J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://jocmr.elmerjournals.com

Review

Volume 17, Number 8, August 2025, pages 409-422

Research on the Impact of Thyroid Disorders on Reproductive Function: A Narrative Review

Figure 1. The mechanisms of thyroid disorders affecting female fertility. Hypothyroidism disrupts follicular development via CHOP and caspase3-mediated apoptosis and causes metabolic imbalance in lipids and glucose accompanied by immune infiltration, impairing ovarian and uterine function. Endometrial receptivity is diminished due to low E2 osteopontin and HOXA10, while uterine gland function is impaired with reduced integrins and LIF and increased MUC1. Uterine hyperplasia and inflammation occur due to elevated VEGF-A, alongside decreased PLINA, TAG and TC. Hyperprolactinemia from excessive TRH and menstrual irregularities further reduce fertility. Hyperthyroidism leads to infertility by elevating SHBG and estradiol which disrupts folliculogenesis through impaired antral follicle growth and dysregulated NOS expression. It also suppresses FSH stimulated aromatase activity in ovarian steroidogenesis and causes decidual imbalance with elevated DBA-positive uNK cells and abnormal cytokine production. SCH contributes to infertility by promoting metabolic dysregulation in lipids and glucose and hyperprolactinemia reducing ovarian reserve and upregulating LIF/STAT3 signaling, which collectively impair endometrial receptivity and decidualization. TAI drives follicular inflammation through IFNγ-induced CXCL9/10/11-mediated recruitment of CXCR3⁺ T cells and enhances NK cell cytotoxicity. Non organ specific antibodies cross react with trophoblasts and disrupt Th1/Th2 balance promoting implantation failure and pregnancy loss. TPOAbs cross reactivity with hCG receptors on the zona pellucida, direct damage by TPOAb and TgAb to reproductive tissues, and reduced ovarian reserve and embryo quality further contribute to reproductive impairment. TSH: thyroid-stimulating hormone; FT4: free thyroxine; FT3: free triiodothyronine; CHOP: C/EBP homologous protein; TAG: triacylglycerol; HOXA10: homeobox A10; LIF: leukemia inhibitory factor; MUC1: mucin 1; VEGF-A: vascular endothelial growth factor A; PLIN-A: perilipin A; DBA: dolichos biflorus agglutinin; uNK: uterine natural killer; IFNγ: interferon-γ; CXCL9/10/11: CXC chemokine ligands 9; CXCR3: CXC chemokine receptor 3; TRH: thyrotropin-releasing hormone; FSH: follicle-stimulating hormone; SHBG: sex hormone-binding globulin; NOS: nitric oxide synthase; PRL: prolactin; TPOAbs: thyroid peroxidase antibodies; TgAbs: thyroglobulin antibodies; hCG: human chorionic gonadotropin; SCH: subclinical hypothyroidism; TAI: thyroid autoimmunity.

Figure 2. The mechanisms of thyroid disorders affecting male fertility. Hyperthyroidism impairs male fertility through multiple mechanisms: suppression of the HPG axis leads to decreased LH and FSH levels; increased SHBG reduces free testosterone; elevated aromatase activity enhances the conversion of testosterone to estrogen; oxidative stress causes sperm membrane and DNA damage; and elevated scrotal temperature impairs spermatogenesis. Hypothyroidism affects fertility via increased hypothalamic Pdyn, which suppresses GnRH release resulting in hypogonadism; reduced PI3K/AKT signaling disrupts thyroid-leptin crosstalk; decreased MAPK/ERK activity contributes to HPG axis suppression; impaired unfolded protein response in the testes; Leydig cell cytotoxicity; and secondary effects such as depression and erectile dysfunction. Subclinical hypothyroidism contributes to infertility through erectile dysfunction, oxidative stress, and increased sperm DFI. TSH: thyroid-stimulating hormone; FT4: free thyroxine; FT3: free triiodothyronine; GnRH: gonadotropin-releasing hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; SHBG: sex hormone-binding globulin; PRL: prolactin; HPG: hypothalamic-pituitary-gonadal; UPR: unfolded protein response; ED: erectile dysfunction; DFI: DNA fragmentation index.

**Table 1.** Multiple Pathogenic Mechanisms Underlie Thyroid Disorder-Induced Infertility
Thyroid disorders	Gender	Pathogenic mechanisms	Reference
GRP78: glucose-regulated protein 78; CHOP: C/EBP homologous protein; TAG: triacylglycerol; TC: total cholesterol; HOXA10: homeobox A10; LIF: leukemia inhibitory factor; MUC1: mucin 1; VEGF-A: vascular endothelial growth factor A; PR: progesterone receptor; ER: estrogen receptor; TRs: thyroid hormone receptors; PLIN-A: perilipin A; DBA: dolichos biflorus agglutinin; uNK: uterine natural killer; IFNγ: interferon-γ; CXCL9/10/11: CXC chemokine ligands 9; CXCR3: CXC chemokine receptor 3; TRH: thyrotropin-releasing hormone; GnRH: gonadotropin-releasing hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; SHBG: sex hormone-binding globulin; NOS: nitric oxide synthase; PRL: prolactin; HPG: hypothalamic-pituitary-gonadal; SV: seminal vesicle; UPR: unfolded protein response; SCs: Sertoli cells; ED: erectile dysfunction; DFI: DNA fragmentation index; TPOAbs: thyroid peroxidase antibodies; TgAbs: thyroglobulin antibodies; hCG: human chorionic gonadotropin; GSSG/GSH: oxidized glutathione to reduced glutathione ratio.
Overt hypothyroidism	Female	Reduce the number of primordial, primary, and preantral follicles, as well as antral follicles and corpora lutea.	[7]
		Activate the apoptotic signaling pathway by downregulating GRP78 and upregulating CHOP and cleaved caspase-3, thereby suppressing follicular development.	[8]
		Alter the level of TAG, TC, oxidized lipids, glycogen, and immune cell infiltration into the ovary and uterus.	[9]
		Affect embryo implantation by lowering E2 levels and reducing the expression of osteopontin and homeobox A10.	[10]
		Cause uterine gland hypertrophy by decreasing integrin β3, integrin αvβ3, LIF, and HOXA10 immune reaction intensities and enhancing MUC1 immunoreactivity.	[11]
		Promote uterine hyperplasia and inflammation through increased expression of VEGF-A, PR, ER, and TRs and decreased uterine content of PLIN-A, TAG, and TC.	[12]
		Cause anovulation and reduce luteal phase function by altering hormone secretion.	[13]
		Induce hyperprolactinemia by stimulating excessive TRH production.	[7]
		Disturb menstrual cycle.	[14]
Overt hyperthyroidism		Induce hormonal alterations, such as elevated levels of SHBG and excessively elevated levels of estradiol.	[7]
		Inhibit the growth of large antral follicles by lowering estrogen and hindering NOS activity.	[15]
		Disrupted ovarian steroidogenesis.	[16]
		Cause an imbalance in the DBA⁺ uNKs cell population and the inflammatory cytokine profile in decidua.	[17]
Overt hypothyroidism	Male	Cause direct damage to testicular Leydig cells, further compromising testosterone synthesis	[19]
		Disrupt crosstalk between thyroid and leptin hormone by downregulating PI3K/AKT signaling pathway.	[20]
		Cause a decline in baseline levels of FSH and LH.	[21]
		Cause hypogonadotropic hypogonadism by impairing the pulsatile production of GnRH through an increase in PRL.	[22]
		Inhibit the HPG axis by upregulating hypothalamic Pdyn expression. Suppress the testicular Kiss1/Kiss1r signaling pathway.	[23]
		Downregulate the expression of genes associated with sperm viability, capacitation, fertilization, oxidative stress defense, and energetic metabolism in the SV.	[24]
		Disrupt the UPR pathway in testicular tissue and induce oxidative stress.	[25]
		Induce alterations in the functional state of SCs and disorders in the process of meiosis that resulted in sperm absence.	[26]
		Disrupt the hypothalamic-pituitary-testicular axis by downregulating nesfatin-1 and subsequently inhibiting the MAPK/ERK signaling pathway.	[27]
		Impair spermatogenesis by raising plasma total homocysteine, total NO metabolites, malondialdehyde, and the GSSG/GSH ratio, as well as by altering intra-mitochondrial thiol redox state.	[28]
		Cause ED.	[29]
		Cause weight gain, fat storage, depression and anxiety.	[30]
Overt hyperthyroidism		Suppress the HPG axis, lowering gonadotropin release (including LH and FSH).	[31]
		Upregulate aromatase activity, thereby accelerating the conversion of testosterone to estrogen.	[32]
		Promote excessive free radical generation, leading to oxidative stress that compromises sperm membrane integrity and causes DNA damage.	[33]
		Increase scrotal temperatures.	[34]
Subclinical hypothyroidism	Female	Exacerbate lipid and glucose metabolic dysregulation.	[35]
		Induce hyperprolactinemia.	[36]
		Influence ovarian reserve.	[37]
		Upregulate the LIF/STAT3 signaling pathway, ultimately leading to decreased endometrial receptivity.	[38]
		Impair decidualization.	[39]
	Male	Elevate risk of abnormal sperm DFI.	[40]
		Cause oxidative stress.	[41]
		Induce ED.	[5]
Thyroid autoimmunity	Female	Initiate an inflammatory cascade mediated by the IFNγ-CXCL9/10/11-CXCR3⁺ T lymphocyte axis within the follicular microenvironment.	[44]
		Work with various autoimmune disorders to exert adverse effects on fertility and pregnancy outcomes.	[45]
		Promotes excessive activation and cytotoxicity of NK cells in uterine tissue.
		Exhibit non-organ-specific antibodies capable of interacting with trophoblastic/placental tissues.	[46]
		Induce implantation failure and pregnancy loss by disrupting the systemic balance of helper lymphocyte subsets. TPOAbs exhibit cross-reactivity with hCG receptors located in the zona pellucida.	[47]
		TPOAbs and TgAbs cause damage to reproductive organs expressing TPO and Tg.	[49]
		TPOAbs negatively impact ovarian reserve and embryo quality.	[50]

Table 1. Multiple Pathogenic Mechanisms Underlie Thyroid Disorder-Induced Infertility

Thyroid disorders

Gender

Pathogenic mechanisms

Reference

GRP78: glucose-regulated protein 78; CHOP: C/EBP homologous protein; TAG: triacylglycerol; TC: total cholesterol; HOXA10: homeobox A10; LIF: leukemia inhibitory factor; MUC1: mucin 1; VEGF-A: vascular endothelial growth factor A; PR: progesterone receptor; ER: estrogen receptor; TRs: thyroid hormone receptors; PLIN-A: perilipin A; DBA: dolichos biflorus agglutinin; uNK: uterine natural killer; IFNγ: interferon-γ; CXCL9/10/11: CXC chemokine ligands 9; CXCR3: CXC chemokine receptor 3; TRH: thyrotropin-releasing hormone; GnRH: gonadotropin-releasing hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; SHBG: sex hormone-binding globulin; NOS: nitric oxide synthase; PRL: prolactin; HPG: hypothalamic-pituitary-gonadal; SV: seminal vesicle; UPR: unfolded protein response; SCs: Sertoli cells; ED: erectile dysfunction; DFI: DNA fragmentation index; TPOAbs: thyroid peroxidase antibodies; TgAbs: thyroglobulin antibodies; hCG: human chorionic gonadotropin; GSSG/GSH: oxidized glutathione to reduced glutathione ratio.

Overt hypothyroidism

Female

Reduce the number of primordial, primary, and preantral follicles, as well as antral follicles and corpora lutea.

[7]

Activate the apoptotic signaling pathway by downregulating GRP78 and upregulating CHOP and cleaved caspase-3, thereby suppressing follicular development.

[8]

Alter the level of TAG, TC, oxidized lipids, glycogen, and immune cell infiltration into the ovary and uterus.

[9]

Affect embryo implantation by lowering E2 levels and reducing the expression of osteopontin and homeobox A10.

[10]

Cause uterine gland hypertrophy by decreasing integrin β3, integrin αvβ3, LIF, and HOXA10 immune reaction intensities and enhancing MUC1 immunoreactivity.

[11]

Promote uterine hyperplasia and inflammation through increased expression of VEGF-A, PR, ER, and TRs and decreased uterine content of PLIN-A, TAG, and TC.

[12]

Cause anovulation and reduce luteal phase function by altering hormone secretion.

[13]

Induce hyperprolactinemia by stimulating excessive TRH production.

[7]

Disturb menstrual cycle.

[14]

Overt hyperthyroidism

Induce hormonal alterations, such as elevated levels of SHBG and excessively elevated levels of estradiol.

[7]

Inhibit the growth of large antral follicles by lowering estrogen and hindering NOS activity.

[15]

Disrupted ovarian steroidogenesis.

[16]

Cause an imbalance in the DBA⁺ uNKs cell population and the inflammatory cytokine profile in decidua.

[17]

Overt hypothyroidism

Male

Cause direct damage to testicular Leydig cells, further compromising testosterone synthesis

[19]

Disrupt crosstalk between thyroid and leptin hormone by downregulating PI3K/AKT signaling pathway.

[20]

Cause a decline in baseline levels of FSH and LH.

[21]

Cause hypogonadotropic hypogonadism by impairing the pulsatile production of GnRH through an increase in PRL.

[22]

Inhibit the HPG axis by upregulating hypothalamic Pdyn expression. Suppress the testicular Kiss1/Kiss1r signaling pathway.

[23]

Downregulate the expression of genes associated with sperm viability, capacitation, fertilization, oxidative stress defense, and energetic metabolism in the SV.

[24]

Disrupt the UPR pathway in testicular tissue and induce oxidative stress.

[25]

Induce alterations in the functional state of SCs and disorders in the process of meiosis that resulted in sperm absence.

[26]

Disrupt the hypothalamic-pituitary-testicular axis by downregulating nesfatin-1 and subsequently inhibiting the MAPK/ERK signaling pathway.

[27]

Impair spermatogenesis by raising plasma total homocysteine, total NO metabolites, malondialdehyde, and the GSSG/GSH ratio, as well as by altering intra-mitochondrial thiol redox state.

[28]

Cause ED.

[29]

Cause weight gain, fat storage, depression and anxiety.

[30]

Overt hyperthyroidism

Suppress the HPG axis, lowering gonadotropin release (including LH and FSH).

[31]

Upregulate aromatase activity, thereby accelerating the conversion of testosterone to estrogen.

[32]

Promote excessive free radical generation, leading to oxidative stress that compromises sperm membrane integrity and causes DNA damage.

[33]

Increase scrotal temperatures.

[34]

Subclinical hypothyroidism

Female

Exacerbate lipid and glucose metabolic dysregulation.

[35]

Induce hyperprolactinemia.

[36]

Influence ovarian reserve.

[37]

Upregulate the LIF/STAT3 signaling pathway, ultimately leading to decreased endometrial receptivity.

[38]

Impair decidualization.

[39]

Male

Elevate risk of abnormal sperm DFI.

[40]

Cause oxidative stress.

[41]

Induce ED.

[5]

Thyroid autoimmunity

Female

Initiate an inflammatory cascade mediated by the IFNγ-CXCL9/10/11-CXCR3⁺ T lymphocyte axis within the follicular microenvironment.

[44]

Work with various autoimmune disorders to exert adverse effects on fertility and pregnancy outcomes.

[45]

Promotes excessive activation and cytotoxicity of NK cells in uterine tissue.

Exhibit non-organ-specific antibodies capable of interacting with trophoblastic/placental tissues.

[46]

Induce implantation failure and pregnancy loss by disrupting the systemic balance of helper lymphocyte subsets. TPOAbs exhibit cross-reactivity with hCG receptors located in the zona pellucida.

[47]

TPOAbs and TgAbs cause damage to reproductive organs expressing TPO and Tg.

[49]

TPOAbs negatively impact ovarian reserve and embryo quality.

[50]

**Table 2.** Thyroid-Targeted Therapeutic Interventions for Infertility
Therapeutic interventions	Thyroid disorders	Gender	Outcomes	Reference
TPOAbs: thyroid peroxidase antibodies; TgAbs: thyroglobulin antibodies; Se: selenium; ALA: alpha-lipoic acid; CBZ: carbimazole; VE: vitamin E; PRP: platelet-rich plasma; Kp10: kisspeptin-10; LH: luteinizing hormone; ECE: Elettaria cardamomum extract.
Levothyroxine	Overt/subclinical hypothyroidism	Female	Decrease the incidence of pregnancy loss.	[12]
			Mitigate the detrimental impact of hypothyroidism on endometrial receptivity.	[10]
Se	Thyroid autoimmunity	Male	Reduce serum levels of TPOAb and TgAb.	[54]
Melatonin	Overt hypothyroidism	Male	Ameliorate gonadal dysfunction associated with hypothyroidism.	[55]
			Stimulate testosterone production.
		Female	Boost T4 levels and stabilized T3 serum levels, thereby reversing hypothyroidism-induced ovarian follicle loss.	[56]
ALA	Overt hypothyroidism	Male	Mitigate the toxic effects of hypothyroidism on spermatogenesis by enhancing the structural integrity of testicular tissues and providing protection against oxidative damage in the testicular environment.	[57]
CBZ combined VE	Overt hyperthyroidism	Male	Attenuate testicular injury through VE’s protective effects against oxidative stress-induced cellular damage.	[58]
PRP	Overt hypothyroidism	Male	Enhance testicular morphology and function. Promote germ cell proliferation.	[59]
Kisspeptin analogs	Overt hypothyroidism	Male	Activate the testicular Kiss1/Kiss1r signaling pathway.	[23]
Kp10	Overt hypothyroidism	Female	Ameliorate ovarian dysfunction by restoring estrous cycle regularity, normalizing plasma LH levels, improving ovarian and uterine morphology, and upregulating mRNA expression of Cyp11a1, 3β-Hsd, and 20α-Hsd in the corpora lutea.	[60]
ECE	Overt hypothyroidism	Male	Counteract the inhibitory effects of hypothyroidism on testicular tissue, enhance spermatogenesis by increasing the number of germ cells, and stimulate testosterone secretion.	[61]

Table 2. Thyroid-Targeted Therapeutic Interventions for Infertility

Therapeutic interventions

Thyroid disorders

Gender

Outcomes

Reference

TPOAbs: thyroid peroxidase antibodies; TgAbs: thyroglobulin antibodies; Se: selenium; ALA: alpha-lipoic acid; CBZ: carbimazole; VE: vitamin E; PRP: platelet-rich plasma; Kp10: kisspeptin-10; LH: luteinizing hormone; ECE: Elettaria cardamomum extract.

Levothyroxine

Overt/subclinical hypothyroidism

Female

Decrease the incidence of pregnancy loss.

[12]

Mitigate the detrimental impact of hypothyroidism on endometrial receptivity.

[10]

Thyroid autoimmunity

Male

Reduce serum levels of TPOAb and TgAb.

[54]

Melatonin

Overt hypothyroidism

Male

Ameliorate gonadal dysfunction associated with hypothyroidism.

[55]

Stimulate testosterone production.

Female

Boost T4 levels and stabilized T3 serum levels, thereby reversing hypothyroidism-induced ovarian follicle loss.

[56]

ALA

Overt hypothyroidism

Male

Mitigate the toxic effects of hypothyroidism on spermatogenesis by enhancing the structural integrity of testicular tissues and providing protection against oxidative damage in the testicular environment.

[57]

CBZ combined VE

Overt hyperthyroidism

Male

Attenuate testicular injury through VE’s protective effects against oxidative stress-induced cellular damage.

[58]

PRP

Overt hypothyroidism

Male

Enhance testicular morphology and function. Promote germ cell proliferation.

[59]

Kisspeptin analogs

Overt hypothyroidism

Male

Activate the testicular Kiss1/Kiss1r signaling pathway.

[23]

Kp10

Overt hypothyroidism

Female

Ameliorate ovarian dysfunction by restoring estrous cycle regularity, normalizing plasma LH levels, improving ovarian and uterine morphology, and upregulating mRNA expression of Cyp11a1, 3β-Hsd, and 20α-Hsd in the corpora lutea.

[60]

ECE

Overt hypothyroidism

Male

Counteract the inhibitory effects of hypothyroidism on testicular tissue, enhance spermatogenesis by increasing the number of germ cells, and stimulate testosterone secretion.

[61]