Ianus Bifrons: The Two Faces of Metformin.

The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open?

An unusual cause of adrenal insufficiency with elevation of 17-hydroxyprogesterone: case report.

BACKGROUND: We present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease. CASE PRESENTATION: An 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease. CONCLUSIONS: In the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the "healthy" adrenal tissue residue than a direct secretory activity by the adrenal tumor.

Modulatory activity of testosterone on growth pattern and IGF-1 levels in vanishing testis syndrome: a case report during 15 years of follow-up.

BACKGROUND: The vanishing testis syndrome (VTS), is a 46, XY disorder of sex development (46, XY DSD) and is characterized by the absence of testis in a 46, XY subject with male genitalia, gonadal dysgenesis and consequent hypergonadotropic hypogonadism. CASE PRESENTATION: A young man affected by VTS has been followed up for more than 15-year in our center. The patient received different testosterone formulations, which modulated his IGF-1 levels and height velocity, depending on different stimulatory effects, mimicking pubertal spurt until achieving a final height in line with his genetic target. Exogenous testosterone, activating GH/IGF-1 system, can directly influence growth pattern. With this particular case report we demonstrate that an accurate monitoring of patients with VTS, as well as a perfect reproduction of testosterone secretion during pubertal spurt, can guarantee a normal growth and development and, consequently, a high level of quality of life in adulthood. CONCLUSION: Testosterone levels act an important role during pubertal spurt in modulating the GH/IGF-1 axis, besides its well-known impact in sexual development. Very little amount of exogenous testosterone can stimulate IGF-1 secretion and provide to growth velocity the drive that characterizes the initial phases of the growth spurt.

Iodoprophylaxis and thyroid autoimmunity: an update.

Adequate iodine intake is necessary for normal thyroid function. Iodine deficiency is associated with serious complications, but also iodine excess can lead to thyroid dysfunction, and iodine supplementation aimed to prevent iodine deficiency disorders has been associated with development of thyroid autoimmunity. The epidemiology of thyroid diseases has undergone profound changes since the implementation of iodoprophylaxis, notably by means of iodine-enriched salt, specifically resulting in decreased prevalence of goiter and neonatal hypothyroidism, improved cognitive function development in infancy, and reduced incidence of more aggressive forms of thyroid cancer. The main question we address with this review is the clinical relevance of the possible effect on autoimmunity exerted by the use of iodine-enriched salt to correct iodine deficiency. In animal models, exogenous iodine is able to trigger or exacerbate thyroid autoimmunity, but it is still not clear whether the observed immunological changes are due to a direct effect of iodine on immune response, or whether they represent a secondary response to a toxic effect of iodine on thyroid tissue. Previous iodine status of a population seems to influence the functional thyroid response to increased iodine intake and possibly the development of thyroid autoimmunity. Moreover, the prevalence of thyroid antibodies, regarded as hallmark of autoimmune thyroid disease, varies between populations under the influence of genetic and environmental factors, and the presence of thyroid antibodies does not always coincide with the presence of thyroid disease or its future development. In addition, the incidence of autoimmune diseases shows a general increasing trend in the last decades. For all these reasons, available data are quite heterogeneous and difficult to analyze and compare. In conclusion, available data from long-term population surveys show that a higher than adequate population iodine intake due to a poorly controlled program of iodine prophylaxis could induce thyroid dysfunction, including thyroid autoimmunity mostly represented by euthyroid or subclinical hypothyroid autoimmune thyroiditis. Close monitoring iodine prophylaxis is therefore advised to ensure that effects of both iodine deficiency and iodine excess are avoided.

Dipeptidyl peptidase-4 inhibitors do not alter GH/IGF-I axis in adult diabetic patients.

PURPOSE: Incretin-based therapies have been introduced in clinical practice for type 2 diabetes mellitus (T2DM) treatment in the last few years. Current available medications of this class include glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. In addition to GLP-1, DPP-4 is able to inactivate many others peptides as hypothalamic growth hormone-releasing hormone (GHRH). The aim of this exploratory study was to evaluate, on adult diabetic patients, the impact of therapy with incretins, particularly DPP-4 inhibitors on GH/IGF-I axis. METHODS: 60 patients with T2DM were included in the study and they were divided into three groups (age and sex comparable) on the basis of their hypoglycemic drugs in the last 4 months: group 1 (17 patients, exenatide or liraglutide + metformin), group 2 (18 patients, sitagliptin or vildagliptin + metformin), group 3 (25 patients, metformin). Anthropometric data, glycemia, glycosylated hemoglobin (HbA1c), IGF-I and acid-labile subunit (ALS) were collected in all patients. RESULTS: Weight, waist circumference and BMI of group 1 were significantly higher (P < 0.05) compared to the other groups. Fasting plasma glucose and HbA1c of the group 1 were similar compared to those of group 3 (P ns) and higher compared to those of group 2 (P < 0.05). IGF-I absolute values, IGF-I SDS were not significantly different in the three groups. CONCLUSIONS: Our data evidence that DPP-4 inhibition does not influence significantly GH/IGF-I system, confirming what was observed in animal models. Further studies are needed to better characterize the properties of these molecules on endocrine system.

One-year GH replacement therapy reduces early cardiac target organ damage (TOD) in adult GHD patients.

Hypopituitarism reduces life expectancy and increases the risk of cardiovascular and cerebrovascular diseases, as well as death. Abnormalities in the cardiovascular system may be independently related to GH deficiency (GHD). The aim of this study was to prospectively investigate coronary flow reserve and diastolic function in GHD adult patients at diagnosis and after 1 year of GH replacement therapy. As control group, an age- and sex-matched population was chosen. All patients and controls were non-smokers, non-diabetic, and normotensive, with no history of vascular disease. 14 patients with adult-onset GHD and 17 controls represent the two study groups. Anthropometric data, blood pressure, lipid profile, glycosylated hemoglobin (HbA1c) and IGF-I plasma levels, coronary flow reserve (CFR), and LV diastolic function (evaluated by E/A) were collected in all subjects before and after 12 months of GH replacement therapy. Compared with controls, systolic and diastolic blood pressure and LDL cholesterol levels were significantly higher at baseline and return, comparable to controls after 1 year of GH replacement (GHRT). GHD patients showed a blunted CFR at baseline (P < 0.001) and a significant improvement after GHRT, returning to values comparable with those recorded in the control group. In addition, after therapy a significant (P < 0.001) improvement in E/A was recorded. One year of GH therapy improves CFR and E/A in the patient population analyzed, thereby encouraging the early start of GHRT.

Unexpected Elevated Free Thyroid Hormones in Pregnancy.

BACKGROUND: The use of thyrotropin and free thyroid hormone assays to evaluate thyroid function is widespread, but in some situations the results are inconsistent with the patient's thyroid status. SUMMARY: A 35-year-old woman with a known diagnosis of chronic autoimmune thyroiditis was referred to the authors' clinic at week 26 of her second pregnancy. The patient was clinically euthyroid. Consistent with this, her serum thyrotropin (TSH) was normal (0.79 mIU/L), but she had elevated free thyroid hormones-free triiodothyronine (fT3) and free thyroxine (fT4)-as determined by a one-step chemiluminescent assay. The patient was taking levothyroxine replacement therapy (125 µg/day), and the dose was confirmed. Previous blood tests showed concordance between TSH and free thyroid hormone values. The patient was followed up throughout gestation and at 12 months postpartum. During gestation, her free thyroid hormones remained high using one-step methods, while the total thyroid hormone concentration values were within the reference range, in agreement with the TSH values. Postpartum fT4 and fT3 values returned progressively to normality, in agreement with the TSH values. The presence of circulating thyroid hormone autoantibodies (THAb) was hypothesized, which are known to interfere, although to a variable extent, with thyroid hormone one-step assays. Using stored frozen sera, this hypothesis was confirmed indirectly by measuring normal levels of fT3 and fT4 with a two-step method, and directly by demonstrating THAb against the two hormones. CONCLUSION: Despite their relative rarity, circulating THAb may be suspected when laboratory data are not consistent and contrast with the clinical picture. To the authors' knowledge, no previous case of transient appearance of THAb in pregnancy has been described.

Pituitary image: pituicytoma.

INTRODUCTION: Pituicytoma is a rare tumor arising from the neurohypophysis or pars intermedia of the adenohypophysis. CASE REPORT: A 36 year old male came to our observation presenting polydipsia, polyuria, polyphagia, decreased libido and altered sleep-wake rhythm. The biochemical tests showed hypotonic urine, mild hyperprolactinemia, hypogonadotropic hypogonadism, central hypothyroidism. Magnetic resonance revealed an expansive lesion of the suprasellar region (slightly isointense on T1, hyperintense on T2, impregnating contrast medium), that was partially removed by trans-cranial neurosurgical approach. The histopathological diagnosis was pituicytoma. After surgery, in addition to endocrine disorders, the patient presented severe neurological sequelae and hyperthermia, likely due to damage of the hypothalamus, followed by a progressive metabolic syndrome. The residual tumor was monitored by MRI, and, due to the early gradual increase in volume, was treated by stereotactic radiosurgery. DISCUSSION/CONCLUSIONS: Pituicytomas are often difficult to distinguish from other hypothalamic or pituitary lesions. However, their identification would be preferable in a pre-operative setting in order to optimize the work-up and to initiate a proactive management of the expected complications.

Autonomic nervous system and cardiovascular risk assessment during one year of growth hormone replacement therapy in adults with growth hormone deficiency.

OBJECTIVE: This prospective study aimed to evaluate the impact of growth hormone deficiency (GHD) on cardiac autonomic tone and on cardiovascular risk and the changes after 12 months of GH replacement therapy (GHRT). GHD is associated with increased cardiovascular morbidity and mortality. This has been attributed to increased markers of cardiovascular risk and to abnormalities of both the cardiac and peripheral autonomic nervous systems. The autonomic cardiac nervous system (ACNS) can be indirectly evaluated by analysis of heart rate variability (HRV) in clinostatism and orthostatism. DESIGN: We compared 14 GHD patients at baseline and after 12 months of GHRT and 17 healthy controls. We analyzed a number of cardiovascular risk factors and we used analysis of HRV during the Tilt Test that identified high frequency (HF) and low frequency (LF), representing parasympathetic and sympathetic activity, respectively. RESULTS: Compared with the control group, in either clinostatism or in orthostatism our patients showed a significantly lower value of LF (P=0.047; P=0.004, respectively), whereas HF was significantly reduced in orthostatism (P=0.037), and indicatively in clinostatism (P=0.065). These values remained unchanged after 12 months of GHRT. No statistically significant differences were found between the LF/HF ratio in untreated and treated patients. In GHD patients, there was a significant reduction of cardiovascular risk in 12 months of replacement therapy (P=0.002). CONCLUSIONS: Our study highlights the absence of sympathovagal imbalance in GHD patients; GHRT does not change ACNS during the first year of GH treatment but it reduces the absolute cardiovascular risk in these patients.

Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency.

OBJECTIVES: Previous studies suggested that vitamin D modulates circulating IGF1. We investigated this effect in adults and its clinical relevance in the management of GH deficiency (GHD). DESIGN AND METHODS: IGF1 levels were prospectively measured before and after 12 weeks of treatment with oral vitamin D3 (5000 or 7000 IU/week) vs no intervention in 39 subjects 61.9±7.9 years old. The frequency of IGF1 values ≥50th age- and sex-specific percentile in relation to vitamin D status, as determined by the concentration of 25-hydroxyvitamin D (25(OH)D), was retrospectively assessed in 69 GHD patients (57.4±16.6 years) on stable hormone replacement and with 25(OH)D and IGF1 concurrently measured. RESULTS: Treatment with 5000 and 7000 IU vitamin D3/week significantly raised 25(OH)D by 12.7±8.4 and 13.1±6.5 ng/ml respectively (both P<0.001 vs baseline). In the 7000 IU group, IGF1 levels also significantly increased by 31.3±36.7 ng/ml (P=0.01). Neither 25(OH)D nor IGF1 significantly varied in controls. IGF1 was ≥50th percentile more frequently in GHD patients with 25(OH)D levels ≥15 than <15 ng/ml (65.9 vs 40.0%, P<0.05). Logistic regression with adjustment for recombinant human GH (rhGH) dose, vitamin D supplements, gender, use of thyroid hormones, corticosteroids or estrogen/testosterone, and season revealed a significant positive association between ≥15 ng/ml 25(OH)D and IGF1 ≥50th percentile (OR 4.4, 95% CI 1.0-18.8, P<0.05). A significant negative correlation between 25(OH)D concentrations and rhGH dose was found after correcting for age and IGF1 (ß -0.042, P<0.01), but not after further adjusting for sex, thyroid, adrenal or gonadal replacement, and season (ß -0.037, P=0.06). CONCLUSIONS: Vitamin D increases circulating IGF1 in adults. As a result, a better vitamin D status may ease the achievement of normal IGF1 values in GHD.

Role of pituitary dysfunction on cardiovascular risk in primary empty sella patients.

OBJECTIVE: Primary empty sella (PES) is a frequent anatomical condition rarely causing pituitary dysfunction. We assessed cardiovascular risk in a cohort of PES patients referred to Endocrine Units. DESIGN: The study was performed in three Italian tertiary referral centres. We evaluated pituitary function and cardiovascular risk, on the basis of lipid and glucose metabolism parameters and of Framingham score (FS), in 94 consecutive patients with PES diagnosis and in 94 gender, age and BMI matched controls. PATIENTS: Pituitary function was normal in 30 patients (group A), whereas a single or multiple pituitary hormone deficiency was demonstrated in 64 (group B). Growth hormone deficiency (GHD) was diagnosed in 56, central hypothyroidism in 35, hypogonadotropic hypogonadism in 32 and central hypoadrenalism in 24 cases. RESULTS: Framingham score was higher and glucose and lipid profile were worse in PES patients than in controls. Cardiovascular risk parameters were not different between group A and B. In group B, increased cardiovascular risk was associated with hypothyroidism and hypogonadism, but not with GHD. In group A, cardiovascular risk was higher and FT3 and FT4 levels were lower than in controls. Moreover, PES patients stratified for BMI showed a worse glucose and lipid profile and (in the overweight subgroup) higher FS than matched controls. CONCLUSIONS: Primary empty sella patients show increased cardiovascular risk, regardless of BMI. A worse lipid and glucose profile and higher FS were associated with secondary hypothyroidism, even subclinical, as well as hypogonadism.

The clinical-molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology.

The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid somatostatin-dopamine compounds have been generated, and recently a completely novel class of molecules has been developed. These advances have opened new perspectives for the medical treatment of patients with pituitary tumours poorly responsive to the present clinically available drugs, and perhaps also for the treatment of other categories of neuroendocrine tumours. The aim of the present review is to summarise the novel insights in somatostatin and dopamine receptor pathophysiology, and to bring these new insights into perspective for the future strategies in the medical treatment of patients with pituitary adenomas.