Augmentation by thyroxine of human granulosa cell gonadotrophin-induced steroidogenesis

Wakim, Alain; Polizotto, Sandra L.; Burholt, Dennis R.

doi:10.1093/oxfordjournals.humrep.a135805

Cited by 47 publications

(28 citation statements)

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“…Furthermore, hypothyroidism worsens PCOS by further decreasing sex hormone binding globulin levels, increasing the conversion of androstenedione to testosterone and aromatization to estradiol and reducing the metabolic clearance rates of androstenedione and estrone. Since thyroid hormones are involved in the gonadotropininduced estradiol and progesterone secretion by human granulosa cells, hypothyroidism will interfere with ovarian function and fertility (51). Animal studies and case reports of PCOS patients with myxoedema also suggest a link between hypothyroidism and the spontaneously occurring ovarian hyper-stimulation syndrome (52) and ovarian cyst formation (53).…”

Section: Discussionmentioning

confidence: 99%

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

Janßen

Mehlmauer

Hahn

et al. 2004

European Journal of Endocrinology

271

190

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Objective: To investigate the prevalence of autoimmune thyroiditis (AIT) in patients with polycystic ovary syndrome (PCOS). Design: Over a period of 30 months, 175 patients with PCOS were recruited to a prospective multicenter study to evaluate thyroid function and morphology; 168 age-matched women without PCOS were studied as a control group. Methods: PCOS was defined as a-or oligomenorrhea, hyperandrogenism and exclusion of other disturbances of estrogen or androgen synthesis. All laboratory parameters were determined with automated immunoassays. Thyroid morphology was assessed by ultrasound. Results: PCOS patients were characterized by an increased LH/FSH ratio, low progesterone, elevated testosterone and a high prevalence of hirsutism (PCOS 83%, control 3%; mean hirsutism score 12^5 and 3^2 respectively), but no differences in estrogen levels were found. Thyroid function and thyroidspecific antibody tests revealed elevated thyroperoxidase (TPO) or thyroglobulin (TG) antibodies in 14 of 168 controls (8.3%), and in 47 of 175 patients with PCOS (26.9%; P , 0.001). On thyroid ultrasound, 42.3% of PCOS patients, but only 6.5% of the controls (P , 0.001) had a hypoechoic tissue typical of AIT; while thyroid hormone levels were normal in all subjects, PCOS patients had a higher mean TSH level (P , 0.001) and a higher incidence of TSH levels above the upper limit of normal (PCOS 10.9%, controls 1.8%; P , 0.001). Conclusion: This prospective study demonstrates a threefold higher prevalence of AIT in patients with PCOS, correlated in part with an increased estrogen-to-progesterone ratio and characterized by early manifestation of the disease.

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Section: Discussionmentioning

confidence: 99%

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

Janßen

Mehlmauer

Hahn

et al. 2004

European Journal of Endocrinology

271

190

View full text Add to dashboard Cite

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“…However, little information is available concerning their role in proliferation and apoptosis of granulosa cells, although a link between thyroid and ovaries has widely been observed (Stradtman 1993, Wakim et al 1995, Doufas & Mastorakos 2000. Our previous work has demonstrated how the granulosa cell population can be considered a thyroid hormone target, being as how their survival is induced by 3,5,3 0 -triiodothyronine (T 3 ) under specific circumstances via cell cycle and metabolism regulation (Verga Falzacappa et al 2009), strengthening our consideration of this hormone as a survival factor.…”

Section: Introductionmentioning

confidence: 99%

T3 preserves ovarian granulosa cells from chemotherapy-induced apoptosis

Falzacappa¹,

Timperi²,

Bucci³

et al. 2012

Journal of Endocrinology

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Infertility is a dramatic and frequent side effect in women who are undergoing chemotherapy. Actual strategies are mainly focused on oocyte cryopreservation, but this is not always a suitable option. Considering the key role that granulosa cells play in follicle life, we studied whether thyroid hormone 3,5,3 0 -triiodothyronine (T 3 ) protects rat ovarian granulosa cells from chemotherapy-induced apoptosis. To this aim, a cell line was established from fresh isolated rat granulosa cells and named rGROV. Cells were exposed to paclitaxel (PTX) and T 3 , and apoptosis, cell viability, and cell cycle distribution were analyzed under different conditions. First, the integrity of the steroidogenic pathway was demonstrated, and the presence of thyroid receptors, transporters, and deiodinases was confirmed by quantitative PCR. Cells were then exposed to PTX alone or contemporary to T 3 . MTT and TUNEL assays revealed that while there was a relevant percentage of dying cells when exposed to PTX (40-60%), the percentage was sensibly reduced (20-30%) in favor of living cells if T 3 was present. Cell cycle analysis showed that cells exposed to PTX alone were first collected in G2 and then died by apoptosis; on the other hand, the T 3 granted the cells to cycle regularly and survive PTX insult. In addition, western blot and FCM analyses confirmed that caspases activation, casp 3 and Bax, were downregulated by T 3 and that Bcl2 and cyclins A and B together with cdk1 were upregulated by T 3 . In conclusion, we demonstrated that thyroid hormone T 3 can counteract the lethal effect of taxol on granulosa cells.

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“…Virtually all molecular mechanisms involved in estrogen and androgen metabolism, sexual maturation, menstrual function, ovulation, fertility and the ability to deliver full-term infants are regulated by T3 [9]. Further, the facts that multiple T3 receptor mRNAs and T3-binding sites have been identified in mammalian granulose cells [6] and that T3 has been shown to directly modulate FSH and LH action on steroid biosynthesis in pigs [7,25], humans [13,39] and mice [6] suggest the direct effect of thyroid hormone on the follicles. The exact mechanism for such reproductive aberrations is not well known; however, it is conceivable that thyroid hormones might have a direct role in reproductive pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Female Infertility in grt Mice is Caused by Thyroid Hormone Deficiency, not by Insufficient TPST2 Activity in the Reproductive Organs

Hosoda

Sasaki

Agui

2008

The Journal of Veterinary Medical Science

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ABSTRACT. The growth-retarded (grt) mouse has an autosomal recessive hypothyroidism and the female shows lifelong infertility. We previously reported that these mutant phenotypes are caused by a deficiency in the enzymatic activity of tyrosylprotein sulfotransferase-2 (TPST2), and severe thyroid hypogenesis and consequent dwarfism are mainly due to the impairment of the tyrosine sulfation of thyroid-stimulating hormone receptor (TSHR) by TPST2. Although TPST2 is ubiquitously expressed and many proteins are predicted to be tyrosine sulfated and involved in many biological processes, the functional roles of tyrosine sulfation in the reproductive organs remain unclear. These findings tempted us to hypothesize two possible mechanisms underlying the infertility; a deficiency in TPST2 activity in the reproductive organs might cause the infertility in grt mice, or a significant decrease in serum thyroid hormones might impair the normal development of reproductive organs. When mutant female mice were fed a diet supplemented with sufficient thyroid powder to correct their growth retardation, the rate of copulation, pregnancy, and parturition was completely restored. Therefore, we concluded that the infertility in grt female is due to a thyroid hormone deficiency. The growth-retarded (grt) mouse has an autosomal recessive, fetal-onset, severe thyroid dysgenesis related to thyroid-stimulating hormone (TSH) hyporesponsiveness [20,41]. We identified that the grt phenotype is caused by a single misssense mutation in the tyrosylprotein sulfotransferase 2 (TPST2) gene with a C-to-G transition at nucleotide 798, leading to the replacement of a highly conserved histidine with glutamine at codon 266 in the sulfotransferase domain by positional cloning [36].TPST catalyzes the transfer of a sulfuryl group from the universal sulfation substrate, 3'-phosphoadenosine 5'-phosphosulfate, to a tyrosyl residue within the acidic motifs of proteins that transit the Golgi apparatus [28]. In mammals, two isozymes, TPST1 and 2, catalyze the tyrosine sulfation of proteins. Although TPST1 and 2 in mammals have 65~67% identical amino acid sequences [28], they seem to have different acceptor preferences [31,37]. Evidence indicates that the posttranslational modification by tyrosine sulfation regulates many important protein-protein interactions and modulates binding affinity and specificity [8,10,11,18,24,26,29,[33][34][35][36]. We previously showed that the sulfation of the tyrosine 385 of TSHR by TPST2 is indispensable for the activation of TSH signaling, and grt mice develop hypothyroidism and dwarfism since they are unable to fully respond to TSH. However, since many proteins besides TSHR are likely to be the substrates of TPST2, severe growth retardation of grt mice might conceal a defect in other proteins that act as substrates of TPST2 [36].

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Augmentation by thyroxine of human granulosa cell gonadotrophin-induced steroidogenesis

Cited by 47 publications

References 0 publications

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

T3 preserves ovarian granulosa cells from chemotherapy-induced apoptosis

Female Infertility in grt Mice is Caused by Thyroid Hormone Deficiency, not by Insufficient TPST2 Activity in the Reproductive Organs

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