The biochemical diagnosis of acromegaly: revising the role of measurement of IGF-I and GH after glucose load in 5 questions.

INTRODUCTION: Acromegaly is a rare disorder characterized by the excessive secretion of growth hormone (GH), mostly caused by pituitary adenomas. While in full-blown cases the diagnosis is easy to establish, milder cases are more challenging. Additionally, establishing whether full cure after surgery is reached may be difficult. AREAS COVERED: In this article, we will review the challenges posed by the variability in measurements of GH and its main effector insulin-like growth factor I (IGF-I) due to both biological changes, co-morbidities, and assays variability. EXPERT OPINION: Interpretation of GH and IGF-I assays is important in establishing an early diagnosis of acromegaly, in avoiding misdiagnosis, and in establishing if cure is achieved by surgery. Physicians should be familiar with the variables that affect measurements of these 2 hormones, and with the performance of the assays available in their practice.

Current Management and Outcome of Pregnancies in Women With Adrenal Insufficiency: Experience from a Multicenter Survey.

CONTEXT: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. OBJECTIVE: Multicenter survey on current clinical approaches in managing AI during pregnancy. DESIGN: Retrospective anonymized data collection from 19 international centers from 2013 to 2019. SETTING AND PATIENTS: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). RESULTS: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. CONCLUSIONS: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Evaluation and Management of Endocrine Hypertension During Pregnancy.

Hypertension is a common clinical complication in pregnancy, representing possible short-term and long-term risks of complications for both mothers and babies. Even if in a majority of cases hypertension is essential, possible secondary causes, which can be related to endocrine disorders, must be detected and correctly managed. This review focuses on the evaluation and the management of primary hyperaldosteronism, Cushing syndrome, and pheochromocytoma in pregnancy.

Medullary Thyroid Carcinoma With Exon 2 p.L56M RET Variant: Clinical Particular Features in Two Patients.

RET (REarranged during Transfection) proto-oncogene variants are essential for the development of familial and sporadic forms of medullary thyroid carcinoma (MTC). The most frequent variants are usually located in exons 10, 11, and 13 through 16 of the RET gene. We report two cases of apparently sporadic MTC associated with the variant in exon 2 of RET gene. Patient 1, a 62-year old man who had undergone adrenalectomy for a 5 cm pheochromocytoma, was screened for type 2 multiple endocrine neoplasia (MEN 2) which showed elevated basal and post-intravenous calcium gluconate calcitonin levels. A fine needle aspiration biopsy (FNAB) confirmed the suspicion of MTC. The patient underwent total thyroidectomy and lymphadenectomy, and the histology showed C-cell hyperplasia with medullary microcarcinoma. Patient 2, a 57 years old woman, underwent total thyroidectomy for toxic multinodular goiter. Pre-operative FNAB had shown benign features, while basal calcitonin levels were only borderline increased. Final histology revealed medullary multifocal microcarcinoma. Genetic testing for RET protoncogene on DNA extracted from peripheral blood was performed in both patients and a missense variant on exon 2 (c.166C>A, p.L56M) was identified. To our knowledge, these are the first time two cases of MTC associated to RET p.L56M variant. Interestingly, one patient had also a pheochromocytoma suggesting a possible pathogenetic role of this variant in the genesis of MEN2A. While the association of this variant with MTC or MEN2A has been never reported, it has been described in association with Hirschsprung's disease.

Secondary adrenal insufficiency: from the physiopathology to the possible role of modified-release hydrocortisone treatment.

Central adrenal insufficiency (AI) represents a life-threatening disorder that results from a reduced cortisol production due to an impairment production of adrenocorticotropic hormone (ACTH). In particular, secondary AI results from pituitary disease that impedes the release of ACTH, while tertiary AI is caused from an impaired synthesis of corticotropin-releasing hormone. Central AI has an estimated prevalence of 150-280 per million, resulting more common than primary AI. Prompt diagnosis and management of this condition is crucial, but the diagnostic investigation can often be challenging, in particular in cases of recent onset of secondary adrenal insufficiency. Moreover, different formulations of steroid replacement therapy are available for both primary and central adrenal insufficiency, but the therapy of choice for the treatment of secondary hypoadrenalism is still debated. In particular, several data confirm the advantages of dual-release hydrocortisone formulation in primary hypoadrenalism, while data for secondary AI are still lacking. However, in spite of few clinical data, the use of dual release hydrocortisone can be extremely favorable in ACTH deficiency, which is associated with an increase of overall and cardiovascular mortality, also due to the risk of overtreatment. In this condition, the use of a modified-release glucocorticoid formulation, which has been demonstrated to improve metabolic profile, can be extremely attractive.

A Rare Case of Lateral Ectopic Thyroid.

Ectopic thyroid tissue is an abnormality caused by aberrant thyroid gland embryogenesis during its passage from the floor of the primitive foregut to its final position. The most frequent place of ectopic thyroid tissue is the base of tongue, whereas lateral thyroid gland is a very rare finding. The present case describes a case of thyroid dysgenesis, caused by a submandibular ectopic thyroid gland. Thyroid scintigraphy was crucial for the diagnosis: in fact, the patient was asymptomatic, and the diagnosis was performed only on the basis of subclinical hypothyroidism.

Endocrinological side-effects of immune checkpoint inhibitors.

PURPOSE OF REVIEW: Three mAbs targeting immune checkpoint proteins are available for the treatment of patients with melanoma, lung, and kidney cancer, and their use will likely expand in the future to additional tumor types. We here update the literature on the incidence and pathophysiology of endocrine toxicities induced by these agents, and discuss management guidance. RECENT FINDINGS: Immune checkpoint inhibition may trigger autoimmune syndromes involving different organs, including several endocrine glands (pituitary, thyroid, adrenals, and endocrine pancreas). Hypophysitis is more frequently associated with ipilimumab, whereas the incidence of thyroid dysfunction is higher with nivolumab/pembrolizumab. Primary adrenal insufficiency can rarely occur with either treatment. Autoimmune diabetes is very rare. As hypophysitis and adrenalitis may be life-threatening, endocrinological evaluation is essential particularly in patients developing fatigue and other symptoms consistent with adrenal insufficiency. Corticosteroids should be promptly used when hypophysitis-induced adrenal insufficiency or adrenalitis are diagnosed, but not in thyroiditis or diabetes. No impact of corticosteroids on the efficacy/activity of immune checkpoint-inhibiting drugs is reported. Hormonal deficiencies are often permanent. SUMMARY: In absence of predicting factors, accurate information to patients provided by the oncology care team is essential for early diagnosis and to limit the consequences of checkpoint inhibition-related endocrine toxicity.

Characteristics and outcomes of Italian patients from the observational, multicentre, hypopituitary control and complications study (HypoCCS) according to tertiles of growth hormone peak concentration following stimulation testing at study entry.

OBJECTIVE: To determine whether characteristics and outcomes of Italian patients in the observational global Hypopituitary Control and Complication Study (HypoCCS) differed according to the degree of GH deficiency (GHD). DESIGN: Patients were grouped by tertiles of stimulated GH peak concentration at baseline (Group A lowest tertile, n = 342; Group B middle tertile, n = 345; Group C highest tertile, n = 338). RESULTS: Baseline demographics, lipid levels, body mass index categories and mean Framingham cardiovascular risk indexes were similar in the three groups and remained substantially unchanged over time, with no subsequent significant between-group differences (except mean levels of triglycerides increased in the highest tertile group). GHD was adult-onset for >75% of patients in all groups. The percentage of patients with multiple pituitary deficiencies was higher in Group A than in the other groups; isolated GHD was reported with highest frequency in Group C. Patients in Group A received the lowest mean starting dose of GH. Hyperlipidaemia at baseline was reported in 35·1%, 31·1% and 24·7% of patients in groups A, B and C, respectively (P = 0·029). Mean duration of GH treatment was 7·21, 5·45 and 4·96 years, respectively. The proportion of patients with adverse events did not differ significantly between groups, with a low prevalence over time of diabetes and cancer. CONCLUSIONS: In Italian patients from HypoCCS, the level of GH deficit did not influence changes over time in metabolic parameters or adverse event profile, despite differences in GHD severity at baseline and in the starting GH dose.

The hypertension of Cushing's syndrome: controversies in the pathophysiology and focus on cardiovascular complications.

Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first 'Altogether to Beat Cushing's syndrome' workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

The role of adrenal scintigraphy in the diagnosis of subclinical Cushing's syndrome and the prediction of post-surgical hypoadrenalism.

BACKGROUND: Management of subclinical Cushing's syndrome (SCS) remains controversial; it is not possible to predict which patients would benefit from adrenalectomy. In the present study we aimed to evaluate the role of adrenocortical scintigraphy (ACS) in the management of patients with SCS. METHODS: The medical records of 33 consecutive patients with adrenal "incidentaloma" and proven or suspected SCS who underwent (131)I-19-iodocholesterol ACS between 2004 and 2010 were reviewed. Sixteen underwent laparoscopic adrenalectomy (surgical group-S-group) and 17 were medically managed (medical group-M-group). Follow-up evaluation was obtained by outpatient consultation. RESULTS: Overall 25 patients (15 in the S-group and 10 in the M-group) had concordant unilateral uptake at ACS (ACS+). In the S-group, the mean follow-up duration was 30.9 ± 16.1 months and, irrespective of the presence of hormonal diagnosis of SCS, in patients who were ACS+ adrenalectomy resulted in a significant increase in HDL cholesterol and decreases in body mass index, glycemia, and blood pressure (BP). One patient reduced antihypertensive medication and three others were able to discontinue it altogether. Prolonged postoperative hypoadrenalism (PH) occurred in 14 patients in the S-group. The overall accuracy in predicting PH was 93.7 % for ACS and 68.7 % for laboratory findings. In the M-group, the mean follow-up duration was 31.5 ± 26.3 months and no patient developed overt Cushing's syndrome, although ACS+ patients experienced a worsening in glycemia and diastolic BP. CONCLUSIONS: Adrenal scintigraphy seems the most accurate diagnostic test for SCS. It is able to predict the metabolic outcome and the occurrence of PH, identifying the patients who could benefit from adrenalectomy irrespective of hormonal diagnosis.

Cushing's syndrome due to a bronchial ACTH-secreting carcinoid successfully treated with radiofrequency ablation (RFA).

CONTEXT: The ectopic production of ACTH is responsible for approximately 10% of cases of Cushing's syndrome. Whenever possible, once hypercortisolemia is under control with medical therapy, the final treatment consists of surgical excision of the tumor. We report a case of a patient with high surgical risk and poor response to medical therapy in which hypercortisolemia has been successfully treated with radiofrequency ablation of the bronchial carcinoid tumor. CASE PRESENTATION: A 43-year-old woman came to our hospital because of severe and rapidly worsening signs and symptoms of hypercortisolism over the previous 3 months. Hormonal tests suggested the presence of Cushing's syndrome due to ectopic ACTH production. Imaging studies detected an 8-mm pulmonary nodule with fluorine-18-fluorodeoxyglucose uptake localized in the middle right lobe. The patient started therapy with ketoconazole with poor response. Middle right lobectomy was indicated but, due to the patient's very high surgical risk, a thermal ablation with radiofrequency of the bronchial nodule was performed. OUTCOMES AND RESULTS: After the procedure, ACTH and cortisol levels dropped and fluorine-18-fluorodeoxyglucose positron emission tomography showed complete response to treatment. Clinical conditions progressively improved, and 6 weeks later, the patient underwent middle lobectomy without complications. Histology showed a 0.7-cm ACTH-producing typical bronchial carcinoid tumor. CONCLUSIONS: Thermal ablation with radiofrequency allows achieving a rapid control of hypercortisolism with subsequent improvement of symptoms. This procedure should therefore be considered as a viable therapeutic option in those cases of bronchial ACTH-secreting tumors in which the surgical approach is initially contraindicated.

"Occult" ovarian Leydig cell tumor: when laboratory tells more than imaging.

Hyperandrogenism is a common finding in premenopausal age and is generally caused by polycystic ovarian syndrome or other benign disease. Androgen-secreting tumors represent only 0.2 % of the causes of hyperandrogenism and usually present with severe clinical features, abrupt onset, and very high androgens levels. We describe here three cases of occult ovarian Leydig cell tumors suspected on the basis of severe clinical features of hyperandrogenism rapidly worsening, with elevated serum total testosterone levels, in which bilateral ovariectomy was performed and tumor was confirmed by post-operative histology. In all three cases, imaging was negative for ovarian tumor. Moreover, in one case the confounding concomitant finding of bilateral adrenal masses posed an additional challenge. Our experience highlights that testosterone levels represent the most helpful marker in the diagnosis of androgen-secreting ovarian tumor. In the absence of imaging findings, bilateral ovariectomy should be indicated, if supported by unequivocal clinical and laboratory data.

Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease.

Specific human monoclonal antibodies antagonize cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4 mAbs), a negative regulator of the immune system, inducing unrestrained T-cell activation. In patients with advanced or metastatic melanoma, one of these agents, ipilimumab, produced considerable disease control rates and, for the first time, a clear improvement in overall survival outcomes. However, accumulating clinical experience with anti-CTLA-4 mAbs identified a novel syndrome of autoimmune and autoinflammatory side effects, designated as "immune-related adverse events," including mainly rash, colitis, and hepatitis. Autoimmune hypophysitis has emerged as a distinctive side effect induced by anti-CTLA-4 mAbs. This condition may be life threatening because of adrenal insufficiency if not promptly recognized, but it may easily be diagnosed and treated if clinically suspected. Hypopituitarism caused by these agents is rarely reversible and prolonged or life-long substitutive hormonal treatment is often required. The precise mechanism of injury to the pituitary triggered by anti-CTLA-4 mAbs is yet to be fully elucidated.

Recognizing menopause in women with amenorrhea induced by cytotoxic chemotherapy for endocrine-responsive early breast cancer.

Cytotoxic anticancer treatment may induce amenorrhea or menopause to a variable extent. These side effects may not only impair or impede fertility but also cause sexual dysfunction, bone loss, and menopausal symptoms, with a strikingly negative effect on quality of life in many women. Aromatase inhibitors (AIs) are a recommended adjuvant endocrine treatment option in postmenopausal patients affected by early breast cancer (EBC) but are contraindicated in premenopausal women and in those with residual ovarian function. Women over 40 years of age with chemotherapy-induced amenorrhea (CIA) and routine hormonal levels consistent with menopause may receive an AI as adjuvant endocrine treatment. For these women, the tools available to identify menopause do not appear to be completely reliable. This review focused on the pathophysiology of ovarian toxicity induced by cytotoxic agents and on potentially useful methods to diagnose chemotherapy-induced menopause in patients treated with adjuvant chemotherapy for endocrine-responsive EBC. Moreover, practical approaches are proposed to distinguish true menopausal women, who would benefit from AIs, from those with transient or persistent CIA.

Video-assisted minimally invasive parathyroidectomy: benefits and long-term results.

BACKGROUND: In recent years several endoscopic and video-assisted techniques for parathyroidectomy have been described. The role of these techniques, with respect to time-honored conventional surgery, has been largely debated. This paper was designed to review the evidence, and make the recommendations, for the video-assisted/endoscopic approach to parathyroidectomy. METHODS: A database search was conducted in PubMed from which abstracts were screened matching our definition. Publications were further assessed and assigned their respective level of evidence. Additional data were obtained on the basis of our personal experience. RESULTS: Thirty-eight mainly retrospective studies have been published. Only four small, prospective, randomized trials, providing level II evidence, and one retrospective case-control comparative study, providing level IV evidence, have been found. Minimally invasive video-assisted parathyroidectomy (MIVAP) has emerged as one of the leading techniques. To date several randomized studies have shown that MIVAP is an efficacious and feasible procedure with the same complications rate as conventional surgery. Moreover, MIVAP seems to have significant advantages in terms of cosmetic result, postoperative pain and recovery, and patient satisfaction. CONCLUSIONS: From an evidence-based point of view, MIVAP should be considered a valid and validated option for the treatment of sporadic primary hyperparathyroidism sustained by a well-localized, single adenoma. Its role for the treatment of multiglandular diseases (familial hyperparathyroidism, secondary hyperparathyroidism) needs to be better clarified.

CT60 single nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen-4 gene region is associated with Graves' disease in an Italian population.

Graves' disease (GD) is an autoimmune and polygenic disorder. Several studies have shown that human leukocyte antigen (HLA) class II and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene are involved in the genetic susceptibility. We performed a case control study on 150 patients with GD and 301 controls, matched for age and gender, to verify the association of three polymorphisms located in CTLA-4 region (A49G, [AT](n)-3'UTR, and CT60) and of HLA-DRB1 and DQB1 loci with the disease in an Italian population. The prevalence of patients with GD carrying the G allele of CT60 was significantly higher compared to control subjects (p = 0.02, odds ratio [OR] = 1.82). The allelic frequency of the G allele of CT60 was also significantly higher in patients with GD (p = 0.02). The G allele frequency of A49G in patients was significantly higher compared to control subjects (p = 0.04). The 280 allele phenotype frequency of (AT)(n)-3'UTR was also significantly higher in patients (p = 0.04). The G allele of A49G, the G allele of CT60, and the 280 allele of (AT)(n)-3'UTR microsatellite were significantly increased in patients with GD with thyroid-associated ophthalmopathy (TAO) compared to controls (p = 0.04, p = 0.03, and p = 0.02, respectively), however, we did not find any significant difference between TAO and non-TAO patients. We also found the HLA-DRB1*03 allele to be associated with GD; interestingly, the association of the CTLA-4 markers was independent from the HLA DRB1*03 status. These results highlight the role of the CTLA-4 locus, in addition to HLA, in the susceptibility to GD. Inside the CTLA-4 region, CT60 appears to be the most associated polymorphism to GD, however, further studies are needed to identify the etiologic variant.