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The Journal of Endocrinology Jun 2018Studies over the past decade have challenged the long-held belief that pituitary hormones have singular functions in regulating specific target tissues, including master... (Review)
Review
Studies over the past decade have challenged the long-held belief that pituitary hormones have singular functions in regulating specific target tissues, including master hormone secretion. Our discovery of the action of thyroid-stimulating hormone (TSH) on bone provided the first glimpse into the non-traditional functions of pituitary hormones. Here we discuss evolving experimental and clinical evidence that growth hormone (GH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin and arginine vasopressin (AVP) regulate bone and other target tissues, such as fat. Notably, genetic and pharmacologic FSH suppression increases bone mass and reduces body fat, laying the framework for targeting the FSH axis for treating obesity and osteoporosis simultaneously with a single agent. Certain 'pituitary' hormones, such as TSH and oxytocin, are also expressed in bone cells, providing local paracrine and autocrine networks for the regulation of bone mass. Overall, the continuing identification of new roles for pituitary hormones in biology provides an entirely new layer of physiologic circuitry, while unmasking new therapeutic targets.
Topics: Adipose Tissue; Adrenocorticotropic Hormone; Animals; Arginine Vasopressin; Bone and Bones; Follicle Stimulating Hormone; Growth Hormone; Humans; Oxytocin; Pituitary Hormones; Prolactin; Thyrotropin
PubMed: 29555849
DOI: 10.1530/JOE-17-0680 -
Frontiers in Endocrinology 2022Growth hormone deficiency (GHD) is the most commonly affected pituitary hormone in childhood with a prevalence of 1 in 4000-10000 live births. GH stimulation testing... (Review)
Review
Growth hormone deficiency (GHD) is the most commonly affected pituitary hormone in childhood with a prevalence of 1 in 4000-10000 live births. GH stimulation testing (GHST) is commonly used in the diagnostic workup of GHD. However, GHD can be diagnosed in some clinical conditions without the need of GHST. The diagnosis of GHD in newborns does not require stimulation testing. Likewise infants/children with delayed growth and/or short stature associated with neuroradiological abnormalities and one or more additional pituitary hormone deficiencies may not need GHST. This review summarizes the current evidence on the diagnosis of GHD without stimulation tests.
Topics: Child; Dwarfism, Pituitary; Human Growth Hormone; Humans; Hypopituitarism; Infant, Newborn; Insulin-Like Growth Factor I; Pituitary Hormones
PubMed: 35250894
DOI: 10.3389/fendo.2022.853290 -
Gynecological Endocrinology : the... Apr 2018Since more than 100 years, it is known that pituitary function depends upon the function of higher centers in the brain. It was already assumed at this time that... (Review)
Review
Since more than 100 years, it is known that pituitary function depends upon the function of higher centers in the brain. It was already assumed at this time that pituitary extracts could influence the gonads and postulated that their use could have practical applications. In 1926, the 'gonadal principle' was discovered revealing the regulation of ovarian function by the pituitary. The two pituitary hormones were called 'Prolan A' and 'Prolan B' which are responsible for ovarian function especially secretion of the hormones: 'lutein' and 'foliculin'. If the names of Prolan A and B are changed to follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and the names of foliculin and lutein to estrogen and progesterone, it becomes obvious that the pituitary-gonadal relationship, as we know it today, was first described in 1930. Then, the next step was the isolation, sequence and synthesis of gonadotropin releasing hormone (GnRH) responsible for the secretion of gonadotropins (Gn). It could be shown that GnRH pulse frequency has differential effects on Gn secretion: low-frequency pulses of GnRH stimulate preferentially FSH and high frequency LH secretion. The pulse frequency control depends from a subpopulation of kisspeptin neurons within the infundibular region of the hypothalamus with coexpression of neurokinin B and dynorphin A - KNDy neurons showing a negative feedback to estrogen. A second group of kisspeptide neurons in the rostral periventricular area of the third ventricle is devoid of neurokinin-B and dynorphin, mediates positive feedback from estrogen and so induces the midcycle LH-surge. Therefore, the variability in the frequency and amplitude of GnRH pulsatility is central to the differential regulation of LH and FSH and thus ovarian follicle development, the correct selection of a single dominant follicle for ovulation, the LH surge and the luteal phase.
Topics: Animals; Female; Follicle Stimulating Hormone; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Luteinizing Hormone; Neurons; Ovary; Ovulation; Pituitary Gland
PubMed: 29171353
DOI: 10.1080/09513590.2017.1405933 -
The Journal of Clinical Endocrinology... Dec 2022Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism....
CONTEXT
Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete.
OBJECTIVE
To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot.
METHODS
Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity.
RESULTS
In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3.
CONCLUSIONS
This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.
Topics: Humans; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 1; Nerve Tissue Proteins; Mutation; Diarrhea; Phenotype; Pituitary Hormones
PubMed: 36149814
DOI: 10.1210/clinem/dgac554 -
Scientific Reports Sep 2023Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and...
Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and their implications for histopathological parameters and prognosis in TGCT using a data-driven explorative approach. Pre-surgery serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2) and prolactin were measured in a retrospective multicenter TGCT cohort (n = 518). Clusters of patients were defined by latent class analysis. Clinical, pathologic and survival parameters were compared between the clusters by statistical hypothesis testing, Random Forest modeling and Peto-Peto test. Cancer tissue expression of sex hormone-related genes was explored in the publicly available TCGA cohort (n = 149). We included 354 patients with pure seminoma and 164 patients with non-seminomatous germ cell tumors (NSGCT), with a median age of 36 years. Three hormonal clusters were defined: 'neutral' (n = 228) with normal sex hormone homeostasis, 'testicle' (n = 91) with elevated T and E2, low pituitary hormones, and finally 'pituitary' subset (n = 103) with increased FSH and LH paralleled by low-to-normal levels of the gonadal hormones. Relapse-free survival in the hormonal subsets was comparable (p = 0.64). Cancer tissue expression of luteinizing hormone- and follicle-stimulating hormone-coding genes was significantly higher in seminomas, while genes of T and E2 biosynthesis enzymes were strongly upregulated in NSGCT. Substantial percentages of TGCT patients are at increased risk of sex hormone dysfunction at primary diagnosis before orchiectomy. TGCT may directly influence systemic hormonal homeostasis by in-situ synthesis of sex hormones.
Topics: Humans; Male; Adult; Neoplasm Recurrence, Local; Testicular Neoplasms; Gonadal Steroid Hormones; Neoplasms, Germ Cell and Embryonal; Luteinizing Hormone; Seminoma; Follicle Stimulating Hormone, Human
PubMed: 37669975
DOI: 10.1038/s41598-023-41915-7 -
Endocrine Jul 2021Nonfunctionning pituitary macroadenomas (NFPMA) are benign tumors that cause symptoms of mass effects including hypopituitarism. Their primary treatment is...
OBJECTIVES
Nonfunctionning pituitary macroadenomas (NFPMA) are benign tumors that cause symptoms of mass effects including hypopituitarism. Their primary treatment is transsphenoidal surgery. We aimed to determine the outcome of pituitary hormone deficits after surgical treatment of NFPMA and to identify factors predicting hormonal recovery.
DESIGN
We retrospectively included 246 patients with NFPMA diagnosed and operated in one of the two participating centers. All hormonal axes were evaluated except growth hormone (GH). Postoperative improvement of pituitary endocrine function was considered if at least one hormonal deficit had recovered and a lower total number of deficits was observed 1 year after surgery.
RESULTS
80% (n = 197) of patients had one or more pituitary deficits and 28% had complete anterior hypopituitarism. Besides GH, the gonadotropic and thyrotropic axes were the most commonly affected (68% and 62%, respectively). The number of hypopituitary patients dropped significantly to 61% at 1 year (p < 0.001) and a significant improvement was observed for all hormonal axes, except central diabetes insipidus. Among patients with preoperative hypopituitarism, 88/175 (50%) showed improved pituitary function at 1 year. Both hyperprolactinemia at diagnosis and a lower tumor diameter independently predicted favorable endocrine outcome.
CONCLUSIONS
Hypopituitarism is present in 80% of patients with NFPMA and nearly half of them will benefit from sustained improvement after surgery. Hyperprolactinaemia at diagnosis and lower tumor dimensions are associated with favorable endocrine prognosis. This supports the option of early surgery in NFPMA patients with pituitary deficits independent of the presence of visual disturbances.
Topics: Adenoma; Humans; Hypopituitarism; Pituitary Hormones; Pituitary Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 33852154
DOI: 10.1007/s12020-021-02701-5 -
Human Molecular Genetics Jan 2023Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in...
Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss-of-function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/-; Pou1f1+/dw double heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked the development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for the activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.
Topics: Child; Humans; Heterozygote; Holoprosencephaly; Hypopituitarism; Transcription Factors; Mutation; Pituitary Hormones; Transcription Factor Pit-1
PubMed: 35951005
DOI: 10.1093/hmg/ddac192 -
Journal of Clinical Research in... Nov 2023Recent reports have indicated the role of the prokineticin receptor 2 gene () in the etiology of pituitary hormone deficiencies, suggesting a potential role for the...
OBJECTIVE
Recent reports have indicated the role of the prokineticin receptor 2 gene () in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with mutations.
METHODS
Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature.
RESULTS
Two different, very rare missense alterations classified as pathogenic (NM_144773.4:c.518T>G; NP_658986.1:p. (Leu173Arg)) and likely pathogenic (NM_144773.4:c.254G>A; NP_658986.1:p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families.
CONCLUSION
dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers.
Topics: Growth Hormone; Pituitary Hormones; Dwarfism, Pituitary; Humans; Pedigree; Male; Female; Infant; Child; Receptors, G-Protein-Coupled; Consanguinity
PubMed: 37338295
DOI: 10.4274/jcrpe.galenos.2023.2023-4-4 -
Hormones (Athens, Greece) Dec 2023To identify changes in anterior pituitary gland hormone levels in brain-dead patients and alterations in free triiodothyronine (fT3), free thyroxine, cortisol,...
PURPOSE
To identify changes in anterior pituitary gland hormone levels in brain-dead patients and alterations in free triiodothyronine (fT3), free thyroxine, cortisol, testosterone, and estradiol levels.
METHODS
Ten postmenopausal women and 22 men with brain death (BD) were included. The first blood sample for determination of hormones (pre-BD) was collected when the clinician observed the first signs of BD. The second blood sample (BD day) was drawn after BD certification.
RESULTS
Female patients exhibited lower follicle-stimulating hormone and prolactin levels pre-BD and luteinizing hormone, follicle-stimulating hormone, and prolactin levels on BD day than the age-matched controls. Male patients' sex hormone levels were similar to those of the age-matched controls, except for testosterone levels, which were low in both consecutive measurements. All gonadotropins and prolactin levels were above the tests' lower detection limits (LDLs), except for one male patient with gonadotropin levels below the LDLs of the tests. Estradiol levels in both sexes ranged from normal to elevated. FT3 levels were significantly decreased in the two measurements. Thyroid-stimulating hormone (TSH) levels were low in eight patients and all low TSH levels were above the test's LDL. The remaining patients had normal or elevated TSH levels. The median adrenocorticotropic hormone (ACTH) and cortisol levels were within normal limits. All cortisol and ACTH levels were above the tests' LDLs, except for one patient with ACTH levels below the LDL in both measurements.
CONCLUSION
This study supports the hypothesis that the anterior pituitary gland continues to function in the brain-dead state.
Topics: Humans; Female; Male; Prolactin; Thyrotropin; Hydrocortisone; Brain Death; Adrenocorticotropic Hormone; Follicle Stimulating Hormone; Testosterone; Estradiol; Brain
PubMed: 37736855
DOI: 10.1007/s42000-023-00489-9 -
Expert Opinion on Drug Discovery Jul 2017Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its... (Review)
Review
Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its importance is often taken for granted. Sleep loss can lead to disease, error and economic loss. Our understanding of how sleep is achieved has greatly advanced in recent years, and with that, the management of sleep disorders has improved. There is still room for improvement and recently many new compounds have reached clinical trials with a few being approved for commercial use. Areas covered: In this review, the authors make the case of sleep disorders as a matter of public health. The mechanisms of sleep transition are discussed emphasizing the wake and sleep promoting interaction of different brain regions. Finally, advances in pharmacotherapy are examined in the context of chronic insomnia and narcolepsy. Expert opinion: The orexinergic system is an example of a breakthrough in sleep medicine that has catalyzed drug development. Nevertheless, sleep is a topic still with many unanswered questions. That being said, the melanin-concentrating hormone system is becoming increasingly relevant and we speculate it will be the next target of sleep medication.
Topics: Animals; Drug Design; Drug Discovery; Humans; Hypothalamic Hormones; Melanins; Narcolepsy; Pituitary Hormones; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders; Wakefulness
PubMed: 28511597
DOI: 10.1080/17460441.2017.1329818