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TRH stimulation test. After TRH administration, blood TSH (a) and T3 levels (b) were determined in the wild-type (, n 6) and homozygous (, n 6) mice. The increment in T3 over the basal level was reduced in the homozygotes.
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Thyrotropin-releasing hormone (TRH) is a brain hypothalamic hormone that regulates thyrotropin (TSH) secretion from the anterior
pituitary and is ubiquitously distributed throughout the brain and other tissues including pancreas. To facilitate studies
into the role of endogenous TRH, we have used homologous recombination to generate mice that lack...
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Context 1
... a decrease in serum TSH levels was expected in the TRH mice, their levels of serum TSH were approxi- mately 2-fold higher than those in the TRH and TRH littermates (Table 1). This elevated TSH was further stimu- lated by TRH injection (Fig. 3a). The successive response of T 3 was significantly impaired in the mutant mice (TRH , 51.6 14.2; TRH , 16.1 4.6% increment over the basal, P 0.05, Fig. 3b). In contrast, stimulation of T 3 secretion after exogenous TSH administration was similar in the TRH and TRH mice (39.5 4.5, n 6 vs. 45.2 6.6% increment over the basal, n ...
Context 2
... in the TRH mice, their levels of serum TSH were approxi- mately 2-fold higher than those in the TRH and TRH littermates (Table 1). This elevated TSH was further stimu- lated by TRH injection (Fig. 3a). The successive response of T 3 was significantly impaired in the mutant mice (TRH , 51.6 14.2; TRH , 16.1 4.6% increment over the basal, P 0.05, Fig. 3b). In contrast, stimulation of T 3 secretion after exogenous TSH administration was similar in the TRH and TRH mice (39.5 4.5, n 6 vs. 45.2 6.6% increment over the basal, n ...
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Citations
... Therefore, TRH might control food intake through central sites of action, but since opposing effects are obtained according to the site of action, global approaches might yield confusing results. Mice lacking the Trh gene show a transient growth retardation, likely related to the hypothyroid status of these animals [122], but quantification of food intake was not reported. Mice constitutively overexpressing Trh in most neurons and other cells have an increased food intake and lower body weight, which is possibly a consequence of increased sympathetic tone and metabolic rate, although thyroid axis hormones have normal serum concentrations [123]. ...
Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food intake is not well understood. We review studies demonstrating that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence points to TRH neurons that are prime candidate vectors for TRH action on food intake. These include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food intake control in each anatomical scene.
... Therefore, TRH might control food-intake through central sites of action, but since opposing effects are obtained according to the site of action, global approaches might yield confusing results. 7 Mice lacking the Trh gene show a transient growth retardation, likely related to the hypothyroid status of these animals [122], but quantification of food-intake was not reported. Mice constitutively overexpressing Trh in most neurons and other cells have an increased food-intake and lower body weight, possibly a consequence of increased sympathetic tone and metabolic rate, although thyroid axis hormones have normal serum concentrations [123]. ...
Thyrotropin releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food-intake is not well understood. We review data that show that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence suggests that TRH neurons that are prime candidate vectors for TRH action on food-intake include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food-intake control in each anatomical scene.
... Indeed, Trh deficient mice show phenotypes similar to those of Trhr knockouts (12). ...
Objective: Loss of function mutations in the insulin receptor substrate 4 (IRS4) gene cause a rare form of X-linked congenital central hypothyroidism in boys and men. Affected individuals show decreased thyroid-stimulation hormone (TSH) secretion. Members of the IRS family canonically act as scaffold proteins between tyrosine kinase receptors and downstream effectors. How loss of IRS4 affects TSH synthesis or secretion is unresolved. We therefore assessed IRS4’s role in the hypothalamic-pituitary-thyroid axis of Irs4 knockout mice.
Methods: We generated two global Irs4 knockout mouse lines harboring either two or four base-pair deletions that result in frameshifts and loss of most of the IRS4 protein.
Results: Under normal laboratory conditions, Irs4 knockout males did not exhibit impairments in pituitary expression of TSH subunit genes (Tshb or Cga) or in the thyrotropin-releasing hormone (TRH) receptor. Additionally, their serum thyroid hormone, T3 (triiodothyronine) and T4 (thyroxine), and hypothalamic Trh expression levels were normal. When Irs4 knockouts were rendered hypothyroid with a low-iodine diet supplemented with propylthiouracil (PTU) for 3 weeks, their serum TSH increased similarly to wild-type males.
Conclusions: Overall, Irs4 knockout mice do not exhibit central hypothyroidism or otherwise appear to phenocopy IRS4 deficient patients. Compensation by another IRS protein may explain euthyroidism in these animals.
... In rodents, by late gestation, each of the different pituitary hormone-producing cell types is detectable, but the organ continues to grow and develop postnatally, and the proportions of the different cell types change substantially 10 . Two hypothalamic releasing hormones, namely growth hormone-releasing hormone (GHRH) and thyrotropin-releasing hormone (TRH), stimulate the expansion of hormone-producing cells in the postnatal period 11,12 . In humans, the pituitary gland has developed morphologically by 13 weeks of gestation and continues to grow until 21 weeks of gestation 7 . ...
Pituitary cells that express the transcription factor SOX2 are stem cells because they can self-renew and differentiate into multiple pituitary hormone-producing cell types as organoids. Wounding and physiological challenges can activate pituitary stem cells, but cell numbers are not fully restored, and the ability to mobilize stem cells decreases with increasing age. The basis of these limitations is still unknown. The regulation of stem cell quiescence and activation involves many different signalling pathways, including those mediated by WNT, Hippo and several cytokines; more research is needed to understand the interactions between these pathways. Pituitary organoids can be formed from human or mouse embryonic stem cells, or from human induced pluripotent stem cells. Human pituitary organoid transplantation is sufficient to induce corticosterone release in hypophysectomized mice, raising the possibility of therapeutic applications. Today, pituitary organoids have the potential to assess the role of individual genes and genetic variants on hormone production ex vivo, providing an important tool for the advancement of exciting frontiers in pituitary stem cell biology and pituitary organogenesis. In this article, we provide an overview of notable discoveries in pituitary stem cell function and highlight important areas for future research.
... The oxytocin (B6;129S-Oxt tm1Wsy /J; stock #2713; Young et al., 1996), Avpr1a (B6.129P2-Avpr1a tm1Dgen /J; stock #5776; Deltagen, Inc. 2005) and Avpr1b knock-out (KO) mouse strains (B6;129 Â 1-Avpr1b tm1Wsy /J; stock #6160; Wersinger et al., 2002) were obtained from The Jackson Laboratory. A Oxtr KO mouse strain described in (Takayanagi et al., 2005) and a Trh KO mouse strain described in (Yamada et al., 1997) were developed by co-authors and available from their laboratories. Another Avpr1a and 1b double KO (DKO) mouse strain (B6;129Sv-V1a tm1Gzt V1b tm1Gzt ; stock #559; Koshimizu et al., 2006) was obtained from the Center for Animal Resources and Development, Kumamoto University (Kumamoto, Japan). ...
... Trh KO mice Yamada et al. (1997) Avpr1a 1/À ; Avpr1b 1/À or À/À ; Trh 1/À or À/À ; Oxt 1/À or À/À (Fig. 4E) ...
... Oxt-Trh DKO mice were born at a Mendelian ratio, and appeared healthy and normal as their littermates with other genotypes, with a minor retardation of body growth of Trh KO mice (Yamada et al., 1997). The majority of DKO virgin females also showed normal allomaternal behaviors (Fig. 3A). ...
Oxytocin, a neuropeptide hormone, is indispensable for milk ejection during nursing and is important for uterine contractions during parturition. The exact functions of oxytocin in postpartum maternal behaviors and motivations require further investigation. To this end, we characterized the role of oxytocin in components of maternal motivations during the mid‐postpartum period, which has not been previously studied. To maintain suckling stimuli, postpartum oxytocin knock‐out (Oxt‐/‐) and heterozygous (Oxt+/‐) littermates were co‐housed with a wild‐type lactating mother and its litter, and were examined for their ability to retrieve pups in standard or high‐risk conditions, nursing behavior, maternal aggression towards an unfamiliar intruder, and motivation to regain contact with separated pups. One‐third of Oxt‐/‐ mothers exhibited prolonged parturition but were otherwise grossly healthy. Despite their inability to eject milk, Oxt‐/‐ mothers displayed nursing behaviors for similar durations to Oxt+/‐ mothers during the second postpartum week. In addition, Oxt‐/‐ mothers were essentially intact for pup retrieval in standard conditions and were motivated to stay close to pups, although they showed a mild decrease in maternal care in high‐risk conditions and increased anxiety‐like behaviors in pup‐related contexts. The present findings indicate that oxytocin is dispensable for nursing behavior and maternal motivations, yet suggest that oxytocin may be relevant for stress resilience in the postpartum period. This article is protected by copyright. All rights reserved.
... Thyrotropin-releasing hormone (TRH) is an indirect PRF which stimulates PRL release through thyrotropin stimulating hormone (TSH). Individuals with primary hypothyroidism and thus high levels of serum TSH developed hyperprolactinemia, and treatment with levothyroxine reversed it (12,13,43,44). Serotonin is a PRF (45), and serotonin antagonists inhibit the nightly increase of PRL level (46,47). ...
... Furthermore, headache incidence was higher in Dopamine inhibitors have headache as a frequent adverse event [76]. Thyrotropin releasing hormone Enhances PRL secretion when administered in doses that stimulate TSH secretion [43]. ...
Objective:
To systemically review clinical studies investigating the role of prolactin and its receptors in headache and migraine.
Background:
Migraine prevalence is more common in women compared to men. As prolactin is a crucial regulator of the hypothalamus-pituitary-gonadal axis, prolactin and its receptors might contribute to signaling mechanisms underlying migraine.
Methods:
In this systematic review, we searched PubMed and EMBASE with the terms: prolactin, hyperprolactinemia, macroprolactinemia, hypoprolactinemia, migraine, headache, head pain and trigeminal pain pathway for clinical studies investigating prolactin signaling in headache and migraine. Two reviewers independently screened 841 articles for population, intervention, comparison, outcome, and study design. Studies were restricted to the English language and were excluded if they had a nonexperimental methodology.
Results:
Nineteen clinical studies met the inclusion criteria and were included in the qualitative and quantitative analysis. The main findings were that serum prolactin levels were found to be higher in individuals with migraine compared to healthy controls, and prolactinomas (prolactin-secreting pituitary adenomas) were correlated with higher incidence of headache in otherwise healthy individuals and migraine attacks in individuals with migraine.
Conclusion:
Considerable evidence suggests a key role of prolactin and its receptors in migraine pathophysiology. Further randomized and placebo-controlled clinical studies targeting prolactin signaling are needed to further clarify influences of prolactin in migraine attack initiation.
... The oxytocin (B6;129S-Oxt tm1Wsy /J; stock #2713; Young et al., 1996), Avpr1a (B6.129P2-Avpr1a tm1Dgen /J; stock #5776; Deltagen, Inc. 2005) and Avpr1b knock-out (KO) mouse strains (B6;129 Â 1-Avpr1b tm1Wsy /J; stock #6160; Wersinger et al., 2002) were obtained from The Jackson Laboratory. A Oxtr KO mouse strain described in (Takayanagi et al., 2005) and a Trh KO mouse strain described in (Yamada et al., 1997) were developed by co-authors and available from their laboratories. Another Avpr1a and 1b double KO (DKO) mouse strain (B6;129Sv-V1a tm1Gzt V1b tm1Gzt ; stock #559; Koshimizu et al., 2006) was obtained from the Center for Animal Resources and Development, Kumamoto University (Kumamoto, Japan). ...
... Trh KO mice Yamada et al. (1997) Avpr1a 1/À ; Avpr1b 1/À or À/À ; Trh 1/À or À/À ; Oxt 1/À or À/À (Fig. 4E) ...
... Oxt-Trh DKO mice were born at a Mendelian ratio, and appeared healthy and normal as their littermates with other genotypes, with a minor retardation of body growth of Trh KO mice (Yamada et al., 1997). The majority of DKO virgin females also showed normal allomaternal behaviors (Fig. 3A). ...
Oxytocin (Oxt) controls reproductive physiology and various kinds of social behaviors, but the exact contribution of Oxt to different components of parental care still needs to be determined. Here, we illustrate the neuroanatomical relations of the parental nurturing-induced neuronal activation with magnocellular Oxt neurons and fibers in the medial preoptic area (MPOA), the brain region critical for parental and alloparental behaviors. We used genetically-targeted mouse lines for Oxt, Oxt receptor (Oxtr), vasopressin receptor 1a (Avpr1a), vasopressin receptor 1b (Avpr1b), and thyrotropin-releasing hormone (Trh) to systematically examine the role of Oxt-related signaling in pup-directed behaviors. The Oxtr-Avpr1a-Avpr1b triple knock-out (TKO), and Oxt-Trh-Avpr1a-Avpr1b quadruple KO (QKO) mice were grossly healthy and fertile, except for their complete deficiency in milk ejection and modest deficiency in parturition secondary to maternal loss of the Oxt or Oxtr gene. In our minimal stress conditions, pup-directed behaviors in TKO and QKO mothers and fathers, virgin females and males were essentially indistinguishable from those of their littermates with other genotypes. However, Oxtr KO virgin females did show decreased pup retrieval in the pup-exposure assay performed right after restraint stress. This stress vulnerability in the Oxtr KO was abolished by the additional Avpr1b KO. The general stress sensitivity, as measured by plasma cortisol elevation after restraint stress or by the behavioral performance in the open field (OF) and elevated plus maze (EPM), were not altered in the Oxtr KO but were reduced in the Avpr1b KO females, indicating that the balance of neurohypophysial hormones affects the outcome of pup-directed behaviors.
... A logical assumption would be that beside TSHB and TRHR also the TRH (OMIM #613879) gene (encoding TRH) might be implicated in isolated central CH. Until now pathogenic variants of TRH have not been associated with central hypothyroidism in humans, but Trh knock-out mice have been generated (33). ...
Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered (IGSF1, TBL1X, IRS4), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition.
... Trh is expressed in β-cells of rat pancreas from embryonic day 19 achieving maximum levels on the first 3 days after birth, being undetectable after the third week; it contributes to the development of pancreatic cells and insulin secretory pathway (35). Furthermore, Trh knockout mice are hyperglycemic (103). The general pattern of CpG methylation of Trh DNA in pancreas was similar to that observed in PVN, with low methylation in the promoter region even though Trh is not expressed after weaning. ...
The hypothalamus-pituitary-thyroid (HPT) axis regulates energy balance through the pleiotropic action of thyroid hormones. HPT basal activity and stimulation by cold or voluntary exercise are repressed by previous chronic stress in adults. Maternal separation (MS) modifies HPT basal activity, we thus studied the response of the axis to energy demands and analyzed possible epigenetic changes on Trh promoter. Non-handled (NH) or MS male Wistar rats were cold exposed 1h at adulthood, only in NH rats Trh expression in the hypothalamic paraventricular nucleus (PVN) and serum TSH concentration were increased. Two weeks of voluntary exercise decreased fat mass, increased Trh expression, and thyroid hormones concentration changed proportionally to running distance in NH male rats and MS male rats. Although NH-females ran more than MS and much more than males, exercise decreased body weight and fat mass only in NH-rats with no change on any parameter of HPT axis, but increased Pomc expression in arcuate-nucleus of NH- whereas Npy in MS-females. Overall methylation pattern of PVN Trh gene promoter was similar in NH-males or -females; MS modified methylation of specific CpG sites, a thyroid-hormone receptor (THR) binding site present after the initiation site was hypomethylated in MS-males; in MS-females, the THR binding-site of the proximal promoter (site 4) and two sites in the first intron were hypermethylated. Our studies showed that, in a sex dimorphic manner, MS blunted the responses of HPT axis to energy demands in adult animals and caused methylation changes on Trh promoter that could alter T3 feedback.
... In the present study, more than half of cases with impaired TSH secretion showed the delayed response. TRH-knockout mice reportedly showed hypothyroidism accompanied with an increased basal TSH level and an increased response to TRH because of biologically inactive TSH [25]. 2) The LH and FSH responses to GnRH in patients with impaired gonadotropin secretion were more severely reduced in RCCs than in NFAs. ...
Although Rathke’s cleft cysts (RCCs) are common sellar/parasellar lesions, studies examining pituitary function in patients with nonsurgical RCC are limited. This study aimed to clarify the importance of RCCs, including small nonsurgical ones, as a cause of hypopituitarism by determining the prevalence of pituitary hormone secretion impairment and its relationship to cyst/tumor size in patients with RCC and in those with nonfunctioning pituitary adenoma (NFA). We retrospectively investigated the basal levels of each anterior pituitary hormone, its responses in the stimulation test(s), and cyst/tumor size in patients with RCC (n = 67) and NFA (n = 111) who were consecutively admitted to our hospital for endocrinological evaluation. RCCs were much smaller than NFAs (median height, 12 vs. 26 mm). The prevalence of gonadotropin, PRL, and GH secretion impairment in RCC was lower in comparison to NFA (19% vs. 44%, 34% vs. 61%, and 24% vs. 46%, respectively), whereas the prevalence of TSH and ACTH secretion impairment was comparable (21–27% and 17–24%, respectively). A significant positive relationship between cyst/tumor size and number of impaired hormones was observed in both groups, but smaller cysts could cause hormone secretion impairment in RCC. Stimulation tests suggested that most hormone secretion impairment was attributable to the interrupted hypothalamic-pituitary axis in both groups. Therefore, RCC, even small ones, can cause pituitary dysfunction. Different mechanisms may underlie hypothalamic–pituitary interruption in RCC and NFA.
