Pituitary Hormone Research Articles

Developmental exposures to common environmental pollutants result in long-term Reprogramming of hypothalamic-pituitary axis in mice

Humans are exposed to a range of endocrine disrupting chemicals (EDCs). Many studies demonstrate that exposures to EDCs during critical windows of development can permanently affect endocrine health outcomes. Most experimental studies address changes in secretion of hormones produced by gonads, thyroid gland and adrenals, and little is known about the ability of EDCs to produce long-term changes in the hypothalamic-pituitary (HP) control axes. Here, we examined the long-term effects of three common EDCs on male mouse HP gene expression, following developmental exposures. Pregnant mice were exposed to 0.2 mg/ml solutions of bisphenol S (BPS), 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), or 3,3′,5,5′-tetrabromobisphenol A (TBBPA) from pregnancy day 8 through lactation day 21 (weaning day). Male offspring were left untreated until postnatal day 140, where pituitaries and hypothalami were collected. Pituitaries were assed for gene expression via RNA sequencing, while specific genes were assessed for expression in hypothalami via RT-qPCR. Differential expression, as well as gene enrichment and pathway analysis, indicated that all three chemicals induced long-term changes, (mostly suppression) in pituitary genes involved in its endocrine function. BPS and BDE-47 produced effects overlapping significantly at the level of effected genes and pathways. All three chemicals altered pathways of gonad and liver HP axes, while BPS altered HP-adrenal and BDE-47 altered HP-thyroid pathways specifically. All three chemicals reduced expression of immune genes in the pituitaries. Targeted gene expression in the hypothalamus indicates down regulation of hypothalamic endocrine control genes by BPS and BDE-47 groups, concordant with changes in the pituitary, suggesting that these chemicals suppress overall HP endocrine function. Interestingly, all three chemicals altered pituitary genes of GPCR-mediated intracellular signaling molecules, key signalers common to many pituitary responses to hormones. The results of this study show that developmental exposures to common EDCs have long-term impacts on hormonal feedback control at the hypothalamic-pituitary level.

Eje hipotálamo-hipofisario. Regulación neurohormonal, implicaciones patológicas, pruebas funcionales hipofisarias, indicaciones e interpretación

The hypothalamic-pituitary axis is a crucial system for maintaining homeostasis by integrating hormonal and neuronal inputs and outputs. Almost all bodily functions are regulated directly or indirectly by this axis. The hypothalamus, a small but vital brain region, monitors various inputs and maintains physiological set points through hormonal secretion, coordinating with the pituitary gland. This regulation involves multiple feedback mechanisms and interactions with other brain areas.The hypothalamus is anatomically divided into several regions and nuclei, each with specific functions. It produces a variety of hormones, including growth hormone-releasing hormone, corticotropin-releasing hormone, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. These hormones regulate the secretion of corresponding hormones from the anterior pituitary gland, which control several physiological processes, including growth, metabolism, reproduction, and stress response.Pathological implications of hypothalamic-pituitary axis dysfunctions include endocrine disorders such as hyperprolactinemia, growth hormone deficiency, and hypogonadism. In addition, hypothalamic damage can lead to neurological and behavioral problems such as sleep disturbances and thermoregulation.

Hipopituitarismo

Hypopituitarism is a rare and likely underdiagnosed disorder caused by a deficiency of one or more pituitary hormones. Clinical features vary with timing of onset, cause and number of pituitary axes disrupted. Diagnosis requires measurement of basal circulating hormone concentrations and stimulation tests according to the affected axis. Treatment is aimed at replacement of deficient hormones, but increased mortality might persist in these patients despite treatment.

Correction: The Effects of Triiodothyronine on the Free Thyroxine Set Point Position in the Hypothalamus Pituitary Thyroid Axis

Correction: The Effects of Triiodothyronine on the Free Thyroxine Set Point Position in the Hypothalamus Pituitary Thyroid Axis

Transcriptional and morphological responses following distinct muscle contraction protocols for Snell dwarf (Pit1dw/dw) mice.

The Snell dwarf mouse (Pit1dw/dw), an animal model of congenital combined pituitary hormone deficiency, displays skeletal muscle weakness. While enhanced responsivity to repeated exposures of muscle contractions have been documented for Snell dwarf mice, the response following single exposure to distinct contraction protocols remained uncharacterized. The purpose of this study was to investigate the muscle recovery of Snell dwarf and control littermate mice following a single exposure to two separate protocols-an intermittent slow velocity (30°/s) contraction protocol or a continuous rapid velocity (500°/s) contraction protocol. Following both protocols for control mice, torque values were 30% and 80% of pre-protocol values at 5 min and 3 days, respectively. At 10 days, performance returned to baseline for the 30°/s protocol and were depressed for the 500°/s protocol. For Snell dwarf mice following both protocols, torques were depressed to 5% of pre-protocol values at 5 min and returned to baseline by 3 days. Recovery following the 30°/s protocol for control mice and both protocols for Snell dwarf mice coincided with increased transcriptional output, upregulation of cytokine-mediated signaling genes, and a distribution shift to smaller muscle fibers with reduced area per nucleus. These features represent efficacious remodeling ubiquitous across distinct contraction paradigms in the context of the Pit1 mutation.

1992: Hypothalamic-pituitary axis dysfunction after irradiation for brain and head and neck cancers

1992: Hypothalamic-pituitary axis dysfunction after irradiation for brain and head and neck cancers

The Effects of Triiodothyronine on the Free Thyroxine Set Point Position in the Hypothalamus Pituitary Thyroid Axis.

In clinical endocrinology, it is often assumed that the results of thyroid hormone function tests (TFTs) before total thyroidectomy are considered euthyroid when the circulating concentrations of thyrotropin [TSH] and free thyroxine [FT4] are within the normal reference ranges. Postoperative thyroid replacement therapy with levothyroxine. The aim of L-T4 is to reproduce the preoperative euthyroid condition. Currently, intra-individual changes in the euthyroid set point before and after total thyroidectomy are only partly understood. After total thyroidectomy, a greater postoperative [FT4] than preoperative [FT4] for equivalent euthyroid [TSH] was found, with differences ranging from 3 to 8 pmol/L. This unexplained difference can be explained by the use of a mathematical model of the hypothalamus-pituitary-thyroid (HPT) axis set point theory. In this article, the postoperative HPT euthyroid set point was calculated using a dataset of total thyroidectomized patients with at least three distinguishable postoperative TFTs. The postoperative [TSH] set point was used as a homeostatic reference for the comparison of preoperative TFTs. The preoperative [FT4] value was equal to the postoperative [FT4] value in 50% of the patients, divided by a factor of ~ 1.25 (within +/- 10%). The factor of 1.25 stems from the lack of postoperative use of thyroidal triiodothyronine (T3). Furthermore, approximately 25% of the patients presented a greater preoperative [FT4] difference than postoperative [FT4]/1.25 combined with a normal [TSH] difference. Based on these observations, the effect of T3 on the value of the [FT4] set point was analyzed and explained from a control theory perspective.

Long-term effects on fertility after central nervous system cancer: A systematic review and meta-analysis

Abstract Background Central nervous system (CNS) cancer represents a common group of solid tumors in childhood and young adults, and less frequently in adults aged 30–40. Due to treatment advancements with increasing survival rates, disorders of the hypothalamus-pituitary axis have become increasingly relevant for patients’ future fertility plans. Most guidelines recommend that physicians should counsel their patients about fertility prognosis before initiating gonadotoxic therapy. However, for fertility preservation measures, gonadal toxicity as the only relevant risk factor has not yet been systematically reviewed. Methods A systematic literature search was performed in MEDLINE, Embase, and Cochrane in January 2024. The systematic review included studies of patients who had undergone treatment for all types of malignant CNS cancer. The outcomes were defined as clinically relevant gonadal toxicity as well as preserved fertility. The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Results The qualitative analysis included 31 studies with a total of 4590 patients after CNS cancer. The overall pooled prevalence of gonadal toxicity was found to be 20% (95% confidence intervals [CI]: 10%–34%). Preserved fertility was present in 75% (95% CI: 64%–83%) of the patients and was maintained after at least 5 years following treatment (75%, 95% CI: 46%–91%). Conclusions This initial meta-analysis provides a basis for fertility counseling after diverse CNS cancer treatments. Due to the high heterogeneity of the study population and lack of individual patient data on fertility outcomes, it is not possible to provide an exact estimation of the fertility prognosis following a specific treatment. Thus, fertility preservation measures should still be recommended.

Gene Misexpression in a Smoc2+ve/Sox2-Low Population in Juvenile Prop1-Mutant Pituitary Gland.

Mutations in the pituitary-specific transcription factor Prophet of Pit-1 (PROP1) are the most common genetic etiology of combined pituitary hormone deficiency (CPHD). CPHD is associated with short stature, attributable to growth hormone deficiency and/or thyroid-stimulating hormone deficiency, as well as hypothyroidism and infertility. Pathogenic lesions impair pituitary development and differentiation of endocrine cells. We performed single-cell RNA sequencing of pituitary cells from a wild-type and a Prop1-mutant P4 female mouse to elucidate population-specific differential gene expression. We observed a Smoc2+ve population that expressed low Sox2, which trajectory analyses suggest are a transitional cell state as stem cells differentiate into endocrine cells. We also detected ectopic expression of Sox21 in these cells in the Prop1df/df mutant. Prop1-mutant mice are known to overexpress Pou3f4, which we now show to be also enriched in this Smoc2+ve population. We sought to elucidate the role of Pou3f4 during pituitary development and to determine the contributions of Pou3f4 upregulation to pituitary disease by utilizing double-mutant mice lacking both Prop1 and Pou3f4. However, our data showed that Pou3f4 is not required for normal pituitary development and function. Double mutants further demonstrated that the upregulation of Pou3f4 was not causative for the overexpression of Sox21. These data indicate loss of Pou3f4 is not a potential cause of CPHD, and further studies may investigate the functional consequence of upregulation of Pou3f4 and Sox21, if any, in the novel Smoc2+ve cell population.

Inhibin subunit beta B (INHBB): an emerging role in tumor progression.

The gene inhibin subunit beta B (INHBB) encodes the inhibin βB subunit, which is involved in forming protein members of the transforming growth factor-β (TGF-β) superfamily. The TGF-β superfamily is extensively involved in cell proliferation, differentiation, adhesion, movement, metabolism, communication, and death. Activins and inhibins, which belong to the TGF-β superfamily, were first discovered in ovarian follicular fluid. They were initially described as regulators of pituitary follicle-stimulating hormone (FSH) secretion both in vivo and in vitro. Later studies found that INHBB is expressed not only in reproductive organs such as the ovary, uterus, and testis but also in numerous other organs, including the brain, spinal cord, liver, kidneys, and adrenal glands. This wide distribution implies its involvement in the normal physiological functions of various organs; however, the mechanisms underlying these functions have not yet been fully elucidated. Recent studies suggest that INHBB plays a significant, yet complex role in tumorigenesis. It appears to have dual effects, promoting tumor progression in some contexts while inhibiting it in others, although these roles are not yet fully understood. In this paper, we review the different expression patterns, functions, and mechanisms of INHBB in normal and tumor tissues to illustrate the research prospects of INHBB in tumor progression.

Practical approaches to diagnosing PitNETs/adenomas based on cell lineage.

The evolution of classification systems of pituitary adenomas (now PitNETs) has culminated in the use of transcription factor (TF) immunohistochemistry (IHC), forming a cell lineage-based system. However, several issues remain to be addressed, including the additional financial and logistic burden of undertaking the complete array of anterior pituitary hormones and TF IHC. To that end, several groups have suggested algorithms to minimise the number of tests performed, with varying levels of diagnostic accuracy. Although the proportion of null cell tumours has decreased following the use of TFs, "multilineage" tumours have been reported and characterised using transcriptomic signatures, most prominently the PIT1-SF1 co-expressing PitNETs, which do not bear a position in the present system of classification. In this review, we examine the proposed practical approaches to the diagnosis of PitNETs. We review the literature on reported PitNET types that challenge the existing classification system, such as those that express multiple TFs, with their potential clinical implications. Finally, we assess limitations in the present system, such as the lack of a standardised system for IHC interpretation, that need to be addressed in the future.

Vitamin D in pituitary driven osteopathies.

The evidence that pituitary hormones may bypass peripheral endocrine glands to exert remarkable effects on the skeleton is gaining ground. Both hormonal excess and deficit may determine impairment in bone structure, and they commonly result in bone loss in patients affected by pituitary and neuroendocrine disorders. Vertebral fractures are the most common skeletal alterations and may occur independently of bone mass. Use of vitamin D (VD) supplementation is still debated in this setting. This review will focus on the interactions between different metabolites of VD and pituitary hormones, and the effects of VD supplementation on bone metabolism in patients with pituitary diseases.

The Association between Vitamin D Status and the Impact of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Women with Subclinical Hypothyroidism.

Metformin inhibits enhanced secretion of anterior pituitary hormones. Its impact on prolactin and gonadotropin concentrations is absent in individuals with hypovitaminosis D. The aim of this prospective cohort study was to investigate whether vitamin D status determines the effect of metformin on hypothalamic-pituitary-thyroid axis activity in levothyroxine-naïve women. The study included three groups of women of reproductive age with subclinical non-autoimmune hypothyroidism, which were matched for age, thyroid-stimulating hormone (TSH) concentration, and insulin sensitivity: untreated women with vitamin D deficiency/insufficiency (group A), women effectively supplemented with exogenous calciferol (group B), and untreated women with normal 25-hydroxyvitamin D concentrations (25OHD) (group C). Owing to concomitant type 2 diabetes or prediabetes, all subjects were treated with metformin. Concentrations of 25OHD, TSH, total and free thyroid hormones, glucose, insulin, glycated hemoglobin (HbA1c), prolactin, and peripheral markers of thyroid hormone action were assayed before metformin treatment and six months later. Based on hormone concentration, structure parameters of thyroid homeostasis were calculated. Except for 25OHD concentrations, there were no between-group differences in baseline values of the measured variables. Metformin reduced glucose, the homeostatic model assessment 1 of insulin resistance ratio (HOMA1-IR), and HbA1c in all study group, but these effects were less pronounced in group A than in the remaining groups. The reduction in TSH and Jostel's index was observed only in groups B and C, and its degree correlated with baseline TSH concentrations, baseline 25OHD concentrations, and the degree of improvement in HOMA1-IR. The drug did not affect circulating levels of 25OHD, free and total thyroid hormones, prolactin, other structure parameters of thyroid homeostasis, and markers of thyroid hormone action. The obtained results allow us to conclude that low vitamin D status in young women mitigates the impact of metformin on thyrotroph secretory function.

IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: Impact of developmental exposures to endocrine-disrupting chemicals on pituitary gland reproductive function.

Endocrine-disrupting chemicals can impact reproduction by affecting the hypothalamic-pituitary-gonadal axis. This review emphasizes the impact of endocrine-disrupting chemicals on pituitary development and function. The pituitary gland is crucial for regulating many physiological systems, including reproduction. Clear evidence suggests that pituitary function can be impaired by exposure to endocrine-disrupting chemicals (EDCs). Humans and animals are exposed to EDCs throughout life, but exposure during critical periods when the pituitary is developing could have more damaging consequences. In this review, we summarize the development of the pituitary gland, including the impact of hormone signals, and describe how in vivo EDC exposure during development might alter pituitary function. These include changes in pituitary hormone, mRNA, and protein expression levels, as well as pituitary cell number and population balance. We focus on reproductive hormone-producing cells as well as other endocrine and pituitary stem/progenitor cells. We reveal the current gaps in knowledge and suggest future directions in terms of understanding the effects of developmental EDC exposure directly on the pituitary gland.

An i-motif-regulated enhancer, eRNA and adjacent lncRNA affect Lhb expression through distinct mechanisms in a sex-specific context

Genome-wide studies have demonstrated regulatory roles for diverse non-coding elements, but their precise and interrelated functions have often remained enigmatic. Addressing the need for mechanistic insight, we studied their roles in expression of Lhb which encodes the pituitary gonadotropic hormone that controls reproduction. We identified a bi-directional enhancer in gonadotrope-specific open chromatin, whose functional eRNA (eRNA2) supports permissive chromatin at the Lhb locus. The central untranscribed region of the enhancer contains an iMotif (iM), and is bound by Hmgb2 which stabilizes the iM and directs transcription specifically towards the functional eRNA2. A distinct downstream lncRNA, associated with an inducible G-quadruplex (G4) and iM, also facilitates Lhb expression, following its splicing in situ. GnRH activates Lhb transcription and increased levels of all three RNAs, eRNA2 showing the highest response, while estradiol, which inhibits Lhb, repressed levels of eRNA2 and the lncRNA. The levels of these regulatory RNAs and Lhb mRNA correlate highly in female mice, though strikingly not in males, suggesting a female-specific function. Our findings, which shed new light on the workings of non-coding elements and non-canonical DNA structures, reveal novel mechanisms regulating transcription which have implications not only in the central control of reproduction but also for other inducible genes.

The Current Understanding of Molecular Mechanisms in Adenomyosis-Associated Infertility and the Treatment Strategy for Assisted Reproductive Technology.

Adenomyosis, endometriosis of the uterus, is associated with an increased likelihood of abnormal endometrial molecular expressions thought to impair implantation and early embryo development, resulting in disrupted fertility, including the local effects of sex steroid and pituitary hormones, immune responses, inflammatory factors, and neuroangiogenic mediators. In the recent literature, all of the proposed pathogenetic mechanisms of adenomyosis reduce endometrial receptivity and alter the adhesion molecule expression necessary for embryo implantation. The evidence so far has shown that adenomyosis causes lower pregnancy and live birth rates, higher miscarriage rates, as well as adverse obstetric and neonatal outcomes. Both pharmaceutical and surgical treatments for adenomyosis seem to have a positive impact on reproductive outcomes, leading to improved pregnancy and live birth rates. In addition, adenomyosis has negative impacts on reproductive outcomes in patients undergoing assisted reproductive technology. This association appears less significant after patients follow a long gonadotropin-releasing hormone agonist (GnRHa) protocol, which improves implantation rates. The pre-treatment of GnRHa can also be beneficial before engaging in natural conception attempts. This review aims to discover adenomyosis-associated infertility and to provide patient-specific treatment options.

PACS-1 Interacts with TRPC3 and ESyt1 to Mediate Protein Trafficking while Promoting SOCE and Cooperatively Regulating Hormone Secretion.

Corticotropic cells of the anterior pituitary gland release adrenocorticotropic hormone (ACTH) in a regulated manner to promote the production of cortisol and androgens. The process of ACTH secretion is partly mediated by the phosphofurin acidic cluster sorting protein 1 (PACS-1); however, the underlying mechanisms behind this regulation remain unclear. Herein, we demonstrated PACS-1 interactions with the short transient receptor potential channel 3 (TRPC3) calcium transporter and the extended synaptotagmin-1 (ESyt1) endoplasmic reticulum-plasma membrane tethering protein. Importantly, PACS-1 promoted interactions between TRPC3 and ESyt1 and regulated their plasma membrane localization. Lastly, we demonstrated that PACS-1 is required for a proper store-operated calcium entry (SOCE) response and that ESyt1 regulates ACTH secretion through an unknown mechanism regulated by PACS-1. Overall, our study provides new insights into the physiological role PACS-1 plays in modulating intracellular calcium levels and regulating ACTH secretion in corticotropic cells.

Differentiation potential of SOX2-positive stem cells in the bovine pituitary gland

The pituitary gland is the master endocrine gland, harboring stem cells with various genetic characteristics; however, data from non-rodent and non-human sources are scarce. In this study, we isolated putative stem cells from the bovine pituitary gland and investigated their potential for differentiation into hormone-producing cells. Immunohistochemical analysis revealed that in calves and heifers, stem cell marker sex-determining region Y-box 2 (SOX2)-positive cells were widely present in the pituitary gland and partially co-localized with anterior pituitary hormones. Next, a single-cell suspension of primary anterior lobe cells from bovines aged 0 and 12 months was subjected to two-dimensional culture. Consequently, some cells proliferated in the culture dishes. The expression levels of Sox2 and several other stem cell markers were higher in these cells after culture. In addition, almost all proliferating cells were positive for SOX2, whereas all were negative for hormones. In three-dimensional cultures, SOX2-positive cells presented a spheroid-like morphology and differentiated into endocrine cells. These results provide evidence that SOX2-positive cells are pituitary stem cells with the potential to differentiate into hormone-producing cells, regardless of age. Our data lay a theoretical foundation for further studies on controlling fundamental processes, such as body growth, reproduction, and lactation.

Video-Based Performance Analysis in Pituitary Surgery - Part 2: Artificial Intelligence Assisted Surgical Coaching

Superior surgical skill improves surgical outcomes in endoscopic pituitary adenoma surgery. Video-based coaching programs, pioneered in professional sports, have shown promise in surgical training. In this study, we developed and assessed a video-based coaching program using artificial intelligence (AI) assistance. An AI-assisted video-based surgical coaching was implemented over 6months with the pituitary surgery team. The program consisted of 1) monthly random video analysis and review; and 2) quarterly 2-hour educational meetings discussing these videos and learning points. Each video was annotated for surgical phases and steps using AI, which improved video interactivity and allowed the calculation of quantitative metrics. Primary outcomes were program feasibility, acceptability, and appropriateness. Surgical performance (via modified Objective Structured Assessment of Technical Skills) and early surgical outcomes were recorded for every case during the 6-month coaching period, and a preceding 6-month control period. Beta and logistic regression were used to assess the change in modified Objective Structured Assessment of Technical Skills scores and surgical outcomes after the coaching program implementation. All participants highly rated the program's feasibility, acceptability, and appropriateness. During the coaching program, 63 endoscopic pituitary adenoma cases were included, with 41 in the control group. Surgical performance across all operative phases improved during the coaching period (P < 0.001), with a reduction in new postoperative anterior pituitary hormone deficit (P= 0.01). We have developed a novel AI-assisted video surgical coaching program for endoscopic pituitary adenoma surgery - demonstrating its viability and impact on surgical performance. Early results also suggest improvement in patient outcomes. Future studies should be multicenter and longer term.

Neuroendocrinology of bone.

The past decade has witnessed significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone in primary and secondary osteoporosis. Recent breakthroughs have primarily emerged from identifying disease-causing mutations and phenocopying human bone disease in rodents. Notably, using genetically-modified rodent models, disrupting the reciprocal relationship with tropic pituitary hormone and effector hormones, we have learned that pituitary hormones have independent roles in skeletal physiology, beyond their effects exerted through target endocrine glands. The rise of follicle-stimulating hormone (FSH) in the late perimenopause may account, at least in part, for the rapid bone loss when estrogen is normal, while low thyroid-stimulating hormone (TSH) levels may contribute to the bone loss in thyrotoxicosis. Admittedly speculative, suppressed levels of adrenocorticotropic hormone (ACTH) may directly exacerbate bone loss in the setting of glucocorticoid-induced osteoporosis. Furthermore, beyond their established roles in reproduction and lactation, oxytocin and prolactin may affect intergenerational calcium transfer and therefore fetal skeletal mineralization, whereas elevated vasopressin levels in chronic hyponatremic states may increase the risk of bone loss.. Here, we discuss the interaction of each pituitary hormone in relation to its role in bone physiology and pathophysiology.