public health outcomes. Finding thyroid problems early is actually very important for pregnant women and women going through menopause. This can definitely prevent serious heart, reproductive, and brain problems that happen when thyroid issues are not treated [70]. Working together across hormone studies, nutrition, and women's health fields is further needed to address this common condition itself.

We are seeing that future research should only focus on long-term studies across many centers that look at how genes and environment work together and find early signs of thyroid problems in women. Studying genes and gut bacteria together will actually change how we understand thyroid diseases. This approach will definitely help us know when and how these diseases start and get worse. Advances in precision medicine surely offer promising ways to personalize hypothyroidism treatment through individualized hormone replacement and nutrigenomic interventions. Moreover, these approaches can improve women's quality of life significantly [71].

Basically, hypothyroidism in women happens because biology, lifestyle, and environment all work together the same way to affect hormone health. By addressing the condition through both biomedical and social lenses, healthcare systems can move closer to preventing rather than merely treating thyroid dysfunction in women worldwide.

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