Extrathyroidal expression of TSH receptor. Williams GR et al. (2011) The TSH receptor expressed on the cell surface of thyroid follicular cells plays a pivotal role in the regulation of thyroid status and growth of the thyroid gland. In recent years it has become evident that the TSH receptor is also expressed widely in a variety of extrathyroidal tissues including: anterior pituitary; hypothalamus; ovary; testis; skin; kidney; immune system; bone marrow and peripheral blood cells; white and brown adipose tissue; orbital preadipocyte fibroblasts and bone. A large body of evidence is emerging to describe the functional roles of the TSH receptor at these various sites but their physiological importance in many cases remains a subject of controversy and much interest. Current understanding of the actions of the TSH receptor in extrathyroidal tissues and their possible physiological implications is discussed.//////////////////
Molecular basis of thyrotropin and thyroid hormone action during implantation and early development. Colicchia M et al. (2014) Implantation and early embryo development are finely regulated processes in which several molecules are involved. Evidence that thyroid hormones (TH: T4 and T3) might be part of this machinery is emerging. An increased demand for TH occurs during gestation, and any alteration in maternal thyroid physiology has significant implications for both maternal and fetal health. Not only overt but also subclinical hypothyroidism is associated with infertility as well as with obstetric complications, including disruptions and disorders of pregnancy, labor, delivery, and troubles in early neonatal life. We searched the PubMed and Google Scholar databases for articles related to TH action on ovary, endometrium, trophoblast maturation and embryo implantation. In addition, articles on the regulation of TH activity at cellular level have been reviewed. The findings are hereby summarized and critically discussed. TH have been shown to influence endometrial, ovarian and placental physiology. TH receptors (TR) and thyrotropin (thyroid-stimulating hormone: TSH) receptors (TSHR) are widely expressed in the feto-maternal unit during implantation, and both the endometrium and the trophoblast might be influenced by TH either directly or through TH effects on the synthesis and activity of implantation-mediating molecules. Interestingly, due to the multiplicity of mechanisms involved in TH action (e.g. differential expression of TR isoforms, heterodimeric receptor partners, interacting cellular proteins, and regulating enzymes), the TH concentration in blood is not always predictive of their cellular availability and activity at both genomic and nongenomic level. In addition to the known role of TH on the hormonal milieu of the ovarian follicle cycle, which is essential for a woman's fertility, evidence is emerging on the importance of TH signaling during implantation and early pregnancy. Based on recent observations, a local action of TH on female reproductive organs and the embryo during implantation appears to be crucial for a successful pregnancy. Furthermore, an imbalance in the spatio-temporal expression of factors involved in TH activity might induce early arrest of pregnancy in women considered as euthyroid, based on their hormonal blood concentration. In conclusion, alterations of the highly regulated local activity of TH may play a crucial, previously underestimated, role in early pregnancy and pregnancy loss. Further studies elucidating this topic should be encouraged.//////////////////
Kumar RS, et al., (2000) Cloned a thyrotropin receptor from the gonads (ovary and testis) of a vertebrate (bony fish) and proposed a potential thyroid-independent role for thyrotropin in reproduction. RT-PCR analysis demonstrated that the striped bass TSHR (stbTSHR, gi:8886877) transcripts were abundant in both the thyroid and gonads and detectable in skeletal muscle, heart and brain tissues. The stbTSHR cDNA encoded a 779-amino acid glycoprotein hormone receptor with much higher homology (57-59%) to the mammalian TSH receptors than the mammalian LH receptors (47-49%) and FSH receptors (47%), and salmon and catfish gonadotropin receptors (42-45%). There was a TSHR-specific insertion in the extracellular domain as seen in mammalian receptors. Moreover, PCR analysis of genomic DNA indicated the absence of the LHR-specific intron in the striped bass TSHR gene. Recombinant stbTSHR expressed in COS1 cells activated reporter genes (luciferase) driven by either a cAMP response element or the c-fos promoter in response to bovine TSH, stbLH or hCG, but not human FSH. In situ hybridization studies revealed the presence of stbTSHR transcripts in the gametes but not in the follicular cells. This pattern of expression is unique and suggests a direct, albeit unknown, role for TSH in gamete physiology.
NCBI Summary:
The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
General function
Receptor
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Cellular localization
Plasma membrane
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Ovarian function
Luteinization
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Hypothyroidism prolongs corpus luteum function in the pregnant rat. Hapon MB et al. (2007) It has been shown that hypothyroidism in the rat produces a prolongation of pregnancy associated with a delay in the fall of circulating progesterone (P4) at term. The aim of the present work is to determine whether the delayed P4 decline in hypothyroid mother rats is due to a retarded induction of P4 degradation to 20alphaOH P4 or to a stimulation of its synthesis, and to investigate the possible mechanisms that may underlie the altered luteal function. We determined by RIA the circulating profile of the hormones (TSH, PRL, LH, P4, PGF2alpha, and PGE2) involved in luteal regulation at the end of pregnancy and, by semiquantitative RT-PCR, the expression of factors involved in P4 synthesis (CytP450scc, StAR, 3betaHSD, PRLR) and metabolism (20alphaHSD, PGF2alphaR, iNOS and COX2). Our results show that the delay in P4 decline and parturition is the resultant of retarded luteal regression, caused by a combination of decreases in luteolytic factors, mainly luteal PGF2alpha, iNOS mRNA expression and also circulating LH, and increased synthesis or action of luteotrophic factors, such as luteal and circulating PGE2 and circulating PRL. All these changes may be direct causes of the decreased 20alphaHSD mRNA and protein (measured by western blot analysis) expression, which in the presence of unchanged expression of the factors involved in P4 synthesis results in elevated luteal and circulating P4 that prolonged pregnancy and also may favor longer survival of the corpus luteum.//////////////////
Expression regulated by
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Ovarian localization
Granulosa, Luteal cells
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Thyrostimulin, but not thyroid-stimulating hormone, acts as a paracrine regulator to activate thyroid-stimulating hormone receptor in the mammalian ovary. Sun SC et al. Thyroid-stimulating hormone receptor (TSHR), activated by either TSH or a newly discovered glycoprotein hormone thyrostimulin, plays a central role in the control of body metabolism. Interestingly, in addition to its thyroid expression, we discovered the mRNA level of THSR is periodically regulated in the rat ovary by gonadotropins. Ovarian microdissection followed by real-time PCR analysis indicated granulosa cells show the highest level of TSHR expression. Cultures of follicles and primary granulosa cells demonstrated the level of TSHR is up-regulated and dampened by the gonadotropin-driven cAMP cascade and estradiol production, respectively. Furthermore, in contrast to the negligible expression of TSH in the ovary, we also found by real-time PCR and immunohistochemical analysis that thyrostimulin is mainly expressed in oocytes. Thyrostimulin, evolving before the appearance of gonadotropins, is considered the most ancestral glycoprotein hormone. Therefore, the presence of thyrostimulin in the ovary suggests it may have a primitive function in reproduction when it activates ovarian TSHR. Next, we generated recombinant thyrostimulin protein and characterized its non-covalent heterodimeric nature. Using purified recombinant thyrostimulin, we showed the human ovarian cell line NIH:OVCAR-3 also expresses endogenous and functional TSHR. Using cultured rat granulosa cells isolated from different ovarian stages, we found that treatment with thyrostimulin increased the cAMP production and c-fos gene response significantly in the presence of gonadotropins. Thus, this study demonstrates that oocyte-derived thyrostimulin and granulosa cell-expressed TSHR comprise a novel paracrine system in the ovary, where the activity is tightly controlled by gonadotropins.
Receptors for thyroid-stimulating hormone and thyroid hormones in human ovarian tissue. Aghajanova L et al. Dysfunction in thyroid regulation can cause menstrual and ovulatory disturbances, the mechanism of which is not clear. The distribution and activity of the thyroid-stimulating hormone (TSHR), and the thyroid hormone receptors (TR) alpha1, alpha2 and beta1 in human ovarian tissue and in granulosa cells was studied using immunohistochemistry, reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative PCR and immunoassays. Strong immunostaining of TSHR, TRalpha1 and TRbeta1 was observed in ovarian surface epithelium and in oocytes of primordial, primary and secondary follicles, with minimal staining in granulosa cells of secondary follicles. Granulosa cells of antral follicles expressed TSHR, TRalpha1 and TRbeta1 proteins. Messenger RNA for all receptors was present in ovarian tissue. Mature human granulosa cells expressed transcripts for 5' deiodinases types 2 and 3, but not type 1, indicating the possibility of conversion of peripheral thyroid hormone thyroxin (T(4)). Granulosa cells stimulated with TSH showed a significant increase in cAMP concentrations after 2 h of culture (P = 0.047), indicating activation through TSHR. Stimulation with T(4) resulted in increased extracellular signal-regulated kinase 1 and 2 activation after 10, 30, 60 min and 24 h. These data demonstrate that TSH and thyroid hormone receptors may participate in the regulation of ovarian function.//////Distribution of thyroid hormone and thyrotropin receptors in reproductive tissues of adult female rabbits. Rodríguez-Castelán J et al. (2016) Thyroid dysfunctions are related to anovulation, miscarriages, and infertility in women and laboratory animals. Mechanisms associated with these effects are unknown, although indirect or direct actions of thyroid hormones and thyrotropin could be assumed. The present study aimed to identify the distribution of thyroid hormones (TRs) and thyrotropin (TSHR) receptors in reproductive organs of female rabbits. Ovary of virgin and pregnant rabbits, as well as the oviduct, uterus, and vagina of virgin rabbits were excised, histologically processed, and cut. Slices from these organs were used for immunohistochemical studies for TRα1-2, TRß1, and TSHR. The presence of TRs and TSHR was found in the primordial, primary, secondary, tertiary, and Graafian follicles of virgin rabbits, as well as in the corpora lutea, corpora albicans, and wall of hemorrhagic cysts of pregnant rabbits. Oviductal regions (fimbria-infundibulum, ampulla, isthmus, and utero-tubal junction), uterus (endometrium and myometrium), and vagina (abdominal, pelvic, and perineal portions) of virgin rabbits showed anti-TRs and anti-TSHR immunoreactivity. Additionally, the distal urethra, paravaginal ganglia, levator ani and iliococcygeus muscles, dorsal nerve and body of the clitoris, perigenital skin, and prostate had TRs and TSHR. The wide presence of TRs and TSHR in female reproductive organs suggests varied effects of thyroid hormones and thyrotropin in reproduction.//////////////////
Follicle stages
Corpus luteum
Comment
Localization of thyrotropin receptor and thyroglobulin in the bovine corpus luteum. Mutinati M et al. The receptor of the Thyroid Stimulating Hormone (TSHr) and thyroglobin (TGB), are two proteic factors necessary for the synthesis of hormones, in the thyrocite. In mammals, many immuno-histochemical reports indicate the presence of the TSHr in extra-thyroidal tissues, but not in the ovary. Triiodothyronine (T(3)) and thyroxine (T(4)) have been widely shown to affect ovarian functions and the synthesis of progesterone (P(4)). The aim of this study was to determine if by immunohistochemistry techniques TSHr and TGB could be found in the bovine corpora haemorragica, lutea and albicantia. A primary rabbit polyclonal antibody against human TSHr and a primary rabbit polyclonal antibody against human TGB were employed. Furthermore, the accuracy of bovine thyroid to the antibodies used in this study was tested. A positivity reaction for the anti-TSHr serum in the large luteal cells and immunostaining of both small and large luteal cells with the anti-TGB serum occurred only in mature corpora lutea. No immunostaining was detected in stromal cells, blood and lymphatic vessels and in corpora haemorragica and albicantia. Bovine thyroid tissue showed immunostaining to both the antibodies employed. These data suggest that the luteal cells of mature corpora lutea may be involved in the synthesis of thyroid hormones, which may modulate P(4) synthesis, acting in an autocrine and paracrine way.