Thyroid Hormones and Functional Ovarian Reserve: Systemic vs. Peripheral Dysfunctions

Abstract

Thyroid hormones (THs) exert pleiotropic effects in different mammalian organs, including gonads. Genetic and non-genetic factors, such as ageing and environmental stressors (e.g., low-iodine intake, exposure to endocrine disruptors, etc.), can alter T₄/T₃ synthesis by the thyroid. In any case, peripheral T_3, controlled by tissue-specific enzymes (deiodinases), receptors and transporters, ensures organ homeostasis. Conflicting reports suggest that both hypothyroidism and hyperthyroidism, assessed by mean of circulating T₄, T₃ and Thyroid-Stimulating Hormone (TSH), could affect the functionality of the ovarian reserve determining infertility. The relationship between ovarian T₃ level and functional ovarian reserve (FOR) is poorly understood despite that the modifications of local T₃ metabolism and signalling have been associated with dysfunctions of several organs. Here, we will summarize the current knowledge on the role of TH signalling and its crosstalk with other pathways in controlling the physiological and premature ovarian ageing and, finally, in preserving FOR. We will consider separately the reports describing the effects of circulating and local THs on the ovarian health to elucidate their role in ovarian dysfunctions.

Keywords: anti-Müllerian hormone (AMH); functional ovarian reserve (FOR); ovarian ageing; ovarian follicle; thyroid hormone signalling; thyroid hormones (THs); thyroid-stimulating hormone (TSH).

Figure 1

HPT-axis and peripheral TH metabolism/signalling in mammals. (A) Hypothalamic-Pituitary-Thyroid (HPT)-axis and its regulatory feedback loops. (B) Mechanisms/enzymes and other proteins involved in the cell/tissue-specific TH metabolism and signalling. (C) Description of the species-specific pattern of the ensemble of proteins involved in TH metabolism and signalling in the ovary. The ovarian follicles are evidenced in the dashed rectangles. The zoom on a single follicle is reported in the upper dashed box in order to evidence the ensemble of the expressed proteins involved in peripheral TH metabolism and signalling. Abbreviations: TRH, thyrotropin releasing hormone; TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothyronine; T2, 3,5-diiodo-L-thyronine; rT3, reverse triiodothyronine; DIO1, DIO2, DIO3, deiodinases; MCT8–10, monocarboxylate transporter 8–10; OATP1C1, organic anion transporting polypeptide 1C1; αVβ3, integrin alpha (V) beta (3); TRα and TRβ, thyroid nuclear receptors isoform α, β; RXR, retinoic acid X receptor; ER, endoplasmic reticulum; Thra, thyroid hormone receptor alpha (Mouse); TRα1, TRα2, TRβ1 thyroid hormone receptors isoform α1, α2, β1 (Human).

Figure 2

Analysis of mouse Amh, Gdf9 and Bmp15 promoters. List of transcription factor binding sites that were identified by the Jaspar tool analysing the 3000 bp upstream sequence of the genes. The ENSEMBLE Transcript ID were: (Amh) ENSMUST00000036016.5; (Gdf9) ENSMUST00000018382.6; (Bmp15) ENSMUST00000024049.7.

Figure 3

Signalling pathways playing a positive or negative role in FOR homeostasis. The figure depicts the main signalling pathways involved in FOR maintenance and how they are impaired by altered TH signalling. Green and red boxes indicate negative and positive interactions playing a role in FOR homeostasis, respectively. Black dashed boxes define “unknown” interaction type. The reported molecular functions are publicly available in Cuomo et al., 2018. Abbreviation: T₃, triiodothyronine; AMH, anti-Müllerian hormone; GDF9, growth differentiation factor 9; BMP15, bone morphogenetic protein 15.