Central precocious puberty secondary to peripheral precocious puberty due to a pineal germ cell tumor: a case and review of literature.

BACKGROUND: The pineal lesion affecting melatonin is a rare cause of central precocious puberty by decreasing the inhibition of hypothalamic-pituitary-gonadal axis. Germ cell tumor secreting human chorionic gonadotropin is a rare cause of peripheral puberty. CASE PRESENTATION: A 5.8-year-old male presented facial hair and phallic growth, deepened voice, and accelerated growth velocity for 6 months. The elevated human chorionic gonadotropin level with undetectable gonadotropin levels indicated peripheral precocious puberty. Brain imaging revealed a pineal mass and further pathology indicated the diagnosis of teratoma. During chemoradiotherapy with operation, the elevated human chorionic gonadotropin level reduced to normal range, while the levels of gonadotropins and testosterone increased. Subsequently, progressing precocious puberty was arrested with gonadotrophin-releasing hormone analog therapy. Previous cases of transition from peripheral precocious puberty to central precocious puberty were reviewed. The transitions were caused by the suddenly reduced feedback inhibition of sex steroid hormones on gonadotropin releasing hormone and gonadotropins. CONCLUSIONS: For patients with human chorionic gonadotropin-secreting tumors, gonadotropin levels increase prior to sex steroid decrease, seems a sign of melatonin-related central PP related to melatonin.

Intracranial germ cell tumors: a view of the endocrinologist.

Intracranial germ cell tumors (iGCTs) are rare malignant neoplasms that mainly affect children and adolescents. The incidence, clinical presentation, and prognosis of iGCTs exhibit high heterogeneity. Previous studies have primarily focused on eliminating tumors, reducing tumor recurrence, and improving survival rates, while neglecting the impact of the tumors and their treatment on neuroendocrine function. Throughout the entire course of the disease, neuroendocrine dysfunction may occur and is frequently overlooked by oncologists, neurosurgeons, and radiologists. Endocrinologists, however, are more interested in this issue and have varying priorities at different stages of the disease. From onset to the diagnostic phase, most patients with iGCTs may present with symptoms related to impaired neuroendocrine function, or even experience these symptoms as their first indication of the condition. Particularly, a minority of patients with sellar/suprasellar lesions may exhibit typical imaging features and elevated tumor markers long after the onset of initial symptoms. This can further complicate the diagnosis process. During the peritumor treatment phase, the neuroendocrine function shows dynamic changes and needs to be evaluated dynamically. Once diabetes insipidus and dysfunction of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes occur, hormone replacement therapy should be administered promptly to ensure successful tumor treatment for the patient. Subsequently, during the long-term management phase after the completion of tumor treatment, the evaluation of growth and development as well as corresponding hormone replacement therapy are the most concerning and complex issues. Thus, this paper reviews the interest of endocrinologists in iGCTs at different stages.

Comparison of different predominant lesions in intracranial bifocal germ cell tumors to predict neuroendocrine outcomes.

Purpose: Intracranial germ cell tumors frequently arise from the midline of the brain, occasionally presenting as bifocal diseases. The predominant lesion might affect clinical characteristics and neuroendocrine outcomes. Method: A retrospective cohort study involving 38 patients with intracranial bifocal germ cell tumors was performed. Result: Twenty-one patients were assigned to the sellar-predominant group, while the other 17 patients were assigned to the non-sellar-predominant group. Differences in gender ratio, age, manifestation, the incidence of metastasis, the incidence of elevated tumor markers, human chorionic gonadotropin levels in serum and in cerebrospinal fluid, diagnostic method, and tumor type were not significant between the sellar-predominant group and the non-sellar-predominant group. Before treatment, the sellar-predominant group had a higher incidence of adenohypophysis hormone deficiencies and central diabetes insipidus than those of the non-sellar-predominant group, without significant differences. After multidisciplinary therapy, the sellar-predominant group also had a higher incidence of adenohypophysis hormone deficiencies and central diabetes insipidus than those of the non-sellar-predominant group. The differences in the hypothalamic-pituitary-adrenal (HPA) axis impairment (P = 0.008), hypothalamic-pituitary-thyroid (HPT) axis impairment (P = 0.048), and hypothalamic-pituitary-gonad (HPG) axis impairment (P = 0.029) were significant between sellar-predominant group and non-sellar-predominant group, while the others were not. At median 6 (3, 43) months of follow-up visit, sellar-predominant group had a higher incidence of adenohypophysis hormone deficiencies than those of non-sellar-predominant group. The differences in the HPA impairment (P = 0.002), HPT impairment (P = 0.024), and HPG impairment (P < 0.000) were significant, while the others were not. Further comparison of the neuroendocrine function between different subtypes of sellar-predominant patients indicated that the differences in adenohypophysis hormone deficiencies and central diabetes insipidus were not significant between the two subtype groups. Conclusion: Bifocal patients with different predominant lesions present similar manifestations and neuroendocrine disorders before treatment. Non-sellar-predominant patients would have better neuroendocrine outcomes after tumor treatment. The distinction of the predominant lesion in patients with bifocal intracranial germ cell tumor plays a valuable role in predicting neuroendocrine outcomes, as well as in optimizing long-term neuroendocrine management during survival time.

Benefits and risks evaluation of recombinant human growth hormone replacement therapy in children with GHD after craniopharyngioma surgery.

OBJECTIVES: Childhood-onset craniopharyngiomas (CPs) have a high incidence of growth hormone deficiency (GHD) leading to growth failure and metabolic disorders. We aim to evaluate the benefits and risks of recombinant human growth hormone replacement therapy (GHRT) in postoperative children. METHODS: We retrospectively analyzed auxological and metabolic parameters and adverse events before and after GHRT of 44 children after CP surgery. RESULTS: The median duration of GHRT was 24 months (IQR, 12.5-36). Growth velocity (GV) increased significantly after different treatment duration (TD) compared with baseline (p<0.001) and attained the greatest GV of 12.06 ± 4.16 cm/year at TD6. The mean height standard deviation score (HtSDS) from -3.20 ± 1.16 at baseline improved significantly to -1.51 ± 1.32 at TD36 (p<0.001). There were significant increases in insulin-like growth factor-1 SDS (IGF-1SDS), insulin-like growth factor binding protein 3 SDS (IGFBP-3SDS), bone age (BA), and BA/chronological age (CA) (p<0.05). There was a significant reduction in waist-to-hip ratio (WHR), but there were no significant changes in weight SDS (WtSDS) or BMISDS. Low-density lipoprotein-cholesterol (LDL-C) levels and the incidence of hypercholesterolemia decreased (p<0.05). Three patients (6.8%) had tumor recurrence after 15, 30, and 42 months, respectively. A patient had residual tumor enlargement after 3 months. There was no adverse influence on glucose metabolism or any severe adverse events. CONCLUSIONS: GHRT effectively accelerates GV, increases HtSDS, and improves lipid profiles without unfavorable effects on glucose metabolism. The benefits are clear and the risks of adverse events are low.

Heterogeneity of IGF-1 Levels in Children with hCG-Induced Precocious Puberty.

Objective: Sex steroid stimulates growth hormone release during puberty. However, the role of IGF-1 levels in human-chorionic-gonadotropin-induced precocious puberty remains unclear. Methods: A retrospective study reviewing thirty patients with precocious puberty due to human-chorionic-gonadotropin-secreting intracranial germ cell tumors was performed. Changes in IGF-1 levels were collected. Result: All patients included were boys. At diagnosis, the median IGF-1 standard deviation was 0.87 (0.1, 1.87). When human-chorionic-gonadotropin normalized, the median IGF-1 standard deviation was 1.58 (-0.53, 2.55), which is slightly higher than baseline (p = 0.408). When patients completed their therapeutic plan, the median IGF-1 standard deviation was 0.10 (-1.05, 0.68), which was significantly lower than that of baseline (p = 0.004) and of human-chorionic-gonadotropin being normalized (p = 0.003). At the last visit, the mean IGF-1 standard deviation was -1.11(-1.97, 0.76), which is slightly lower than that of baseline (p = 0.109) and post-therapy levels (p = 0.575), but significantly lower than that of human-chorionic-gonadotropin being normalized. Two patients had IGF-1 levels above 2 standard deviations at diagnosis, eight at the time when human-chorionic-gonadotropin normalized, and two at the end of therapy. Only one patient had an IGF-1 level below 2 standard deviations at diagnosis and at the time when human-chorionic-gonadotropin normalized, and two patients at the end of therapy. At the last follow-up, all patients had normal IGF-1 levels. Conclusion: IGF-1 levels in patients with human-chorionic-gonadotropin-induced precocious puberty have heterogeneity, but IGF-1 standard deviations are mostly within the normal range. If elevated, it might decline later with a decrease in human-chorionic-gonadotropin level. IGF-1 levels seem not valuable enough to assess human-chorionic-gonadotropin-induced precocity regression.

Precocious puberty due to intracranial germ cell tumors: a case-control study.

Children with intracranial germ cell tumors may present premature sexual development via either gonadotrophin-releasing hormone (GnRH)-dependent cause or GnRH-independent cause. We conducted a single-center retrospective study on 37 precocious puberty (PP) patients with intracranial germ cell tumors and 25 age-matched prepubertal patients with elevated human chorionic gonadotropin (hCG) levels. Classification of PP was derived from hCG, gonadotropin and sex steroid levels and their changes. Five boys were assigned to GnRH-dependent group (G1). Thirty-one boys and one girl were assigned to GnRH-independent group (G2) with a median hCG of 76.75 (8.29-2747) IU/L. Seven boys and 18 girls were conducted as controls, with a median hCG of 17.12 (2.91-1062) IU/L. Patients in G1 had constant pubertal LH and testosterone levels after tumor complete response. Patients in G2 had hCG levels that decreased simultaneously with testosterone/estradiol levels, prior to tumor regression. The differences in hCG levels and the gender ratio were significant between G2 and controls (P = 0.006 and P < 0.001, separately). Among intracranial germ cell tumor patients with positive hCG, boys with significantly higher hCG levels more easily developed PP. Our results suggest that GnRH-independent PP commonly regresses together with tumor regression. In comparison, results were inconclusive in tying tumor regression to the regression of GnRH-dependent PP.

Pituitary Stalk Germ Cell Tumors: Retrospective Case Series and Literature Review.

Objective: Intracranial germ cell tumors with isolated pituitary stalk involvement are rare. Early recognition and long-term monitoring deserve further exploration. Methods: A retrospective study reviewing eleven intracranial germ cell tumor patients with isolated pituitary stalk involvement was performed. Results: Seven boys and four girls who presented with a hyperintense pituitary stalk on postcontrast T1-weighted magnetic resonance imaging without a posterior pituitary signal were included. The average maximum width of the pituitary stalk was 5.2 ± 1.6 mm. Polydipsia and polyuria occurred in all patients, followed by growth retardation, fatigue, and amenorrhoea. Eight patients (72%) had concomitant partial anterior pituitary hormone deficiency. Seven patients initially had elevated human chorionic gonadotropin levels. After chemoradiotherapy, ten patients attended follow-up. Central diabetes insipidus remained in all survivors, and four (40%) of them had concomitant partial anterior pituitary hormone deficiency, primarily of growth hormone and insulin-like growth factor-1. The causes of the delayed diagnosis of previous studies were mainly negative tumor markers and the initial pathological diagnosis of autoimmune diseases. Conclusion: Isolated pituitary stalk lesions could be a signal of intracranial germ cell tumors, especially coexisting with diabetes insipidus, hypopituitarism, and a worse response to glucocorticoid therapy. Negative results of tumor markers and pathology could not exclude the diagnosis. Chemoradiotherapy is an effective therapy, leaving mild-t-moderate hypothalamus-pituitary dysfunction. This rare neuroimaging feature may be used as a factor to predict long-term neuroendocrine outcomes.

Comparison of neuroendocrine dysfunction in patients with adamantinomatous and papillary craniopharyngiomas.

Craniopharyngiomas (CPs) are rare epithelial tumors mainly located in the sellar/parasellar region. They may be classified into two major histological subtypes, which exhibit clinical and pathological differences: Adamantinomatous CP (ACP) and papillary CP (PCP). The aim of the present study was to compare the neuroendocrine dysfunction between ACP and PCP prior to and after surgical resection. According to their pathological classification, the patients were assigned to the ACP group or the PCP group. The neuroendocrine dysfunction in these two CP subtypes was evaluated using a scoring method prior to and after surgery. A total of 741 patients with CPs were included in the present study, of which 622 were ACP and 119 were PCP. The scores on the tumor mass effect, hypothalamic dysfunction and pituitary-target gland axis dysfunction, as well as the incidence of central diabetes insipidus in the PCP group were all significantly higher than those in the ACP group, regardless of whether the surgery had been performed or not (all P<0.05). After surgery, the scores on the tumor mass effect were significantly decreased in the ACP and PCP patients (all P<0.05), while the scores on hypothalamic dysfunction and pituitary-target gland axis dysfunction, as well as the incidence of central diabetes insipidus were all significantly increased in ACP and PCP patients (all P<0.05). Prior to and after surgery, the PCP variant exhibited a greater damage to the neuroendocrine function compared with the ACP variant.

Diabetes mellitus and the risk of gastrointestinal cancer in women compared with men: a meta-analysis of cohort studies.

BACKGROUND: The increasing epidemic proportions of diabetes mellitus (DM) are a major cause of premature illness and death. However, whether DM confers the same excess risk of gastrointestinal cancer for women as it does for men remains controversial. The purpose of this study was to estimate the relation between DM and gastrointestinal cancer in women compared with men after accounting for other major risk factors based on cohort studies. METHODS: We performed a meta-analysis of cohort studies published through May 2017 from PubMed, Embase, and the Cochrane Library. Studies with cohort designs were stratified by sex and reported the relation between DM and esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), hepatocellular carcinoma (HCC), or pancreatic cancer (PC) risk. The ratio of relative risk (RRR) between men and women was employed to measure the sex differences in the relation between DM and gastrointestinal cancer with a random effects model with inverse variance weighting. RESULTS: We included 38 cohort studies reporting data on 18,060,698 individuals. The pooled RRR indicated DM women was associated with an increased risk of GC (RRR: 1.14; 95%CI: 1.06-1.22; p < 0.001), while the risk of HCC was lower (RRR: 0.88; 95%CI: 0.79-0.99; p = 0.031) as compared with DM men. Further, there was no evidence of sex differences in the RRR between participants who had DM compared with those without DM for EC (p = 0.068), CRC (p = 0.618), and PC (p = 0.976). In addition, the pooled RRR showed a statistically significant association between DM and the risk of CC in women compared with men (RRR: 0.93; 95%CI: 0.86-1.00; p = 0.050), and there was no evidence of sex differences for RC among participants with DM compared to those without DM (p = 0.648). Finally, the sex differences of the comparison between DM and non-DM for gastrointestinal cancer risk at different sites were variable after stratification for different effect estimates. CONCLUSIONS: The findings of this study suggested female-to-male RRR of DM was increased for GC, while reduced for HCC and CC. However, there were no sex differences for the relation between DM and the risk of EC, CRC, PC, and RC.

Short-term Preoperative Octreotide for Thyrotropin-secreting Pituitary Adenoma.

BACKGROUND: Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism. Somatostatin (SST) analogs work by interacting with somatostatin receptors (SSTRs). This study aimed to evaluate short-term preoperative octreotide (OCT) use in TSHoma patients and to investigate SSTR2 and SSTR5 expression and observe structural changes in tumor tissue. METHODS: We reviewed records and samples from eight TSHoma patients treated between July 2012 and July 2015. We tested immunohistochemically for SSTR2/5 expression and examined TSHoma cells for morphological changes. Signed rank sum test was used to compare the efficacy of short-term preoperative OCT treatment. RESULTS: OCT treatment (median time: 7.9 days, range: 3-16 days; median total dose: 1.8 mg, range: 0.9-4.2 mg) led to significant decrease in all patients' thyroid hormone levels (FT3 [nmol/L]: 8.33 [7.02, 12.29] to 4.67 [3.52, 5.37] [P = 0.008]; FT4 [pmol/L]: 25.36 [21.34, 28.99] to 16.66 [14.88, 21.49] [P = 0.016]; and TSH [µU/ml]: 5.80 [4.37, 6.78] to 0.57 [0.19, 1.24] [P = 0.008]). All the eight tumor specimens expressed high SSTR2 protein levels; 5/8 expressed high SSTR5, but 3/8 that expressed low SSTR5 presented a significantly higher TSH suppression rate (P = 0.036). Electron microscopy showed subcellular level impairments, including clumped nuclear chromatin and reduced cytoplasmic volume. Golgi complexes were observed in the OCT-treated TSHoma specimens. CONCLUSIONS: OCT can control hormone levels and damage the ultrastructure of tumor cells and organelles. Short-term response to OCT may be related to SSTR5 expression. Preoperative SST analog treatment for TSHoma could be considered as a combination therapy.

Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: A meta-analysis of data from 58,160 patients in 13 randomized controlled trials.

BACKGROUND: Previous trials indicated that intensive glucose lowering in treatment of patients with type 2 diabetes mellitus (T2DM) was associated with a higher incidence of mortality. We therefore conducted a meta-analysis to evaluate the benefits and harms of intensive glucose lowering therapy in treatment of T2DM patients on major cardiovascular outcomes. METHODS: Randomized controlled trials (RCTs) were obtained from searches of PubMed, EmBase, and the Cochrane Library electronic databases until Feb. 2016. Relative risk (RR) was used to measure the treatment effect by random-effect model. Meta-regression, sensitivity analyses, subgroup analyses, and publication biases were also conducted. RESULTS: Thirteen RCTs were included with 58,160 T2DM patients and reported 5719 major cardiovascular events (MACEs), 6569 deaths, 2057 cardiac death cases, 3201 myocardial infarction (MI) cases, 1835 stroke cases, and 1778 congestive heart failure cases. Intensive glucose lowering therapy significantly reduced risk of MACEs (RR: 0.92; 95%CI: 0.85-1.00; P=0.042), and MI (RR: 0.90; 95%CI: 0.82-0.98; P=0.020) compared with conventional glucose control therapy. Furthermore, intensive glucose lowering therapy has no significant effect on the incidence of total mortality (RR: 0.98; 95%CI: 0.91-1.07; P=0.693), cardiac death (RR: 1.00; 95%CI: 0.87-1.04; P=0.999), stroke (RR: 0.94; 95%CI: 0.84-1.06; P=0.333), and congestive heart failure (RR: 1.19; 95%CI: 0.96-1.48; P=0.108). CONCLUSION: T2DM patients who received intensive glucose lowering therapy are associated with a reduced risk of MACEs and MI, whereas it has no significant effect on the risk of total mortality, cardiac death, stroke, and congestive heart failure. These effects might differ when stratified by baseline characteristics in T2DM patients.

Efficacy of the long-acting octreotide formulation in patients with thyroid-stimulating hormone-secreting pituitary adenomas after incomplete surgery and octreotide treatment failure.

BACKGROUND: Little information about the current management of patients with thyroid-stimulating hormone (TSH)-secreting pituitary adenomas or about the usefulness of the somatostatin analogue octreotide was contained in the literature. This study aimed to report the efficacy and safety of the long-acting octreotide formulation in patients with TSH-secreting pituitary adenomas after incomplete surgery and octreotide treatment failure. METHODS: Fifteen patients with TSH-secreting pituitary adenomas (8 men and 7 women), who previously underwent incomplete surgical resection and/or adjuvant radiotherapy (n = 12) and failure of octreotide treatment (n = 15), followed between 2007 and 2010 in Beijing Tiantan Hospital were included in this study. All patients received 1- to 2-months of the long-acting octreotide formulation treatment after the above combination of treatment. Paired samples t-test was used to analysis the variables. RESULTS: After two-month duration of the long-acting octreotide formulation treatment, the mean serum free or unbound thyroxine (FT4) ((16.02 ± 1.72) pmol/L) and free triiodothyronine (FT3) ((2.87 ± 0.43) pmol/L) levels of 15 patients significantly decreased compared with those after octreotide-treatment (FT4, (35.36 ± 7.42) pmol/L, P < 0.001; FT3, (17.85 ± 7.22) pmol/L, P < 0.001). Mean TSH levels stayed in the normal range after the long-acting octreotide formulation treatment ((0.72 ± 0.21) mU/L) and were significantly lower than the pretreatment value ((5.27 ± 1.04) mU/L, P < 0.001), post-surgery value ((3.37 ± 0.31) mU/L, P < 0.001) and post-octreotide-treatment value ((4.52 ± 0.41) mU/L, P < 0.001). In these patients with TSH-secreting pituitary adenomas there was no evidence of tachyphylaxis. CONCLUSION: The long-acting octreotide formulation may be a useful and safe therapeutic tool to facilitate the medical treatment of TSH-secreting pituitary adenomas in patients who underwent incomplete surgery or need long-term somatostatin analog therapy.

Hyperglycemia induces the variations of 11ß-hydroxysteroid dehydrogenase type 1 and peroxisome proliferator-activated receptor-γ expression in hippocampus and hypothalamus of diabetic rats.

In this paper, we first observed that there were differences in expressions of 11ß-HSD1 and PPAR-γ, in hippocampi and hypothalami, among constant hyperglycemia group, control group and the fluctuant glycemia group, using Immunohistochemical analysis. However, whether in expression o f 11ß-HSD1 or PPAR-γ, there were no statistic differences between the control group or the fluctuant glycemia group. So, we removed the fluctuant glycemia group, retaining only constant hyperglycemia group and control group, being fed for 8 weeks. After 8 weeks of induction, 11ß-HSD1 expression increased and PPAR-γ expression decreased in the constant hyperglycemia group compared with control group, both in hippocampi and hypothalami, by Western Blot. The constant hyperglycemia group also showed impaired cognition in MORRIS watermaze, lower serum corticosterone level, and higher Serum ACTH concentration after 8 weeks. We inferred that the cognition impairment may be related to the abnormal expression of 11ß-HSD1 and PPAR-γ in central nerves system. As for 11ß-HSD1 is a regulating enzyme, converting the inactive 11-dehydrocorticosterone into the active glucocorticoid corticosterone, thus amplifying GC action in local tissues. It is also well known that high local GC levels can affect the cognitive function. In addition, PPAR-a protective receptor, which is related to cognition.