Growth Hormone Adenomas Research Articles

Co-expression of multiple transcription factors is associated with clinical features and endocrine prognosis in growth hormone-secreting pituitary adenomas.

The types of growth hormone-secreting pituitary adenomas are diverse, we have found that there are significant differences in clinical features and prognosis between PIT-1 single-cell spectrum growth hormone adenomas and growth hormone phenotypic polyhormonal adenomas. This study examined a cohort of 193 patients with growth hormone-secreting pituitary adenoma (GHPA), stratifying them into two groups: PIT-1 single transcription factor positive growth hormone adenoma (STF-GHPA) and Multiple transcription factor-positive growth hormone-secreting adenomas (MTF-GHPA). The objective was to compare these two groups' clinical characteristics. Within the MTF-GHPA group, we further subtyped them based on transcription factors to evaluate potential variations in clinical manifestations. Logistic regression analyses were employed to develop a risk factor model for investigating factors influencing hormone remission. There were no statistically significant differences in terms of age, gender, serum GH, and IGF-1 levels between patients diagnosed with MTF-GHPA and STF-GHPA. However, patients with MTF-GHPA exhibited a higher proportion of hypopituitarism compared to those with STF-GHPA. Furthermore, MTF-GHPA were characterized by smaller tumor size and less invasiveness, as indicated by lower Knosp classes. However, patients with MTF-GHPA have a lower rate of hormonal remission (30.8%) and more postoperative complications (31.0%), which means that STF-GHPA (hormonal remission:71.6%; postoperative complications:13.4%) has a better endocrine outcome than MTF-GHPA patients. Between the PIT-1 + SF-1+ and PIT-1 + TPIT+ subtypes within MTF-GHPA, significant differences were also observed in tumor size, endocrine outcomes, and postoperative complications. Risk factors influencing hormonal remission for GHPA included preoperative GH level, primary/recurrent, extent of resection, and transcription factor expression. Co-expression of multiple transcription factors is an important factor associated with clinical behavior and endocrine outcomes in patients with GHPA.

Clinical Characteristics and Management of Cosecreting Thyroid Stimulating Hormone or Prolactin Pituitary Growth Hormone Adenomas: A Case-Control Study

ObjectiveCosecreting thyroid stimulating hormone (TSH) or prolactin (PRL) in patients with pituitary growth hormone (GH) adenomas has been rarely reported. Our study aimed to elucidate their clinical characteristics. MethodsWe retrospectively collected data of 22 cases of cosecreting GH and TSH pituitary adenomas [(GH+TSH)oma] and 10 cases of cosecreting GH and PRL pituitary adenomas [(GH+PRL)oma] from Beijing Tiantan Hospital, Capital Medical University between January 2009 and January 2023. The clinical manifestation, preoperative hormone levels, imaging features, pathologic characteristics, and biochemical remission rates were compared among 335 patients with solo-secreting GH adenomas (GHoma) and 49 patients with solo-secreting TSH adenoma (TSHoma). Patients with (GH+TSH)oma and (GH+PRL)oma were grouped according to biochemical remission to explore the risk factors leading to biochemical nonremission. ResultsCosecreting pituitary GH adenomas had various clinical manifestations and a larger tumor volume and were more likely to invade the cavernous sinus bilaterally and compress the optic chiasm. GH and TSH levels were lower in (GH+TSH)oma than in GHoma or TSHoma. Solo part remission was observed both in (GH+TSH)oma and (GH+PRL)oma. Cavernous sinus invasion was an independent risk factor for biochemical nonremission in patients with (GH+TSH)oma and (GH+PRL)oma. ConclusionsThe clinical manifestation of (GH+TSH)oma and (GH+PRL)oma may be atypical. When screening for pituitary adenomas, a comprehensive evaluation of all pituitary target gland hormones is needed. Cosecreting pituitary GH adenomas are more aggressive and surgery is often unable to completely remove the tumor, requiring pharmacologic or radiological treatment if necessary. Clinicians should give high priority to biochemical remission, although solo part remission may occur.

Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma.

Somatostatin analogues (SSTA) are first-line pharmacological treatment choice for acromegaly, which received satisfying tumor shrinkage and normalization of growth hormone. However, there are still patients unresponsive to SSTA, and the underline mechanism remains unknown. Besides, there is no evidence regarding the role of endoplasmic reticulum stress (ERS) and its transmission in SSTA resistance, which also require investigation. Primary growth hormone adenoma cells and cell lines were treated with SSTA; autophagy double-labeled LC3 (mRFP-GFP) adenovirus transfection, flow cytometry sorting, western blotting, calcium imaging as well as immunofluorescence staining were used to determine ERS and autophagy signal transmission; xenograft and syngeneic tumor in vivo model were exploited to confirm the ERS signal transmission mediated effect. Our results revealed that SSTA induces ERS in pituitary growth hormone (GH) adenoma cells. The ERS signals can be intercellularly transmitted, leading to less responsible to SSTA treatment. Moreover, SSTA stimulates inositol triphosphate (IP3) elevation, mediating ERS intercellular transfer. In addition, connexin 36 tunnels ERS transmission, and its blocker, Quinine, exhibits a synergistic effect with SSTA treating GH adenoma. Our study provided insight into ERS intercellular transmission mediated SSTA resistance, which could be translated into clinical usage to improve SSTA efficiency in GH adenoma treatment.

Treatment outcomes of neuroendoscopic and microscopic trans-sphenoidal pituitary adenomectomies and the effects on hormone levels.

We aimed to compare the treatment outcomes of neuroendoscopic and microscopic trans-sphenoidal pituitary adenomectomies, as well as the effects on hormone levels and clinical symptoms. A total of 82 patients with pituitary adenomas that were surgically resected from June 2018 to March 2021 were selected and divided into a group receiving neuroendoscopic trans-sphenoidal pituitary adenomectomy (group A, N.=40), and the other group receiving microscopic surgery (group B, N.=42). Surgery-related indices, hormone levels before discharge and alleviation of symptoms 24 weeks after surgery were compared. Both groups had significantly different degrees of tumor resection (P<0.05). The proportion of cases receiving total adenomectomy in group A significantly exceeded that of group B (P<0.05). The surgical time of group A was significantly longer than that of group B (P<0.05). Group A had significantly shorter mean hospitalization stay than that of group B (P<0.05). The postoperative hormone levels of both groups decreased significantly differently (P<0.05). Before discharge, the hormone recovery rate of group A significantly surpassed that of group B (P<0.05). The hormone levels of cases with prolactinoma, adrenocorticotropic hormone adenoma and growth hormone adenoma in group A dropped more significantly than those of group B did (P<0.05). Compared with microscopic surgery, neuroendoscopic trans-sphenoidal pituitary adenomectomy worked more effectively, induced fewer postoperative complications and better promoted the postoperative recovery of hormone levels.

Quality of Life After Endoscopic Surgical Management of Pituitary Adenomas.

Patient-reported quality of life (QOL) is a vital metric for surgical success. To assess the effect of surgery on QOL in the largest prospectively collected, longitudinal cohort of surgically managed pituitary adenomas. A consecutive surgical adenoma cohort (n = 304) between late 2016 and mid-2020 underwent a scheduled overall (Anterior Skull Base Questionnaire-35) and sinonasal-specific (Sinonasal Outcome Test-22) QOL assessment. Scores were stratified by adenoma subtype and analyzed for clinical predictors of QOL changes. The average age was 53.8 ± 16 yr, and 53% of participants were female. 60.9% of adenomas were nonfunctioning while adrenocorticotropic hormone adenomas (16.4%), growth hormone adenomas (14.1%), and prolactinomas (5.9%) were the most prevalent secreting adenomas. Baseline overall QOL differed between tumor types (P = .006), with adrenocorticotropic hormone adenomas worse than growth hormone adenomas (P = .03) and nonfunctioning pituitary adenomas (NFPA) (P < .001). Sinonasal QOL worsened in the 3 wk after surgery but returned to baseline by 6 wk and beyond. Overall QOL worsened at 3 wk after surgery (P < .001) but significantly improved from baseline by 3 mo (P = .009) and beyond (P < .001). Emotional functioning improved soon after surgery, followed by performance and pain, and then, by 6 mo, physical function and vitality. Predictors of improved QOL were sellar/suprasellar lesions (P = .01), prolactinomas (P = .003), and NFPA (P = .04). Conversely, new postoperative hypopituitarism (P = .04) and larger adenoma volume (P = .04) predicted QOL worsening. QOL is worsened after surgery at early time points. Prolactinomas and NFPA enjoy significant QOL improvements from surgery as early as 3 mo postoperatively. Other functional tumors may experience early benefits in younger patients without hypopituitarism and when isolated to the sellar/suprasellar region. These findings provide valuable information for counseling patients and setting expectations for surgery.

Predicting Subtype of Growth Hormone Pituitary Adenoma based on Magnetic Resonance Imaging Characteristics.

This study aimed to investigate the value of magnetic resonance (MR) characteristics in differentiating the subtypes of growth hormone pituitary adenomas. The clinical and MR imaging data of 70 patients with growth hormone pituitary adenoma confirmed by surgery and pathology were retrospectively analyzed. The tumors were divided into dense granular (DG; 36 cases) and sparse granular subtypes (SG; 34 cases). The tumors' MR features were analyzed, including the mean and maximum diameters, T2 signal intensity, T2 relative signal intensity (rSI), homogeneity, enhancement degree, and invasiveness (Knosp grade). Mann-Whitney U test and χ2 test were used to analyze MR characteristics between the 2 groups. The independent predictors and predictive probabilities of tumor subtypes were obtained via a logistic regression model, and the efficacy was compared by receiver operating characteristic curve. The mean and maximum diameters of growth hormone adenoma in DG and SG were 1.77 versus 2.45 and 1.95 versus 3.00 cm (median, P < 0.05), respectively. There was a significant difference between the 2 groups in T2 signal intensity and rSI (P values were 0.02 and 0.001, respectively). Most DG adenomas (86.1%) appeared as hypointense on T2 images, and 38.2% of SG adenomas were hyperintense. There was no significant difference in tumor homogeneity (P = 0.622). A significant difference was found in the Knosp grade between the 2 subtypes (P = 0.004). In addition, the enhancement degree of SG adenomas was significantly higher than that of DG adenomas (P = 0.001). Logistic regression analysis showed that high T2 rSI value and marked contrast enhancement were independent predictors of the 2 subtypes, and the odds ratios were 4.811 and 4.649, respectively. The multivariate logistic model obtained relatively high predicting efficacy, and the area under the curve, sensitivity, and specificity were 0.765, 0.882, and 0.500, respectively. There are significant differences in tumor size, T2 signal intensity, T2 rSI, enhancement degree, and invasiveness between DG and SG adenomas. The logistic model based on the marked contrast enhancement and high T2 rSI value has an important value in predicting the subtype of growth hormone adenoma.

Primary Amenorrhea and Hyperandrogenism: Presenting Features of a Growth Hormone Producing Pituitary Adenoma in a Female Adolescent

Background: The combination of obesity, metabolic syndrome, hyperandrogenism and amenorrhea can be a common presentation of conditions such as polycystic ovarian syndrome. Growth hormone (GH) secreting pituitary adenomas are rare in children, but can present with a similar picture. Clinical Case: A 15-year 4-month old female was evaluated for primary amenorrhea and metabolic syndrome. Her weight was +2.96 SD, height +3.0 SD (mid-parental height 44th percentile, -0.1 SD) and BMI +2.53 SD, all >99th percentile. Weight and BMI were >99th percentile (weight +3.0 SD, BMI +2.4 SD) since 11 years of age and height was >99th percentile (+ 2.7 SD) since 8 years of age. Physical exam was remarkable for acanthosis, deepened voice, no hirsutism, Tanner III breasts and Tanner IV pubic hair. Laboratory evaluation was notable for prolactin (PRL) 147.8 ng/dL (2.6-18.0), LH <0.02 mIU/mL, FSH <0.09 mIU/mL, estradiol 23 pg/mL, total testosterone 81 ng/dL (<41), androstenedione 673 ng/mL (43-180), DHEA-S 627 mcg/dL (42-162), dyslipidemia and normal 17 hydroxy-progesterone and thyroid function tests. Bone age was 16 years. Brain MRI showed a 15x7mm pituitary macroadenoma without suprasellar invasion. Pituitary evaluation revealed IGF-1 619 ng/mL (192-568), IGF-BP3 5.15 mg/L (2.64-6.43) and adrenal insufficiency. Treatment with cabergoline 0.5 mg/week and maintenance hydrocortisone were initiated. An OGTT demonstrated baseline GH 4.9 ng/mL (0-6) and nadir 3.62 ng/mL (normal <1) consistent with GH excess. Surgery for the pituitary adenoma was recommended but unfortunately postponed. Four months later, her BP was elevated, she had clinical signs of diabetes insipidus (DI), PRL was 43.2 ng/dL and she failed a repeat GH suppression test. Follow-up MRI showed pituitary mass enlargement (17x9mm). Patient underwent total trans-sphenoidal tumor resection. Pathology confirmed a sparsely granulated (SG) GH adenoma immunoreactive for GH, PRL and estrogen receptor. Post-operative OGTT showed adequate GH suppression, normal prolactin levels, persistent testosterone elevation and DI. Conclusions: Hyperprolactinemia, hyperandrogenism and metabolic syndrome could be the presenting features of pituitary GH adenomas even in the absence of acromegalic features. Specifically, SG pituitary adenomas are frequently seen in young adults, are larger, more invasive and less likely to respond to medical treatment. Timely diagnosis and surgical treatment of GH adenomas is essential to prevent the high morbidity and mortality.

Carney Complex With Endocrine Involvement Isolated to the Thyroid Gland

Abstract Introduction: Carney complex is a rare autosomal dominant disorder characterized by pigmented lesions of skin and mucosae, endocrine neoplasms or overactivity, and myxomas of the heart, skin, and other organs. Most patients have at least two affected endocrine organs at time of diagnosis. We present a case of Carney complex with endocrine involvement limited to the thyroid gland. Case: A 48-year-old female was referred for evaluation of thyroid nodules incidentally discovered on imaging for submandibular salivary gland swelling. Ultrasound evaluation of the thyroid revealed numerous, bilateral nodules that were mostly cystic or spongiform, though some had irregular borders and microcalcifications. A brother with Carney complex had been diagnosed with papillary carcinoma, and the patient decided to undergo thyroidectomy. Fortunately, no thyroid carcinoma was found on postsurgical histopathology. Initial biochemical evaluation showed no evidence of hypercortisolemia (8 AM cortisol 1.7 mcg/dL on 1 mg dexamethasone suppression test; 24-h urine cortisol 26.1 mcg [reference: 4-50]), growth hormone excess (IGF-1 190 ng/mL [reference: 52-328]), or hyperprolactinemia (prolactin 10 ng/mL [reference: 2.74-26.72]). Imaging showed no pituitary or adrenal masses. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy for endometrial cancer prior to referral. She was diagnosed with Carney complex at age 19 years, and her manifestations included atrial and ventricular myxomas, intraductal adenoma of the breast, multiple skin lesions (lentigines, blue nevi, and cutaneous myxomas), and myxomas of the external auditory canals. She is in a Carney complex kindred that includes her mother, two brothers, and a niece. Discussion: Carney complex is usually caused by inactivating mutations or large deletions in the protein kinase A type I alpha regulatory subunit (PRKAR1A) gene located on chromosome 17q22-24. Most mutations are inherited in an autosomal dominant manner, though approximately 30% of cases are due to de novo mutations. In a review of 365 cases, the median age at diagnosis was 20 years. Growth hormone adenomas or somatomammotroph hyperplasia occurs in approximately 75% of patients, and most have at least one additional endocrine abnormality including multinodular goiter, primary pigmented nodular adrenocortical hyperplasia, and testicular or ovarian masses. There is an approximately 10% chance of developing well differentiated thyroid carcinoma. Treatment for Carney complex is individualized depending on the patient’s presentation and includes excision or surgical removal of myxomas, neoplasms, and skin lesions, as well as regular evaluation for cardiac myxomas and endocrine overactivity. This case of Carney complex is unusual because the only endocrinopathy is multinodular goiter.

Extensive subdural ossification with meningioma

Abstract Rationale: Intracranial tumors can stimulate the occurrence of intracranial ossification, and previous studies have reported intracranial ossification with astrocytoma, glioblastoma multiforme and growth hormone adenoma. For meningiomas derived from arachnoid cells, the outcome of abnormal arachnoid cells is not only tumorigenesis, but also calcium deposition. To the best of our knowledge, meningioma with subdural ossification has not been reported. Patient concerns: A 60 year old woman was admitted to the hospital with a 1-year-old history of right blepharoptosis. Diagnoses: The preoperative examination of the patient was suggestive of meningioma on magnetic resonance imaging plain scan and enhancement. After the surgery, Endothelial cell type meningioma (WHO I grade) with intracranial ossification was diagnosed. Interventions: The patient underwent right extended pterional approach craniotomy and the neoplasm was gross totally resected. The patient was scheduled for follow-up and regular observation of the intracranial ossification. Outcomes: Intracranial computed tomography showed that extensive ossification still existed, but the symptoms of right blepharoptosis were significantly improved. Lessons: The authors report a rare case of meningioma complicated with extensive subdural ossification. Further studies are needed to confirm whether intracranial ossification in meningioma is related to arachnoid granulosa cells.

Clinical Relevance and Immunohistochemical Patterns of Silent Pituitary Adenomas: 10 Years of Single-centre Experience

Background:Silent pituitary adenomas are clinically non-functional (i.e., without clinically evident pituitary hormone production).Introduction:The aim of this study was to investigate subjects with silent pituitary adenomas for possible variations in their clinical status.Methods:A total of 102 patients who had undergone surgery for pituitary adenoma and had been diagnosed with silent pituitary adenoma was included in the study. The patients’ preoperative and postoperative hormonal parameters and magnetic resonance imaging (MRI) features were collected, and pathological specimens were re-evaluated.Results:Immunohistochemistry results of the 102 patients were as follows: hormone-negative adenomas (n=35) 35.5%; FSH+LH-positivity (n=32) 31.3%; ACTH-positivity (n=11) 10.7%; α-subunit- positivity (n= 9) 8.8%; prolactin-positivity (n=8) 7.8%; GH-positivity (n=6) 5.4%; and plurihormonal adenoma (n=1). The mean sizes of SGA, SGHA, and SCA were 28.0±12.7, 30.0±16.0, and 27.7±8.9mm (p&gt;0.05), respectively. With the exception of silent gonadotroph adenomas (SGAs), female gender dominance was shown in patients with silent growth hormone adenoma (SGHA) and silent corticotroph adenoma (SCA). Although no clinical relevance was observed in relation to hormonal excess, preoperative GH (4.21±4.6, vs. 0.27±0.36 p=0.00) was slightly more elevated in SGHA than in GH-negative adenomas. Additionally, preoperative basal ACTH values (47.3±28.7 vs. 23.9±14.4, p=0.003) were also higher in SCA compared to the other types. Our findings revealed SCAs to be of more aggressive behaviour than SGHAs and SGAs due to invasiveness in radiological imaging, their elevated re-operation, and postoperative ACTH values.Conclusion:Silent pituitary adenomas represent a challenging diagnostic tumour group. Careful initial evaluation of patients with pituitary adenomas should consider any mild signs and symptoms of functionality, particularly in cases of GH- and ACTH-secreting adenomas.

Sex differences in acromegaly at diagnosis: A nationwide cohort study and meta-analysis of the literature.

Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies. A nationwide cohort study including all incident cases of acromegaly (1978-2010, n=596) and a meta-analysis on sex differences in active acromegaly (40 studies) were performed. Sex-dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin-like growth factor 1 (IGF-I) and growth hormone (GH) concentrations were estimated. The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5-49.8 (males) vs. 47.2 CI95% 45.5-48.9 (females), p=0.4). The incidence rate significantly increased during the study period (R2 =0.42, p<0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p=0.03). IGF-ISDS was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females. In the meta-analysis, the weighted percentage female was 53.3% (CI95% 51.5-55.2) with considerable heterogeneity (I2 =85%) among the studies. The mean age difference at diagnosis between genders was 3.1years (CI95% 1.9-4.4), and the diagnostic delay was longer in females by 0.9years (CI95% -0.4 to 2.1). Serum IGF-I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable. There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF-I concentrations and a longer diagnostic delay.

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic options. As a promising therapeutic approach, cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The purpose of this review is to report the progress of immunotherapy in pituitary tumors, including refractory PAs and PCs. The tumor immune microenvironment has been recognized as a key contributor to tumorigenesis, progression, and prognosis. One study indicated that the number of CD68+ macrophages was positively correlated with tumor size and Knosp classification grade for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but pituitary growth hormone (GH) adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in pituitary tumor size and invasiveness. Another study suggested that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogs in acromegaly patients, highlighting a potential role of the tumor immune microenvironment in determining the prognosis of somatotroph pituitary tumors. Preclinical studies have indicated that widely varying degrees of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are found among different subtypes. Functional PAs and aggressive PAs express significantly higher levels of PD-L1 and TILs than other subtypes, indicating that PD-1 blockade might be a promising alternative therapy for patients with aggressive PAs. PD-L1 transcript and protein levels were found to be significantly increased in functioning (GH and prolactin-expressing) pituitary tumors compared to nonfunctioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary tumors harbored higher levels of PD-L1 mRNA than recurrent tumors. These findings suggest the possibility of considering checkpoint blockade immunotherapy for functioning pituitary tumors refractory to conventional management. Animal models of Cushing’s disease also demonstrated PD-L1 and TIL expression in cultured tumors and murine models, as well as the effectiveness of checkpoint blockade therapy in reducing the tumor mass, decreasing hormone secretion, and increasing the survival rate. Clinical studies show that immunotherapy may be an effective treatment in patients with pituitary tumors. One corticotroph carcinoma patient showed a significant reduction in hormone levels and shrinkage of the tumor size of primary and metastatic lesions immediately after investigational treatment with ipilimumab and nivolumab. However, another patient with corticotroph adenoma progressed rapidly after four cycles of anti-PD-1 (pembrolizumab) treatment. To date, there are two registered clinical trials of immunotherapy for pituitary tumors. One of them is the phase II clinical trial of nivolumab combined with ipilimumab for patients with aggressive pituitary tumors (NCT04042753). The other one is also a phase II clinical trial of the combination of nivolumab and ipilimumab for rare tumors, including pituitary tumors (NCT02834013). Both clinical trials are in the stage of recruiting patients and have not been completed. In summary, the results from preclinical research and clinical studies indicated that immunotherapy might be a promising alternative therapy for PCs and refractory PAs resistant to conventional treatments. The combination of immunotherapy and radiotherapy or temozolomide may have synergistic effects compared to a single treatment. More preclinical and clinical studies are needed to further indicate the exact efficacy of immunotherapy in pituitary tumors.

Cystic appearance on magnetic resonance imaging in bihormonal growth hormone and prolactin tumors in acromegaly.

To investigate demographic, imaging and laboratory characteristics, and treatment outcomes of acromegaly patients who have bihormonal (BA) growth hormone (GH) and prolactin (PRL) immunoreactive adenomas compared to patients who have densely granulated GH adenomas (DGA) and sparsely granulated GH adenomas (SGA). Retrospective review of single-center surgically treated acromegaly patients; pathology was analyzed by asingle neuropathologist using 2017 WHO criteria. Preoperative magnetic resonance imaging was assessed to evaluate tumor size, cystic component, invasion and T2 signal intensity. Seventy-seven patients; 19 BA (9 mammosomatotroph and 10 mixed GH and PRL adenomas) were compared with 30 DGA, and 28 SGA. Patients with BA were older than SGA (49.6 vs 38.5years, p = 0.035), had a higher IGF-1 index (3.3 vs 2.3, p = 0.040) and tumors were less frequently invasive (15.8% vs 57.1%, p = 0.005). BA more frequently had a cystic component on MRI than both SGA and DGA (52.6% vs 14.3%, and 22%, p = 0.005 and 0.033, respectively). When all histological types were combined, biochemical remission postoperatively was more common in non-cystic than cystic tumors (50% vs 22.5%, p = 0.042). Somatostatin receptor ligand response rate was 66.7%, 90.9% and 37.5% in BA, DGA and SGA patients, respectively (p = 0.053). Imaging characteristics are an increasingly important adenoma behavior determinant. An adenoma cystic component may suggest that a GH adenoma is a BA. Cystic tumors exhibited lower rates of surgical remission in this series; therefore, optimized individual patient treatment is needed, as patients could be candidates for primary medical treatment.

Secondary pituitary hormonal dysfunction patterns: tumor size and subtype matter.

Patients with sellar masses (SM) frequently have secondary hormonal deficiency (SHD) at initial presentation. While larger SM are more likely to present with SHD, it is unclear whether SHD at presentation is influenced by the type of SM. We conducted a retrospective analysis of patients with SM prospectively enrolled in our comprehensive provincial neuropituitary registry between November 2005 and December 2018. SM were subdivided based on size: < 1cm, 1-1.9cm, 2-2.9cm, and > 3cm. A total of 914 patients met the inclusion criteria, including: 346 nonfunctioning adenomas (NFA), 261 prolactinomas (PRLoma), 51 growth hormone adenomas, 36 adrenocorticotropic adenomas, 93 Rathke's cleft cysts, 70 craniopharyngiomas and 57 meningiomas. The overall rate of SHD at presentation was highest in PRLoma (62.8%) and craniopharyngiomas (64.3%) and lowest in meningiomas (14%). While larger SM were significantly more likely to have SHD, the rate of SHD within each group was significantly different despite similar size (p < 0.001). Of the two largest groups of SM (NFA and PRLoma), NFA had significantly higher odds ratio (3.34, CI 1.89-5.89) of having multiple SHDs when compare with PRLoma, even when corrected for age, gender and size of tumor (p < 0.001). Our study shows that the rate and distribution of SHD in SM vary dependent upon the size of the tumor and specific pathology; in particular, NFA are more likely to present with multiple SHDs. Our data will help clinicians in determining adequate hormonal testing strategy for different SM.

SAT-LB61 METTL3 Promotes Sparsely Granulated GH-Secreting Pituitary Adenomas to Behavior as Densely Granulated Adenomas

Background: Growth hormone (GH)-secreting pituitary adenomas can be divided into densely and sparsely granulated subtypes, based on electron microscopic studies. The latter are frequently associated with more invasive behavior, and respond worse to somatostatin analogues. The underlining mechanisms are largely unknown. Increasing evidence showed that N6-methyladenosine (m6A) of messenger RNAs (mRNAs) participated in the development of various tumors. We aimed to investigate the role of RNA m6A modification in the classification of GH-secreting pituitary adenomas. Methods: The main components of m6A methyltransferase complex, demethylase, and RNA m6A levels were compared between sparsely and densely GH-secreting tumors. The role of METTL3 was functionally studied. Results: The level of m6A methyltransferases (METTL3, WTAP and METTL14) and demethylase (FTO and ALKBH5) were significantly downregulated in GH adenomas, comparing to the normal pituitary tissues. However, only METTL3 and METTL14 were shown to significantly higher in densely granulated tumors than those in sparsely ones. Consistently, the level of RNA m6A was markedly increased in densely granulated GH adenomas. In addition, the expression of METTL3 was positively correlated with the level of RNA m6A among tumor samples, and METTL3 silencing decreased RNA m6A of GH3 cells. METTL3 was demonstrated to function as a tumor suppressor based on in vivo and in vitro evidence, using patient-derived and GH3 cells. Moreover, the sensitivity of GH3 cells to pasireotide was increased with METTL3 overexpression, but decreased when METTL3 was silenced. Consistently, METTL3 silencing inhibited GH secretory, and decreased the expression of SSTR2 and SSTR5. Conclusions: METTL3 functions as a tumor suppressor in GH secreting adenomas, and enhance tumor cells sensitivity to medical treatment. Our work uncovers the critical roles of METTL3 in the pathogenesis of GH adenomas, since it potentially promotes the transition from sparsely to densely granulated subtypes.

Patients with true mixed growth hormone and prolactin-secreting pituitary adenoma: a case series of 12 patients

Objective: Mixed growth hormone (GH) and prolactin (PRL) secreting adenomas are the most common type of plurihormonal pituitary adenomas. We assessed the clinical presentations and impacts of transsphenoidal surgery (TS) on patients with mixed GH and PRL adenomas including surgical outcomes, complications, and prognosis.Method and patients: Twelve patients (7 males, 5 females) were operated in the neurosurgery department of Qilu hospital affiliated to Shandong University, Shandong, China. We analyzed hormone levels of preoperation, postoperation (within 24 h) and at 12-month follow-up and correlated levels with tumor volumes.Results: The remission rate was 66.7% (8/12), the recurrence rate was 16.7% (2/12), the cause-specific mortality was 0 and the overall mortality rate was 16.7% (2/12) due to stroke and myocardial infarction respectively. A significant drop was seen in GH, PRL, and Insulin-like-growth-factor-1 (IGF-1) levels between preoperation and postoperation with mean values from 52.6 to 9.9 ng/ml (p = 0.0015), from 321.6 to 190.9 ng/ml (p = 0.0026) and from 815.7 to 230.6 ng/ml (p = 0.0004), respectively. This drop was more significant between preoperation and follow-up with mean values from 52.6 to 3.0 ng/ml (p = 0.002), from 321.6 to 61.6 ng/ml (p < 0.0001), and from 815.7 to 195.0 ng/ml (p = 0.0001), respectively. However, there was no significant correlation between tumor volume and all of the hormone levels.Conclusions: Most mixed GH and PRL adenomas are aggressive with a high risk of recurrence and mortality.

Morphometric Alterations of the Sphenoid Ostium and other Landmarks in Acromegaly: Anatomical Considerations and Implications in Endoscopic Pituitary Surgery.

The sphenoid ostium (SO) is an important landmark for the endoscopic surgeon. Changes in size and position of the SO and variations in other skull base landmarks in acromegalics have not been adequately evaluated. The authors evaluated the morphometry and location of the SO and other landmarks in acromegaly and compared these findings with those in nonfunctioning pituitary adenomas (NFPAs). In this retrospective case-control study, the dimensions and location of the SO and other skull base landmarks were radiologically evaluated in 18 patients with growth hormone (GH)-secreting adenomas. These findings were analyzed in relation to preoperative GH levels and compared with 18 age- and sex-matched controls with NFPAs. The dimensions of the SO were significantly larger in the GH-adenoma group (P < 0.05). The SO was further from the midline (P = 0.04) and closer to the sphenopalatine foramen (SPF) (P = 0.02) in the GH-adenoma group, and this finding correlated with increasing preoperative GH levels. Acromegalics demonstrated larger intracavernous carotid diameters (P = 0.05) and smaller intercarotid distances than the patients with NFPAs (P = 0.02). The SO is larger and located higher up in the sphenoid face and closer to the SPF in patients with GH adenomas. Increasing GH levels in these patients correlate with the upward and lateral displacement of the SO. These patients demonstrate larger intracavernous carotid diameters and smaller intercarotid distances than patients with NFPAs. These morphological alterations are of particular relevance to the pituitary surgeon.

Effects of intelligent nursing and transfusion system on transfusion management in patients with growth hormone adenoma complicated with cardiomyopathy

Objective To evaluate the effects of the intelligent nursing and transfusion system on transfusion management in patients with growth hormone adenoma complicated with cardiomyopathy. Methods The patients with growth hormone adenoma complicated with cardiomyopathy treated in the Department of Neurosurgery in a ClassⅢ Grade A hospital from January 2018 to May 2019 were selected. Totally 78 patients receiving conventional transfusion management from January to October 2018 were included into the control group, while 70 patients admitted from November 2018 to May 2019 after the intelligent nursing and transfusion system was applied were included into the experimental group. The incidence rate of adverse effects in transfusion, correct rate of transfusion speed, incidence rate of arrhythmia and patients' compliant rate in terms of transfusion were evaluated between the two groups. Results The incidence rate of adverse effects in transfusion in the experimental group was 5.7%, lower than 16.7% in the control group. The correct rate of transfusion speed was 97.0% in the experimental group, higher than 89.3% in the control group, and there was statistically significant difference between the two groups (P 0.05) . The compliant rate about transfusion was 5.7% in the experimental group, lower than 16.7% in the control group, and there was statistically significant difference between the two groups (P<0.05) . Conclusions The intelligent nursing and transfusion system can improve transfusion management in clinical practice, which not only reduce the incidence rate of adverse effects in transfusion and improve the transfusion safety in patients with growth hormone adenoma complicated with cardiomyopathy, and also reduce the compliant rate about transfusion and improve patients' satisfaction. Key words: Growth hormone adenoma; Cardiomyopathy; Venous transfusion; Intelligent nursing and transfusion system; Transfusion management; Informatization

Mixed gangliocytoma-pituitary adenoma containing GH and GHRH co-secreting adenoma cells.

SummaryA 67-year-old woman with a past history of type 2 diabetes mellitus presented with worsening glycemic control. She had some acromegaly symptoms and magnetic resonance imaging demonstrated a pituitary tumor. Endocrinological examination found the resting growth hormone (GH) level within the normal range, but elevated insulin-like growth factor 1 level. A 75 g oral glucose tolerance test showed inadequate suppression of nadir GH levels. Acromegaly due to GH-secreting pituitary tumor was diagnosed. The patient underwent endoscopic transsphenoidal surgery resulting in gross total removal of the tumor and recovered well postoperatively. Histological examination of the tumor showed coexistence of relatively large gangliocytoma cells and pituitary adenoma cells, suggesting mixed gangliocytoma-pituitary adenoma. In addition, colocalization of GH and GH-releasing hormone (GHRH) in pituitary adenoma cells was revealed, so the adenomatous components were more likely to produce GHRH in our mixed gangliocytoma-pituitary adenoma case. Mixed gangliocytoma-pituitary adenoma is very rare, and the present unique case demonstrated only the adenomatous components associated with GHRH production.Learning points:Sellar gangliocytoma coexisting with pituitary adenoma is recognized as a mixed gangliocytoma-pituitary adenoma and is very rare.A proposed developmental mechanism of growth hormone (GH)-secreting mixed gangliocytoma-pituitary adenoma involves GH-releasing hormone (GHRH) produced by the gangliocytic components promoting the growth of tumor including GH-secreting adenomatous components.Since our present case indicated that the adenomatous components of mixed gangliocytoma-pituitary adenoma could secrete both GH and GHRH simultaneously, progression of GH-secreting mixed gangliocytoma and pituitary adenoma may involve exposure to spontaneously produced GHRH due to the adenomatous components.

MON-LB076 Patterns of Secondary Hormonal Deficiency Vary among Different Types of Sellar Masses Despite Similar Tumour Size at Presentation

BACKGROUND: Secondary hormonal deficiency (SHD) is common in patients with sellar masses (SM); however, it is unclear if the rate and type of SHD at presentation is related to the size or type of SM. We conducted a study comparing SHD in various SM based on pathology and size at presentation. METHODS: A retrospective analysis of all SM in a tertiary care neuropituitary program, enrolled between November 2005 and December 2018, was conducted based on type of SM and maximum tumor size, comparing rate of secondary hypogonadism (SHG), secondary hypothyroidism (SHT), secondary hypoadrenalism (SHA), growth hormone deficiency (GHD) and diabetes insipidus (DI). RESULTS: A total of 914 patients were identified including: nonfunctioning adenoma (NFA) = 346, prolactinoma (PRLoma) = 261, growth hormone (GH) adenoma = 51, ACTH adenoma = 36, meningioma = 57, craniopharyngioma (cranio) = 70 and Rathke’s cleft cyst (RCC) = 93. SM were further subdivided based on initial size into < 9mm (group A), 10-19mm (group B), 20-29mm (group C) and ≥ 30 mm (group D). The overall SHD (%), single vs. multiple SHD (%) and most prevalent SHD, respectively, for each group were as follow. Group A - NFA (10%, 56% vs. 44%, SHG and SHT), PRLoma (48%, 90% vs. 10%, SHG), GH adenoma (13%, 100% vs 0, SHG), ACTH adenoma (29%, 83% vs. 17%, SHG), cranio (50%, 100% vs. 0, GHD) and RCC (11%, 100% vs. 0, SHG); Group B - NFA (35%, 43% vs. 57%, SHG), PRLoma (73%, 77% vs. 23%, SHG), GH adenoma (23%, 71% vs. 29%, SHG), ACTH adenoma (30%, 67% vs. 33%, SHG), meningioma (5%, 0 vs. 100%, SHG and SHA), cranio (48%, 73% vs. 27%, SHT), RCC (17%, 43% vs. 57%, SHT); Group C - NFA (64%, 28% vs. 72%, SHG), PRLoma (78%, 50% vs. 50%, SHG), GH adenoma (75%, 50% vs. 50%, SHG), ACTH adenoma (100%, 33% vs. 67%, SHG), meningioma (16%, 100% vs. 0, SHT), cranio (70%, 38% vs. 62%, SHG), RCC (41%, 29% vs. 71%, SHG): Group D - NFA (83%, 40% vs. 60%, SHG), PRLoma (100%, 47% vs. 53%, SHG), GH adenoma (80%, 0 vs. 100%, SHG and SHT), meningioma (27%, 75% vs. 25%, SHG), cranio (88%, 36% vs. 64%, SHG) [all p <0.001]. CONCLUSION: This is the first study to show that SHD patterns vary considerably in various SM of similar size at presentation. While there is a higher risk of SHD in larger SM, the pattern of SHD is also dependent upon the underlying pathology. Of the two largest categories i.e., NFA and PRLoma, NFA are more likely to present with multiple SHD while PRLoma predominantly present with single SHD. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.