Multiple Hormone Deficiencies Research Articles

MON-246 A Diagnostic Dilemma of Primary Versus Secondary Thyroid and Adrenal Hormone Insufficiencies: A Unique Case of Widely Metastatic Renal Cell Carcinoma After Brain Radiation

Background Identifying the etiology of hormonal insufficiency is important for correct diagnosis and for appropriate hormone supplementation. Usually multiple hormone deficiencies are driven by pituitary pathology, but here we present a case that poses a unique diagnostic and therapeutic dilemma. Clinical Case A 55 y/o lady with HTN and recently diagnosed metastatic Renal Cell Carcinoma (RCC) presented with weakness, dizziness, altered mental status, polydipsia and polyuria. Her metastases included the bilateral adrenal glands, thyroid, brain, and she had a sellar lesion displacing the pituitary as well as infundibular thickening. She had been treated with dexamethasone due to vasogenic edema, whole brain radiation, and was going to start immunotherapy (Ipilumimab&Nivolumimab). On exam she had relative hypotension and tachycardia (BP 115/58, HR 108). She was diagnosed with non-PTH mediated hypercalcemia (Ca 13.9/ 15.3 corrected for albumin 2.3, PTH 6.5, PTH-RP 69, Vitamin D-25 19.4). Her calcium normalized after fluid resuscitation and bisphosphonate treatment, but weakness and hypotension persisted. We tested thyroid and adrenal function given the location of her lesions, recent whole brain radiation, and recent steroid use. Her TSH was 0.017 (0.270 - 4.200 µIU/mL), fT4 0.84 (0.80 - 1.50 ng/dL), T3 0.59 (72.0 - 153.0 ng/dL), ACTH was 1.7 (7.2-63.3 pg/ml), cortisol 1.3 (6.0 - 18.4 ug/dL), aldosterone 3 (< or = 28 ng/dL), renin 7.87 (0.25 - 5.82 ng/mL/h), renin/aldosterone 0.4 (0.9 - 28.9). At 30 minutes after cosyntropin administration cortisol was 7.7 ug/dL, aldosterone 26 ng/dL, and at 60 minutes cortisol was 10.3 ug/dL. Hydrocortisone was initiated while tapering off dexamethasone, and levothyroxine was offered but declined. She opted to postpone further workup. Conclusion This patient presents a dilemma in identifying the primary causes of hormonal abnormalities given potential pituitary and primary thyroid and adrenal disease. The thyroid abnormalities could represent sick euthyroid physiology with lower T4 to T3 conversion or the effects of steroids which can also suppress TSH vs. hypothalamic or pituitary disease. Primary hypothyroidism from gland destruction was unlikely. The low ACTH and cortisol levels were expected since she was on dexamethasone, but low aldosterone with raised renin activity was concerning for primary adrenal insufficiency. However, after cosyntropin the suboptimal cortisol yet preserved aldosterone response supported secondary or tertiary adrenal insufficiency, and only cortisol was supplemented. Understanding her endocrine disease had implications for longer term management given that replacement may only need to be temporary and adrenal recovery might be possible. Further, the use of a 30 minute aldosterone level can be helpful in cases where multiple factors and discrepant laboratory findings may exist.

SUN-310 Growth Hormone Deficiency and Replacement Therapy: Association with Health-Related Physical Fitness

Objective: To compare health-related physical fitness (HRPF) in patients with severe adult growth hormone deficiency (AGHD) according to the deficiency onset phase, and to evaluate the effects of a six-months human growth hormone (rhGH) replacement therapy on HRPF, in a subgroup of patients. Methods: First arm: cross-sectional observational study at baseline of naive rhGH multiple pituitary hormonal deficiency (MPHD) hypopituitarism patients - adult-onset growth hormone deficiency (AO-GHD) versus child onset growth hormone deficiency (CO-GHD). Second arm: a 6-month intervention clinical trial in a selected group of a non-randomized, non-controlled cohort. HRPF was evaluated by measuring isokinetic and isometric torque stensor strength at the knee using an isokinetic dynamometer, handgrip strength and six-minute walk test. Body composition was assessed by DXA. Results: Patients who presented AO-GHD had higher BMI than CO-GHD (28.1±3.5 x 22.4±4.8; p=0.017), but body composition (lean body mass%:57.9±7.9 x 58.9±8.6;p=0.816/fatty body mass%:39.3±6.8 x 36.0±9.1;p=0.434), stensor peak torque/body weight at 60, 90 and 180deg/s (2.18±0.6 x 2.18±0.6; p=0.580/1.99±0.5 x 2.14±0.5;p=0.546/1.52±0.4 x 1.64±0.4;p=0.547), isometric torque/body weight at the knee (2.62±0.7 x 2.91±0.6;p=0.357) and six-minute walk test (570.2±76.0cm x 554.1±91.0cm;p= 0.703) did not differ between groups. Handgrip strength test also showed significant reduction in scores for age and gender in both groups of GHD patients. After six months of rhGH, no improvement in muscular strength tests was found. There was a significant worsening in the six-minute walk test (575.1±84cm x 545.4±90.6cm; p=0.033) despite the improvement in body composition (lean body mass%:59.7±8.6 x 63.6±11.1;p=0.005/fatty body mass%:35.7±9.2 x 32.9±10.0;p=0.003). Conclusion: Despite differences in BMI, there were no other differences in HRPF between AO-GHD and CO-GHD patients. The decrease of the six-minute walking test performance after rhGH replacement therapy supports the clinical evidence that the GH regulates bioenergetics in human skeletal muscle fibers. Although the treatment had a short period, GH might have stimulated the anaerobic and suppressed the aerobic energy system.

MON-256 A Late-Onset Case of Sheehan’s Syndrome Presenting as Life Threatening Adrenal Insufficiency

OBJECTIVESheehan’s syndrome or postpartum pituitary necrosis, is an important but rare cause of hypopituitarism, caused due to severe postpartum hemorrhage. Seen more commonly in the developing world, it is less common in developed countries due to advanced obstetric practices. It can present acutely but more frequently has an insidious course (onset 10-20 years later) with variable hormonal deficiencies. Here, we report a late-onset case of Sheehan’s syndrome, 24 years after the incident event, presenting as life threatening adrenal failure.CASE PRESENTATIONA 48-year-old female with no significant past medical history was admitted to the hospital after being found unresponsive at home. She had not seen a physician for many years. She complained of weakness and lethargy for a week and recently established care with a primary care physician. The patient was severely hypotensive in the emergency department and had an elevated temperature of 101°F. Physical examination showed no significant abnormalities. CBC and metabolic panel were not significantly altered. CSF analysis and CSF/blood cultures were negative for any infection. TSH was 4.29 mIU/mL (0.27-4.20) but the total and free T4 (fT4) were severely low at 1.1 mcg/mL (4.6-12) and 0.24 ng/dL (0.93-1.70) respectively. On further questioning, patient reported severe postpartum hemorrhage 24 years ago, needing multiple units of blood transfusion. This was followed by inability to lactate and menstruate but was never worked up as she had not seen any physician all these years. Pituitary hormonal panel was obtained, demonstrating multiple hormonal deficiencies with fT4 severely low at 0.24 ng/dL, ACTH of 2.6 pg/mL (7.2-63.3), prolactin (PRL) 1 ng/mL (4.8-23.3) and insulin like growth factor-1 (IGF-1) low at 10 ng/mL (56-194). Cortisol level was elevated in the hospital due to administration of high dose IV steroids but a morning cortisol level obtained 1 week prior by her primary was 1.5 mcg/dL (10-20). Estradiol levels were low with FSH and LH levels inappropriately normal. MRI of the pituitary was obtained which showed an empty sella turcica. Patient was diagnosed as late-onset Sheehan’s syndrome. She was started on hormone replacement with hydrocortisone followed by levothyroxine and had marked improvement in her symptoms. She continues to do well.CONCLUSIONOur patient presented late due to lack of medical care and awareness. A great number of patients with Sheehan’s diseasae go undiagnosed due to subtle clinical presentations, thus delaying treatment. It is imperative to diagnose this condition timely with appropriate obstetric/gynecological history and clinical suspicion to avoid late manifestations of the disease, especially adrenal crisis. Patients at risk need long term follow-up. Early treatment is necessary to improve quality of life and reduce morbidity and mortality associated with this condition.

Bone morbidity in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), currently the most common pediatric leukemia, has a high curability rate of up to 90%. Endocrine disorders are highly prevalent in children with ALL, and skeletal morbidity is a major issue induced by multiple factors associated with ALL. Leukemia itself is a predominant risk factor for decreased bone formation, and major bone destruction occurs secondary to chemotherapeutic agents. Glucocorticoids are cornerstone drugs used throughout the course of ALL treatment that exert significant effects on demineralization and osteoclastogenesis. After completion of treatment, ALL survivors are prone to multiple hormone deficiencies that eventually affect bone mineral accrual. Dual-energy X-ray absorptiometry, the most widely used method of measuring bone mineral density, is used to determine the presence of childhood osteoporosis and vertebral fracture. Supplementation with calcium and vitamin D, administration of pyrophosphate analogues, and promotion of mobility and exercise are effective options to prevent further bone resorption and fracture incidence. This review focuses on addressing bone morbidity after pediatric ALL treatment and provides an overview of bone pathology based on skeletal outcomes to increase awareness among pediatric hemato-oncologists and endocrinologists.

MULTIPLE HORMONAL AND METABOLIC DEFICIENCY SYNDROME REDUCES SURVIVAL IN CHRONIC HEART FAILURE: THE TOSCA REGISTRY

Multiple hormonal deficiency syndrome (MHDS) is common in heart failure (HF). To date, no large observational study has unequivocally demonstrated that MHDS impacts on HF progression. Aim of the T.O.S.CA. Registry ([NCT02335801][1]) was to test whether MHDS affects morbidity and mortality in a large

Evidence of Pituitary Hypoplasia Associated with Partial Central Diabetes Insipidus in a Young Persian Cat

Background: Congenital anomalies are an uncommon pituitary hypofunction cause associated to multiple hormone deficiencies. Congenital hyposomatotropism is often related to an inherited anomaly, characterized mainly by delayed growth. It is not uncommon to find associated thyroid-stimulating hormone and gonadotropin deficiencies. Pituitary malformation may be associated to progressive cystic lesion expansion. Central diabetes insipidus (CDI) is another rare disease associated to polyuria (PU) and polydipsia (PD) secondary to antidiuretic hormone (ADH) deficient secretion. The aim of this report is to describe a likely case of pituitary hypoplasia, associated with partial CDI in a cat.Case: A 9-month-old unneutered male Persian cat weighing 2 kg was presented due to severe polyuria and polydipsia associated with growth deficit when compared with its sibling. After clinical and laboratory evaluations during the months in which the patient was monitored, a reduced serum concentration of insulin-like growth factor-1 (IGF-1), thyroid-stimulating hormone (TSH), thyroid hormones, and testosterone was documented, confirming the diagnosis of hyposomatotropism, hypogonadism, and secondary hypothyroidism. Furthermore, therapeutic diagnosis with desmopressin revealed partial central diabetes insipidus (CDI). As the sibling showed normal development aging 13-months, a radiographic examination of the forelimb (carpus) was performed on both cats. There was lack of growth plate fusion in the patient, without any other evidence of dysgenesis, whereas complete epiphyseal closure was observed in the sibling. Despite desmopressin and levothyroxine therapeutic prescription the owners refuse further follow-up to the case.Discussion: Notwhistanding neuroimaging was not available for investigation of pituitary aspect in this particular case, the clinical symptoms added to the results of the complementary tests were consistent with pituitary hypoplasia, associated with hyposomatotropism, secondary hypothyroidism, hypogonadism, and partial CDI. Hyposomatotropism was presumably diagnosed based on the patient’s clinical characteristics, which included proportional growth delay, delayed tooth eruption, delayed growth plate fusion, associated with serum reduced IGF-1 results in comparison with its sibling. The report of low free T4 by equilibrium dialysis and of low total T4 levels, associated with low TSH levels, was considered compatible with secondary hypothyroidism. TRH stimulation test is considered the gold standard for secondary hypothyroidism diagnosis since low TSH could be secondary to assay´s low sensibility. However, normal TSH and thyroid hormone results in the sibling results ruled out this possible dismissed diagnose. The patient’s lack of sexual interest, associated with hypotestosteronemia and underdeveloped genitals (absence of penile spines and testicular hypoplasia), indicates hypogonadism. Finally, partial CDI diagnosis was demonstrated by cat´s partial ability to increase urinary specific gravity under water deprivation often made by the owners, as well as the response pattern to desmopressin therapy. Owing the lack of neurological signs expected to be associated with neoplastic or traumatic hypopituitarism etiology, hypoplasia hypothesis was raised. Quite often, patients with pituitary hypoplasia develop Rathke cleft cysts that might expand over time. In the present case, partial CDI is likely to be caused by the compression of the neurohypophysis by cyst formation secondary to adenohypophyseal hypoplasia since this kind of pituitary congenital anomaly does not justify per se neurohypophysis implications.

Combined effects of growth hormone and testosterone replacement treatment in heart failure.

AimsAlthough preliminary studies have demonstrated safety and effectiveness of single replacement therapy for growth hormone deficiency or testosterone deficiency in heart failure (HF), no data are available regarding the combined treatment with both GH and T in this setting. Thus, the aim of the present hypothesis generating pilot study was to evaluate the effectiveness and safety of multiple hormonal replacement therapies in chronic HF.Methods and resultsFive stable HF with reduced ejection fraction patients, with a concomitant diagnosis of growth hormone deficiency and testosterone deficiency, on top of guideline‐based HF treatment underwent 1 year of GH replacement therapy by subcutaneous injections of somatotropin at a dose of 0.012 mg/kg every second day. After 12 months, a T replacement treatment was added at a dosage of 1000 mg every 3 months. Each patient underwent a complete M‐mode, two‐dimensional, and Doppler echocardiographic examination, and an incremental symptom‐limited cardiopulmonary exercise test on a bicycle ergometer at baseline (BL), after 1 year of GH treatment (V1), and after 1 year of combined GH + T treatments (V2). One‐year of GH treatment resulted in a significant improvement in left ventricular ejection fraction (+5.4%, P < 0.01), New York Heart Association functional class (P < 0.05), and peak oxygen consumption (VO2 peak) (+19.3%, P < 0.01), and in a significant reduction in NT‐proBNP levels (−35.1%, P < 0.01). Notably, one additional year of combined GH and T replacement therapy induced a further increase in VO2 peak (+27.7%, final delta change + 52.44%, P < 0.01), as well as a significant improvement in muscular strength, as assessed by handgrip dynamometry (+17.5%, final delta change + 25.8%, P < 0.01). These beneficial effects were paralleled with an improvement of the overall clinical status (as assessed by New York Heart Association class). Of note, neither adverse effects nor cardiovascular events were reported during the follow‐up period.ConclusionsOur preliminary data suggest for the first time that combined replacement therapy with GH and T could be considered safe and therapeutic in HF patients with multiple hormone deficiencies, supporting the hypothesis that multiple hormone deficiencies syndrome can be considered as a novel and promising therapeutic target in HF. Further studies with a more robust design and larger population are needed.

Transient Elastography and Controlled Attenuation Parameter (CAP) in the Assessment of Liver Steatosis in Severe Adult Growth Hormone Deficiency.

Non-alcoholic fatty liver disease (NAFLD) is common in patients with growth hormone deficiency (GHD). Some noninvasive techniques have been used to quantify liver fat, such as the controlled attenuation parameter (CAP).Objective: To evaluate CAP as a tool to identify liver steatosis and its relationship with different clinical and biochemical metabolic parameters in a group of patients with severe adult growth hormone deficiency (AGHD), and to compare the evolution of metabolic profiles after 6 months of human growth hormone (rhGH) replacement therapy in a subgroup of patients.Methods: Cross-sectional observational study at baseline of naive rhGH multiple pituitary hormonal deficiency (MPHD) hypopituitarism patients. A 6-month intervention clinical trial in a selected group of a non-randomized, non-controlled cohort was also applied.Results: Liver stiffness measurement (LSM) was normal in severe AGHD patients. CAP evaluation showed steatosis in 36.3% of baseline patients (8/22), associated with higher BMI, waist circumference, insulin, and alanine aminotransferase (ALT) levels. According to steatosis degree by CAP, child-onset growth hormone deficiency (CO-GHD) was graded as 68.75% (11/16) S0, 12.5% (2/16) S1, and 18.75% (3/16) S3, whereas AO-GHD was graded as 50% (3/6) S0, 16.66% (1/6) S2, and 33.33% S3. After 6 months of hrGH replacement, CAP measurements did not change significantly, neither on group without hepatic steatosis at baseline (194.4 ± 24.3 vs. 215.4 ± 51.3; p = 0.267) nor on the group with hepatic steatosis (297.2 ± 32.3 vs. 276.4 ± 27.8; p = 0.082). A significant improvement of body composition was observed only in the first group.Conclusions: We have demonstrated the importance of CAP as a non-invasive tool in the liver steatosis identification on hypopituitary patients. This method may be an important indicator of the severity of metabolic disorders in MPHD patients. In our study, no liver health modification in LSM at baseline or after 6 months of rhGH replacement was found. Longer studies can help to establish the potential repercussions of growth hormone replacement therapy on liver steatosis.

MON-LB071 Panhypopituitarism Causing a Life Threatening Prolonged QT Interval Which Can Be Reversible with Treatment of Underlying Endocrine Disorders

Introduction: Panhypopituitarism can lead to major metabolic consequences as a result of multiple hormonal deficiencies. However, its association with life-threatening arrhythmias is not well known. Only a few cases have been reported in the literature. Case Report: A 38 year old woman with no past medical history presented with amenorrhea. She was found to have a high prolactin level and subsequent MRI showed a 2.7 cm pituitary adenoma. She underwent transsphenoidal resection and developed panhypopituitarism after surgery. She was placed on hydrocortisone, levothyroxine and desmopressin but was not been compliant with the medications. A few months later, she had a sudden onset syncopal episode without any prodromal symptom. On presentation, she had a heart rate of 43 bpm and prolonged QT/QTc of 668/564ms. Laboratory tests were significant for a troponin of 0.8ng/ml, n <0.03ng/ml, severe hypothyroidism (FT4 0.1ng/dl, n 0.8-2.2ng/dl; FT3 1.03pg/ml, n 2.77-5.27pg/ml) and adrenal insufficiency (AM cortisol <0.2mcg/dL, n 4.5-22.7mcg/dL). There were no other clinical findings to explain this. Her syncopal episode strongly suggested a VT/VF arrest. Echocardiogram showed no structural heart disease. She was treated appropriately for her hypothyroidism and adrenal insufficiency; and she wore a wearable defibrillator while the endocrine disorders were corrected. After treatment, her bradycardia resolved and her QT interval normalized. Genetic screening for underlying Long QT Syndromes was negative. Clinical Lesson: Panhypopituitarism, including hypothyroidism and adrenal insufficiency, can cause life threatening arrhythmias such as ventricular tachycardia and fibrillation. This can lead to extensive noninvasive and invasive cardiac testing and intervention. It is critical that clinicians be aware that these arrhythmias can be reversed by correcting the underlying endocrine disorders. 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.

MON-457 One in Five Patients Develop Multiple Hormone Deficiencies Following Radiotherapy for Acromegaly or Cushing's Disease

Aim: To characterise the use of radiotherapy (RTx) for corticotropinomas and somatotropinomas and the long-term clinical outcome for these patients. Methods: All patients with corticotropinomas (CD) and somatotropinomas (AC) who were treated at the Royal Melbourne and the Royal Adelaide Hospitals between 1980 and 2017 were included. Long-term clinical outcome data were obtained via a clinical database (Biogrid) and medical records from the respective hospitals. There were no standard guidelines for recommending RTx during this period at either institution, however, it was considered in the presence of non-operable persistent or relapsed disease. Statistical analyses applied included binary logistic regression, propensity score matching and Fisher’s exact test. Results In total, 171 patients were assessed and 30 patients were excluded due to insufficient data. Of the 141 patients included, 32 patients (23%) received RTx (20 - AC, 12 - CD). The non-RTx group (n=109) consisted of 78 CD and 31 AC patients. Patients with macroadenomas were significantly more likely to receive RTx (OR 5.93, p < 0.05, CI 1.9-18.3). Details regarding the modality of RTx were recorded in 18 of 32 patients: 9 fractionated stereotactic, 7 single dose radiosurgery, 2 deep-radiotherapy. Twenty-nine (21%) patients in this study had evidence of persistent ACTH or GH hyper-secretion post initial surgery and 14 received RTx. Amongst 9 AC patients who required medical therapy for disease control, 6 patients (67%) were able to stop their medication post RTx. The median time for medication cessation was 78 months (IQR 31, 106). None of the patients (n=12, 2 had CD, 10 had AC) in non-RTx group were able to cease medication (p < 0.05). After adjustment for tumour size, number of surgeries and surgery performed within the past 10 years, RTx was independently associated with increasing risk of hypopituitarism (adjusted OR 3.04, CI 1.01-9.17, p = 0.048). Overall, 11 out of 32 patients (34%) in the RTx group developed hypopituitarism. The median time to onset of first hormone deficiency post RTx was 36 months (IQR 7-60). Hypogonadotrophic hypogonadism was the most common deficiency detected (n=7), followed by ACTH (n=5) and TSH deficiency (n=4). Seven patients (22%) developed more than one hormone axis deficiency and 2 patients (6%) developed panhypopituitarism. Conclusion In this study, approximately 1 in 5 (22%) corticotropinoma and somatotropinoma patients developed multiple hormone deficiency post RTx. The median time to develop first hormone deficit was 36 months, confirming that long-term follow-up is required for these patients. Further studies are needed to compare mortality and cost-effectiveness of RTx versus medical therapy for persistent or recurrent corticotropinomas and somatotropinomas.

Hypopituitarism after Gamma Knife radiosurgery for pituitary adenomas: a multicenter, international study.

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS. Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing's disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6-246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism. At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38). Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

Growth hormone in heart failure revisited: An old story retold.

Heart failure (HF) is a disease characterized by increasing prevalence, huge direct and indirect costs, and an ominous prognosis, worse than many cancers. At the beginning of the 90s, growth hormone (GH) was proposed as potential adjunctive therapy in HF mostly due to its growth-promoting, vasodilating, and anti-apoptotic actions. However, although several uncontrolled clinical studies showed that GH therapy improved several cardiovascular parameters, two robust trials failed to confirm these findings. Dwelling upon potential explanations for such apparent discrepancy led to the hypothesis that HF patients exhibit an inhomogeneous basal activity of the GH/insulin-like growth factor 1 (IGF-1) axis, ranging from GH/IGF-1 deficiency to GH resistance. This complex phenomenon was then reconsidered in the context of the so-called multiple hormone deficiency syndrome (MHD), that is the recognition that HF is characterized not only by the hyperactivation of several signaling pathways including the adrenergic, the renin-angiotensin-aldosterone and cytokine systems, but also by a reduced anabolic drive leading to a state of anabolic/catabolic imbalance. Mounting evidence support the concept that such imbalance is not a mere epiphenomen, since it exerts a significant impact on clinical performance and more importantly, on survival. Therefore, the paradigm shift to reconsider HF as MHD represented the underpinning to implement clinical trials focused on hormone replacement therapies in congestive heart failure (CHF). With regard to GH replacement therapy, one controlled single-blind study yielded promising results, and we are currently conducting a double-blind controlled trial, as well a large Registry study to evaluate the impact of MHD on HF progression.

Panhypopituitarism- An unusual presenation of tuberculous meningitis

Pituitary gland involvement is a very rare entity of central nervous system tuberculosis. Tubercular meningitis (TBM) is a chronic meningitis on hypothalamic-pituitary axis which causes high morbidity and mortality hence it is the most dreaded form of extra pulmonary tuberculosis. Here we report a case of 24 year old female presenting with three months history of fever and headache along with altered sensorium since four days. There was also complain of secondary amenorrhea and generalised apathy. Neuroimaging revealed subependymal tuberculomas with meningitis and obstructive hydrocephalus. Cerebrospinal fluid (CSF) examination was also suggestive of tubercular meningitis. Endocrinological investigations showed multiple hormonal deficiencies manifesting as pituitary hypothyroidism, hypocortisolism, hypogonadotropic hypogonadism, and hypoprolactinemia. Anti-tuberculosis treatment was started, and it led to significant improvement in the general condition of the patient.

Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry.

Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by "Federico II" University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of VO2 peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF.

Pseudopseudohypoparathyroidism: an unusual case

We report unusual case of a 22-year-old male patient who presented with phenotypic features of Albright's hereditary osteodystrophy, but had associated multiple hormonal deficiencies suggestive of pseudo-pseudohypararthyroidism.

Individual Clinically Diagnosed with CHARGE Syndrome but with a Mutation in KMT2D, a Gene Associated with Kabuki Syndrome: A Case Report.

We report a Japanese female patient presenting with classic features of CHARGE syndrome, including choanal atresia, growth and development retardation, ear malformations, genital anomalies, multiple endocrine deficiency, and unilateral facial nerve palsy. She was clinically diagnosed with typical CHARGE syndrome, but genetic analysis using the TruSight One Sequence Panel revealed a germline heterozygous mutation in KMT2D with no pathogenic CHD7 alterations associated with CHARGE syndrome. Kabuki syndrome is a rare multisystem disorder characterized by five cardinal manifestations including typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate intellectual disability, and postnatal growth deficiency. Germline mutations in KMT2D underlie the molecular pathogenesis of 52–76% of patients with Kabuki syndrome. This is an instructive case that clearly represents a phenotypic overlap between Kabuki syndrome and CHARGE syndrome. It suggests the importance of considering the possibility of a diagnosis of Kabuki syndrome even if patients present with typical symptoms and meet diagnostic criteria of CHARGE syndrome. The case also emphasizes the impact of non-biased exhaustive genetic analysis by next-generation sequencing in the genetic diagnosis of rare congenital disorders with atypical manifestations.

A 16 years old follow up in one case of congenital multiple hormone deficiency: growth, sexual development and bone metabolism

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction

Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction

Bone Disease in Thalassemia: A Molecular and Clinical Overview.

Thalassemia bone disease is a common and severe complication of thalassemia-an inherited blood disorder due to mutations in the α or β hemoglobin gene. In its more severe form, severe anemia is present, and treatment with frequent red blood cell transfusion is necessary. Because the body has limited capacity to excrete iron, concomitant iron chelation is required to prevent the complications of iron overload. The effects of chronic anemia and iron overload can lead to multiple end-organ complications such as cardiomyopathy, increased risks of blood-borne diseases, and liver, pituitary, and bone disease. However, our understanding of thalassemia bone disease is incomplete and is composed of a complex piecemeal of risk factors that include genetic factors, hormonal deficiency, marrow expansion, skeletal dysmorphism, iron toxicity, chelators, and increased bone turnover. The high prevalence of bone disease in transfusion-dependent thalassemia is seen in both younger and older patients as life expectancy continues to improve. Indeed, hypogonadism and GH deficiency contribute to a failure to achieve peak bone mass in this group. The contribution of kidney dysfunction to bone disease in thalassemia is a new and significant complication. This coincides with studies confirming an increase in kidney stones and associated accelerated bone loss in the thalassemia cohort. However, multiple factors are also associated with reduced bone mineral density and include marrow expansion, iron toxicity, iron chelators, increased bone turnover, GH deficiency, and hypogonadism. Thalassemia bone disease is a composite of not only multiple hormonal deficiencies but also multiorgan diseases. This review will address the molecular mechanisms and clinical risk factors associated with thalassemia bone disease and the clinical implications for monitoring and treating this disorder.

High Frequency of Normal Response during GH Stimulation Tests in Patients with Ectopic Posterior Pituitary Gland: A Source of False-Negative Diagnosis of Pituitary Insufficiency

Aims: To report false-negative normal growth hormone (GH) peak response in patients with ectopic posterior pituitary gland (EPP) identified with a simplified magnetic resonance imaging (FAST1-MRI). Methods: We analyzed 75 EPP patients with short stature and reduced growth velocity. Sagittal-T1 imaging (thickness: 2 mm and gap: 0.2 mm) without gadolinium administration was used. A GH peak of ≥5 ng/ml after clonidine or insulin stimulation was considered normal. Results: Normal GH response was observed in 15 of 75 (20%) patients [mean (SDS) peak = 8.2 (4.1) ng/ml]. Age at diagnosis [6.5 (3.0) years vs. 7.8 (4.1) years], gender (10 males/5 females vs. 44 males/16 females), pubertal stage (14 prepubertal/1 pubertal vs. 51 prepubertal/7 pubertal), and target height [-0.4 (0.6) vs. -0.4 (0.9)] were recorded. The perinatal history did not differ between responsive and nonresponsive patients. There was a trend to more frequent multiple hormone deficiency in nonresponsive when compared with responsive patients [3/15 (20%) and 31/60 (51.7%), respectively (p = 0.055)]. Height at diagnosis was lower in nonresponsive patients (p = 0.042). No significant difference in the IGF1 levels (p = 0.598) was observed between the groups. Conclusion: Normal GH values after stimulation tests do not exclude EPP-associated GH deficiency. A simplified fast acquisition sagittal-T1 MRI protocol investigation included at the initial diagnostic approach is able to prevent misdiagnosis of GH deficiency in patients with short stature.