Decidual γδT cells of early human pregnancy produce angiogenic and immunomodulatory proteins while also possessing cytotoxic potential.

During pregnancy, the maternal immune system must allow and support the growth of the developing placenta while maintaining the integrity of the mother's body. The trophoblast's unique HLA signature is a key factor in this physiological process. This study focuses on decidual γδT cell populations and examines their expression of receptors that bind to non-classical HLA molecules, HLA-E and HLA-G. We demonstrate that decidual γδT cell subsets, including Vδ1, Vδ2, and double-negative (DN) Vδ1-/Vδ2- cells express HLA-specific regulatory receptors, such as NKG2C, NKG2A, ILT2, and KIR2DL4, each with varying dominance. Furthermore, decidual γδT cells produce cytokines (G-CSF, FGF2) and cytotoxic mediators (Granulysin, IFN-γ), suggesting functions in placental growth and pathogen defense. However, these processes seem to be controlled by factors other than trophoblast-derived non-classical HLA molecules. These findings indicate that decidual γδT cells have the potential to actively contribute to the maintenance of healthy human pregnancy.

Integrative Epigenetic and Molecular Analysis Reveals a Novel Promoter for a New Isoform of the Transcription Factor TEAD4.

TEAD4 is a transcription factor that plays a crucial role in the Hippo pathway by regulating the expression of genes related to proliferation and apoptosis. It is also involved in the maintenance and differentiation of the trophectoderm during pre- and post-implantation embryonic development. An alternative promoter for the TEAD4 gene was identified through epigenetic profile analysis, and a new transcript from the intronic region of TEAD4 was discovered using the 5'RACE method. The transcript of the novel promoter encodes a TEAD4 isoform (TEAD4-ΔN) that lacks the DNA-binding domain but retains the C-terminal protein-protein interaction domain. Gene expression studies, including end-point PCR and Western blotting, showed that full-length TEAD4 was present in all investigated tissues. However, TEAD4-ΔN was only detectable in certain cell types. The TEAD4-ΔN promoter is conserved throughout evolution and demonstrates transcriptional activity in transient-expression experiments. Our study reveals that TEAD4 interacts with the alternative promoter and increases the expression of the truncated isoform. DNA methylation plays a crucial function in the restricted expression of the TEAD4-ΔN isoform in specific tissues, including the umbilical cord and the placenta. The data presented indicate that the DNA-methylation status of the TEAD4-ΔN promoter plays a critical role in regulating organ size, cancer development, and placenta differentiation.

[Conservative and surgical treatments performed for symptomatic pelvic organ prolapse and stress urinary incontinence in Hungary.] / A kismedencei szervek süllyedésének és a noi terheléses vizeletvesztésnek a konzervatív és sebészi kezelése Magyarországon.

INTRODUCTION AND OBJECTIVE: As clinical guidelines are available for the treatment of stress urinary incontinence, but not pelvic organ prolapse, in Hungary, the treatment of pelvic organ prolapse varies widely throughout the country and is not standardized. Due to the establishment of the Hungarian Continence and Urogynecological Association, we aimed to determine current conservative and surgical treatment trends and strategies for these conditions in Hungary and compare them with international practice. METHOD: An online questionnaire consisting of 20 multiple-choice, checkbox, multiple-choice grid, and short-answer items was sent to 40 urology and 65 gynecology departments in Hungary in September and October 2021. RESULTS: The overall response rate was 24.76%. Almost all (96.15%) respondents reported that conservative treatment options were offered as first-line therapy to patients with symptomatic pelvic organ prolapse. For symptomatic anterior-wall prolapse, anterior repair, and laparoscopic sacrohysteropexy/sacrocolpopexy were the preferred surgical options (by 28.96% and 27.42% of respondents, respectively). For apical prolapse, laparoscopic sacrofixation was the first-choice treatment (35.88%). For stress urinary incontinence, mid-urethral sling insertion with a transobturator (61.53%) or retropubic (15%) approach was the preferred intervention. CONCLUSION: The low overall response rate in this study alone reflects the current condition of Hungarian urogynecology. Our findings might provide a good basis for the improvement and refinement of diagnosis and therapy for female urinary incontinence and pelvic organ prolapse in the country. As Hungary is a new affiliated partner of the European Urogynecological Association, we hope that this goal can be achieved soon. In addition, a curriculum for urogynecological specialization is needed. Orv Hetil. 2022; 163(52): 2072-2078.

Key to Life: Physiological Role and Clinical Implications of Progesterone.

The most recent studies of progesterone research provide remarkable insights into the physiological role and clinical importance of this hormone. Although the name progesterone itself means "promoting gestation", this steroid hormone is far more than a gestational agent. Progesterone is recognized as a key physiological component of not only the menstrual cycle and pregnancy but also as an essential steroidogenic precursor of other gonadal and non-gonadal hormones such as aldosterone, cortisol, estradiol, and testosterone. Based on current findings, progesterone and novel progesterone-based drugs have many important functions, including contraception, treatment of dysfunctional uterine bleeding, immune response, and prevention of cancer. Considering the above, reproduction and life are not possible without progesterone; thus, a better understanding of this essential molecule could enable safe and effective use of this hormone in many clinical conditions.

The Role of Growth Hormone in Depression: A Human Model.

BACKGROUND: Although the relationship between acromegaly and depression has been ascribed to the effects of chronic disease, the role of growth hormone (GH), and insulin like growth factor-1 (IGF-1) is not clear. OBJECTIVE: To determine whether related hormones levels in acromegalics are correlated with depressive symptoms and whether these symptoms are ameliorated following surgery. MATERIALS AND METHODS: A prospective cohort study was conducted on patients diagnosed with acromegaly (n = 15) or non-functioning pituitary adenomas (NFPA; n = 20, as controls) and undergoing first-time surgery, who completed the Center for Epidemiological Studies Depression (CES-D) questionnaire both pre-surgery and post-surgery. The primary outcome was the patient's severity of depression symptomatology using the CES-D score; GH, IGF-1 levels, and tumor characteristics were also measured. RESULTS: Hormone levels (GH and IGF-1) and depression scores in acromegaly patients showed significant reductions following surgery (p < 0.05). The average change in CES-D score was 5.73 ± 2.58 (mean ± SE). A moderate correlation was found between GH levels and CES-D scores (r = 0.52, p < 0.01). The depressed affect subscale accounted for the most improvement in CES-D scores postoperatively and correlated most highly with GH levels. We did not find similar declines in the matched cohort of NFPA patients. CONCLUSION AND RELEVANCE: Surgical resection of the pituitary tumor in acromegaly patients leads to reduction in GH levels that is correlated with reduction in CES-D scores. The results suggest a role for GH in depression and provide a stronger foundation on which to build the hypothesis that GH impacts affect. The study also suggests that hormones should be factored into the matrix that entails the neuro-biological underpinnings of depressive disorders. Future work could explore the mechanisms involved, further brain and neuropeptide interactions, and, novel potential therapeutic targets in depressive and other mental health disorders.

Development and validation of the disease-specific QOL-CD quality of life questionnaire for patients with Cushing's disease.

OBJECTIVE: Cushing's disease (CD) patients experience a range of debilitating symptoms that impair quality of life (QOL) as assessed using generic measures. These generic measures are inadequate to capture the disease-specific burden of illness. The development of the CD-specific QOL-CD measure of QOL using items generated by CD patients and healthcare professionals will provide a holistic assessment of patient outcomes and efficacy of novel therapies. METHODS: A total of 96 CD patients participated. A list of 177 items (version 1.0) was generated by treated CD patients (n = 9), caregivers (n = 2), healthcare providers (n = 7), and results of a MEDLINE search. Item reduction was performed through content analysis and dual scaling. Patients' rating of importance was incorporated to reduce to a final version of 56 items (version 3.0). Evidence for test-retest reliability was sought through administering the QOL-CD 1 week apart and Cronbach's α of each subscale. Construct validity was assessed through extreme group analysis and comparison with the normal Canadian population. Concurrent validity was sought through comparison with the SF-36, Functional Assessment of Cancer Therapy-Brain (FACT-Br), and Karnofsky Performance Status (KPS). Perioperative testing was conducted on CD patients (n = 25) against nonfunctioning pituitary adenoma controls (n = 25) through pre- and postoperative testing. RESULTS: A total of 96 CD patients (86 females and 10 males; mean age 45.23 ± 14.16 years) participated. The QOL-CD was feasible (mean completion time 15 minutes, with 70% believing accurate capture of QOL), reliable (CD 1 week apart: r = 0.86; control 1 week apart: r = 0.83; Cronbach's α: general health = 0.73, emotional health = 0.85, physical health = 0.78, mental status = 0.82, social well-being = 0.63, medical treatment = 0.54), and valid (extreme group testing p < 0.001; SF-36 and QOL-CD general health: r = 0.56, social well-being: r = 0.21, emotional health: r = 0.61, total score: r = 0.58; FACT-Br and QOL-CD physical health: r = 0.47, social well-being: r = 0.21, emotional health: r = 0.34, total score: r = 0.68; KPS and QOL-CD general health: r = 0.32, total score: r = 0.14). Perioperative testing of CD patients (n = 25) demonstrated improvement in all subscales postoperatively, with a significant difference in emotional health (p < 0.001) and physical health (p < 0.001). CONCLUSIONS: The QOL-CD questionnaire has been developed for patients with CD and has demonstrated evidence for validity and reliability.

Effect of thyroxin on cell morphology and hormone secretion of pituitary grafts in rats.

INTRODUCTION: Growth hormone and prolactin secretion is affected by thyroid hormones. To see if this influence is subsidiary to the hyptothalamus, we investigated the effects of thyroxin (T4) on hormone secretion and histology of sellar pituitaries and pituitary grafts detached from the hypothalamus (autografted or allografted under the kidney capsule). MATERIALS AND METHODS: Male Wistar rats were divided into eight groups: control, thyroidectomised, pituitary autografted, pituitary allografted, and four additional groups that were injected with T4 for two weeks, starting four weeks after surgery. At sacrifice, adenohypophysial hormone blood levels were assessed, and tissue from sellar and grafted pituitaries were investigated by histology and electron microscopy. RESULTS: Growth hormone and prolactin blood levels, as well as the number of growth hormone immunopositive cells increased in T4-treated groups. Both pituitary auto- and allo-grafts showed lactotroph hyperplasia and displayed spongiform areas containing cells with vesicles in their cytoplasm resembling thyroidectomy cells. This phenomenon was minimized in their respective T4-treated group. Thyroidectomy cells were identified in pituitary grafts, indicating that hypothalamic control was not essential to induce them. DISCUSSION AND CONCLUSION: It is intriguing that the pituitary allografted group, even maintaining normal T4 blood levels, developed thyroidectomy cells in their grafts, suggesting that a long- term deficit of vascularization (>4 weeks) prevented T4 from reaching the graft. After 6 weeks, post T4 treatment of two weeks seemed to be the determining factor to minimize thyroidectomy cells in both pituitary autografted + T4 and pituitary allografted + T4 grafts compared to the untreated groups, although more time and/or higher T4 doses may be required to fully restore the euthyroid morphology.

Resection of the medial wall of the cavernous sinus in functioning pituitary adenomas: Technical note and outcomes in a matched-cohort study.

BACKGROUND: Parasellar dural invasion can be associated with treatment failure after excision of functioning pituitary adenomas. Because the medial wall of the cavernous sinus is a common site of microscopic disease, we hypothesize that its resection may lead to improvement in biochemical remission and recurrence rates. We aim to describe our technique in the resection of the medial wall of the cavernous sinus using binasal endoscopic transsphenoidal surgery (BETS); and compare tumor control and biochemical remission rates against a matched cohort. METHODS: Patients with functioning pituitary adenomas who underwent resection of the medial cavernous wall in addition to tumor excision via BETS were compared to a cohort matched for tumor type, size, and Knosp grade. Biochemical remission rates, tumor control at follow-up, and complication rates were assessed. RESULTS: Sixteen patients underwent resection of the medial wall of the cavernous sinus. Of 14 cases with wall specimens deemed adequate for histopathologic analysis, 43 % had microscopic evidence of tumor. Two of three patients with Knosp grade 0 scores had microscopic tumor invasion of the medial wall. The mean blood loss in the cohort was 175 mL (comparable to control, p = 0.895), with no operative complications noted. Gross total excision was achieved in 81 % of cases in the treatment cohort. At a median follow-up of 11 months, no statistical difference was noted in the biochemical remission and oncologic control rates between groups. CONCLUSION: Resection of the medial wall of the cavernous sinus is safe and technically feasible using BETS when performed by experienced surgeons. The Knosp classification may not be reliable for microscopic tumor invasion. The effect of this technique on clinical outcomes remains to be determined by larger cohorts with matched controls and long-term follow-up.

Leuprolide Acetate, a GnRH Agonist, Improves the Neurogenic Bowel in Ovariectomized Rats with Spinal Cord Injury.

BACKGROUND: Electromyographic studies have shown that external anal sphincter activity is modified in response to distension in animals with spinal cord injury. Gonadotropin-releasing hormone and its agonist leuprolide acetate have neurotrophic properties in animals with spinal cord injury. AIM: This study was to determine the effects of leuprolide acetate treatment on electromyographic activity of the external anal sphincter and anorectal manometry in ovariectomized rats with spinal cord injury. METHODS: Adult ovariectomized rats were divided in three groups: (a) sham of spinal cord injury, (b) spinal cord injury treated with saline solution, and (c) spinal cord injury treated with leuprolide acetate. The spinal cord injury was induced by clamping at level T9. Leuprolide acetate dosage of 10 µg/kg was proctored intramuscular for 5 weeks, commencing the day after the lesion. Electromyography of the external anal sphincter, anorectal manometry, and volume of the cecum were evaluated in all groups. RESULTS: The electromyographic study of the external anal sphincter activity showed a significant improvement in injured rats treated with leuprolide acetate. Manometric analysis and cecum volume data obtained in animals with leuprolide acetate were very similar to those found in the sham group. CONCLUSIONS: These results demonstrate that leuprolide acetate treatment improves the neurogenic colon in ovariectomized rats with spinal cord injury.

Ectopic cushing's syndrome due to corticotropin releasing hormone.

Cushing's syndrome (CS) secondary to corticotropin releasing hormone (CRH) producing tumors is rare. In this paper we present an Iranian patient who was admitted to our hospital with classic signs and symptoms of CS. Laboratory evaluation revealed high serum and urine cortisol which could not be suppressed with dexamethasone. Abdominal CT scan revealed a mass in abdominal cavity. A percutaneous needle biopsy was performed and histopathologic evaluation revealed that the mass was a neuroendocrine tumor. A multi-disciplinary approach including resection of the mass, bilateral adrenalectomy somatostatin analogue and chemotherapy was applied for management of the disease. Extensive review of English literature focusing on the topic from 1971 to 2018 revealed that there have been only 75 similar cases. Clinical, laboratory, imaging, histopathologic characteristics and managements of these patients will also be discussed in this paper.

Follicular fluid progesterone concentration is associated with fertilization outcome after IVF: a systematic review and meta-analysis.

Follicular fluid is a key biochemical environment for oocyte development. The potential effect of follicular progesterone level on successful fertilization is a subject of debate, and so the aim of this study was to provide a summary of the currently available evidence on the association between follicular fluid progesterone level and fertilization outcome. To do so, a systematic review and a meta-analysis were performed, with the literature searches being conducted in three databases (PubMed, Embase and the Cochrane Library) to identify all relevant studies published up to 19 August 2017. Data were available from 13 studies (four intracytoplasmic sperm injection [ICSI] and nine conventional IVF) and 1009 individually aspirated follicular fluid samples were included in the analysis. The progesterone levels in follicular fluid were significantly higher in normal fertilization than in failed fertilization, both in conventional IVF (33% difference, P < 0.001) and ICSI (34% difference, P = 0.004). Although these data show that fertilized oocytes are derived from follicles with higher levels of progesterone, the results must be interpreted with caution, because of various progesterone measurement methods and different treatment protocols and it is too early to state that follicular fluid progesterone level could be considered as a marker for oocyte quality.

Pituitary pathology in traumatic brain injury: a review.

PURPOSE: Traumatic brain injury most commonly affects young adults under the age of 35 and frequently results in reduced quality of life, disability, and death. In long-term survivors, hypopituitarism is a common complication. RESULTS: Pituitary dysfunction occurs in approximately 20-40% of patients diagnosed with moderate and severe traumatic brain injury giving rise to growth hormone deficiency, hypogonadism, hypothyroidism, hypocortisolism, and central diabetes insipidus. Varying degrees of hypopituitarism have been identified in patients during both the acute and chronic phase. Anterior pituitary hormone deficiency has been shown to cause morbidity and increase mortality in TBI patients, already encumbered by other complications. Hypopituitarism after childhood traumatic brain injury may cause treatable morbidity in those survivors. Prospective studies indicate that the incidence rate of hypopituitarism may be ten-fold higher than assumed; factors altering reports include case definition, geographic location, variable hospital coding, and lost notes. While the precise pathophysiology of post traumatic hypopituitarism has not yet been elucidated, it has been hypothesized that, apart from the primary mechanical event, secondary insults such as hypotension, hypoxia, increased intracranial pressure, as well as changes in cerebral flow and metabolism may contribute to hypothalamic-pituitary damage. A number of mechanisms have been proposed to clarify the causes of primary mechanical events giving rise to ischemic adenohypophysial infarction and the ensuing development of hypopituitarism. CONCLUSION: Future research should focus more on experimental and clinical studies to elucidate the exact mechanisms behind post-traumatic pituitary damage. The use of preventive medical measures to limit possible damage in the pituitary gland and hypothalamic pituitary axis in order to maintain or re-establish near normal physiologic functions are crucial to minimize the effects of TBI.

Recovery Room Cortisol Predicts Long-Term Glucocorticoid Need After Transsphenoidal Surgery for Pituitary Tumors.

BACKGROUND: Accurate assessment of the need for glucocorticoid therapy is essential after transsphenoidal surgery (TSS) for pituitary tumors. Agreement on the best test to use in the early postoperative setting is lacking. OBJECTIVE: To examine recovery room (RR) cortisol as a predictor of long-term need for glucocorticoids. METHODS: We conducted a retrospective cohort study of 149 patients who underwent TSS for pituitary tumors between January 2007 and December 2014. Pathological tumor diagnoses were confirmed. Endocrinologists assessed the need for glucocorticoid supplementation within 6 to 8 wk after TSS. We extracted data on preoperative, RR, and day 1 to 3 post-TSS morning serum cortisol (MSC). We reported areas under the receiver operating characteristic curve (AUC) and diagnostic measures for different cortisol measures. We also conducted a logistic regression to identify the most predictive variables. RESULTS: Eighteen patients required glucocorticoid supplementation at follow-up. RR cortisol was the most accurate measurement in the early postoperative period (AUC [95% confidence interval (CI)], .92 [.85-.99]; P < .001), followed by day 1, 2, and 3 post-TSS MSC, respectively. A threshold RR cortisol of 744.0 nmol/L (26.97 µg/dL) had 90.9% sensitivity and 73.7% specificity for detecting patients in the hypocortisolism group, while 757.5 nmol/L (27.46 µg/dL) had 100% and 70.0%, respectively. The logistic regression identified RR cortisol as the sole significant predictor (odds ratio [CI], .36[.18-.71] for every 100 nmol/L increase; P = .0033). CONCLUSION: The RR cortisol is accurate in predicting long-term glucocorticoid supplementation and may be the best early postoperative measure. Future larger studies should validate these findings and derive optimal RR cortisol threshold values.

Corrigendum to "Amiodarone Induced Hyponatremia Masquerading as Syndrome of Inappropriate Antidiuretic Hormone Secretion by Anaplastic Carcinoma of Prostate".

[This corrects the article DOI: 10.1155/2014/136984.].

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions.

Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.

65 YEARS OF THE DOUBLE HELIX: Treatment of pituitary tumors with temozolomide: an update.

Temozolomide is an alkylating chemotherapeutic agent used in malignant neuroendocrine neoplasia, melanoma, brain metastases and an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and anaplastic astrocytoma. Since 2006, it has been used for the treatment of pituitary carcinomas and aggressive pituitary adenomas. Here, we discuss the current indications and results of temozolomide therapy in pituitary tumors, as well as frequently asked questions regarding temozolomide treatment, duration of therapy, dosage, tumor recurrence and resistance.

DICER1 gene mutations in endocrine tumors.

In this review, the importance of the DICER1 gene in the function of endocrine cells is discussed. There is conclusive evidence that DICER1 mutations play a crucial role in the development, progression, cell proliferation, therapeutic responsiveness and behavior of several endocrine tumors. We review the literature of DICER1 gene mutations in thyroid, parathyroid, pituitary, pineal gland, endocrine pancreas, paragangliomas, medullary, adrenocortical, ovarian and testicular tumors. Although significant progress has been made during the last few years, much more work is needed to fully understand the significance of DICER1 mutations.

Alpha subunit in clinically non-functioning pituitary adenomas: An immunohistochemical study.

Pituitary adenomas may be classified as either functioning or non-functioning, depending on whether excess hormone secretion can be clinically identified. Of the six hormones produced in the anterior pituitary, TSH, FSH and LH are known as glycoproteins and contain two subunits (α and ß). While α-subunit is identical within all of them, each ß-subunit is unique and biologically specific. Independently, the α- and ß-subunits are inactive and only induce a hormonal response when they are non-covalently associated. Studies have shown that in certain cases, pituitary adenomas may abnormally secrete only α-subunit, detectable in the serum or through immunohistochemical analysis. In the present study, we examined α-subunit immunoexpression in surgically removed non-functioning pituitary adenomas and analyzed its prognostic value. Results showed that expression of α-subunit in clinically non-functioning pituitary adenomas is not a rare occurrence. While there were no age/gender differences between tumors that expressed α-subunit and those that did not, α-subunit immunonegative adenomas presented with suprasellar extension more frequently and had an Ki67 proliferation greater than 3%. The use of immunohistochemical techniques to determine the presence of α-subunit may provide information on tumor cell proliferation and biologic behavior. To fully understand the role of α-subunit in pituitary adenomas more work is needed.

Vasculogenic Mimicry in Clinically Non-functioning Pituitary Adenomas: a Histologic Study.

The term "vasculogenic mimicry" (VM) refers to the phenomenon in which vascular-like channels, which are not lined by endothelial cells, are formed in tumors. Since its discovery in 1999, it has been observed in several tumor types and is proposed to provide blood perfusion to tumors in absence of co-apted or neo-angiogenic blood vessels. Pituitary tumors are generally slow growing, benign adenomas which are less vascularized than the normal pituitary gland. To date, VM in pituitary adenomas has not been described. In this histological study, we assessed the presence of VM in a series of surgically resected clinically non-functioning pituitary adenomas (NFPAs) using CD34 and Periodic Acid-Schiff (PAS) double staining. To identify VM, slides were assessed for the presence of CD34-negative and PAS-positive channels indicating that they were not lined by endothelial cells. The histological staining pattern suggestive of VM was noted in 22/49 (44.9%) of the specimens studied. VM was observed in both recurring and non-recurring NFPAs. The incidence of VM present varied from case to case and within groups. There was no association between the presence of VM and gender, tumor size, Ki-67 index, recurrence or cavernous sinus invasion. VM was not noted in cases of non-tumorous pituitaries. Our findings suggest the existence of a complementary perfusion system in pituitary adenomas, implying potential clinical implications with respect to response to therapy and clinical course. Further research is warranted to confirm the presence of VM in pituitary adenomas to elucidate its clinical relevance in patients diagnosed with a pituitary adenoma.