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Meeting Reports

93rd Annual Meeting & Expo of the Endocrine Society, ENDO 2011
June 4 - 7, 2011
Boston, Massachusetts, USA

INTRODUCTION


With warm weather inviting people to sit on outdoor terraces when they were not in front of the convention center’s outflow screens, this year’s ENDO meeting in Boston also invited them to exercise in order to track down all poster locations around the exhibition floor. Indeed, three days of poster sessions sandwiched between exhibitions and oral presentations made attendees walk, not just sit and listen, with no need for reminders of the benefits of physical exercise. However, given all the choices, from oral sessions and poster presentations, to information points within the exhibition floor and the terraces along Newbury Street, many of even the most attentive congress goers certainly missed part of the information discussed during the meeting. DiabetesPro presents a brief overview of the take-home messages on the treatment of endocrine diseases from ENDO 2011 in the report below as a complement to the meeting itself and other information available through the Endocrine Society website.

GROWTH FAILURE

Recombinant growth hormone replacement for growth hormone deficiency in adults and children and idiopathic short stature in children proved effective and safe over the long term [Kanzaki, S. et al., Abst P1-748; Hughes, I.P. et al., Abst P1-753; Hughes, I.P. et al., Abst P1-752; Hiort, O. et al., Abst P1-751; Blankenstein, O. et al., Abst P1-750; Fukuda, I. et al., Abst P2-415], although relatively limited effects were noted in elderly growth hormone-deficient patients [Kokshoorn, N.E. et al., Abst P2-413] and the treatment resulted in increased mortality, largely explained by cardiovascular disease and subarachnoid or intracerebral hemorrhage, especially when doses over 50 mcg/kg/day were administered [Carel, J.C. et al., Abst LB-5]. However, growth hormone replacement resulted in increased height standard deviation scores without major safety concerns in children with Noonan's syndrome, Turner's syndrome or other causes of growth failure, despite the cardiovascular anomalies in Noonan's syndrome patients [Lee, P.A. et al., Abst P1-744; Ross, J. et al., Abst P1-742; Rotenstein, D. et al., Abst P1-743; Ross, J.L. et al., Abst P1-741; Ranke, M.B. et al., Abst P1-738], although less favorable outcomes were noted in patients with Turner's syndrome homozygous for the full-length growth hormone receptor exon 3 and insulin-like growth factor-binding protein-3 -202 C allele [Braz, A.F. et al., Abst P1-737], patients with less responding genotypes benefiting from initial dose adjustments [Clayton, P. et al., Abst P1-736; Chatelain, P. et al., Abst P1-735]. In adults with growth hormone deficiency, replacement therapy resulted in improved physical and psychological well-being, reduced body weight and fat content, and increased bone mineral density that was more marked in men than women, more intense with shorter delay between childhood-onset and adult growth hormone replacement therapy and greater in the lumbar spine compared to the femoral neck [Payer, J. et al., Abst P2-365; Tritos, N.A. et al., Abst P2-364; Della Casa, S. et al., Abst P2-362; Hazem, A., et al., Abst P2-360]. Growth hormone replacement in adults also improved fatty liver and hepatic dysfunction [Kurimoto, M. et al., Abst P2-414]. In that context, a novel long-acting human growth hormone for weekly or less frequent administration was described, which was well tolerated in healthy volunteers [Jung, S.Y. et al., Abst P2-355], whereas a monthly growth hormone-XTEN construct, VRS-317, proved to be safe and effective in a phase I trial in adults with growth hormone deficiency [Cleland, J.L. et al., Abst P2-371]. As a side comment, pulsed subcutaneous recombinant growth hormone therapy proved successful for inducing pregnancy without in vitro fertilization in a patient with a craniopharyngioma resulting in hypothalamic hypogonadism [Iwabuchi, M. & Miyake, H., Abst P3-229].

Improved height gain also resulted from adding oxandrolone to growth hormone replacement in girls with Turner's syndrome, with transient deceleration of breast development not interfering with final breast size [Freriks, K. et al., Abst P1-739]. In a similar way, anastrozole improved adult height in male adolescents with idiopathic short stature [De Rosa, A. et al., Abst P1-755], while ciproterone controlled bone maturation and improved final height in patients with congenital adrenal hyperplasia [Zucare, J.R.Z. et al., Abst P2-737]. Furthermore, coadministration of recombinant human somatropin and the gonadotropin-releasing hormone analogue triptorelin improved growth outcomes in pubertal adolescents with the disease [Colmenares, A. et al., Abst P1-754].

In addition to growth hormone deficiency, a placebo-controlled trial also confirmed the efficacy of growth hormone in fibromyalgia syndrome, with benefits on pain, other symptoms and bother comparable to those obtained with drugs commonly used to treat the disease [Cuatrecasas, G. et al., Abst P2-417] (Fig. 1).

Fig. 1. Percent of patients with < 11 tender points after 12 months of treatment with growth hormone (GH) or placebo [Cuatrecasas, G. et al., Abst P2-417].

ACROMEGALY AND PITUITARY TUMORS

By attaining biochemical control of the disease, the use of somatostatin analogues in the treatment of acromegaly resulted in an increased life expectancy [Vandeva, S. et al., Abst P3-294]. In that sense, octreotide remains a useful therapeutic option for the treatment of acromegaly, with clinical activity also against thyroid-stimulating and growth hormone co-secreting pituitary macroadenomas [Cheung, A.S. et al., Abst P3-292; Agrawal, V. et al., Abst P3-328], as well as anemic bleeding metastatic neuroendocrine tumors [Crowley, R.K. et al., Abst P3-262], and at least one case of remission of chronic lymphocytic leukemia in a patient with comorbid acromegaly receiving octreotide and the dopamine agonist bromocriptine [Del Rivero, J. et al., Abst P3-301]. In the case of acromegaly, the benefits of octreotide were related to KI-67 expression irrespective of somatostatin receptor type 2 expression [de Pinho, L.K.J. et al., Abst P3-288]. A subcutaneous hydrogel implant formulation of octreotide provided effective, with sustained suppression of growth hormone and insulin-like growth factor I over a 6-month period, with pharmacokinetic stability [Chieffo, C. et al., Abst P3-289; Chieffo, C. et al., Abst P3-290; Chieffo, C. et al., Abst P3-291]. Studies in experimental animals indicated improved uptake, bioavailability and half-life of octreotide in an alkylsaccharide absorption enhancer after oral compared to subcutaneous administration [Maggio, E.E. et al., Abst P1-285].

Compared to octreotide, the use of lanreotide saved nursing and patient wait time, which, in addition to the reduced likelihood for needle clogging with the former, resulted in a possible pharmacoeconomic advantage for the latter [Schweinsberg, K. et al., Abst P1-451]. As a side comment, comparable pharmacokinetics of lanreotide autogel were observed in healthy volunteers and patients with carcinoid neuroendocrine tumors [Troconiz, I. et al., Abst P3-258], with self- or partner injection being safe and actually preferred by the patients [Johanson, V. et al., Abst P3-257].

As an alternative approach, intensified medical therapy with pegvisomant and a greater use of surgery was historically related to an improved control of acromegaly in patient registries and nationwide surveys [Zilli, R.W. et al., Abst P3-295; Buchfelder, M. et al., Abst P3-296; Bex, M.A. et al., Abst P3-298], the activity of the agent showing some dependence on gender, body mass index, baseline insulin-like growth factor I levels and genetic variability in the growth hormone receptor locus [Kamenicky, P. et al., Abst P3-297]. However, while discontinuing long-acting octreotide in patients with acromegaly without tumor regrowth was considered to be feasible in a minority of patients, then requiring active surveillance [Rabago, J. et al., Abst OR36-5], pegvisomant continuation in patients previously on combination therapy plus pegvisomant plus a somatostatin analogue maintained control of the disease in most patients [O'Connor, R.D. et al., Abst OR36-4].

In the experimental domain, botulinum toxin-derived targeted secretion inhibitors with potential for inhibiting growth hormone synthesis and secretion suggested innovative therapeutic approaches to acromegaly that proved feasible in in vivo animal models [Somm, E. et al., Abst P1-413; Legget, J.D. et al., Abst P2-332].

Favorable responses to cabergoline were documented in patients with nonfunctioning pituitary macroadenomas, with control of hypercortisolemia and tumor regression in some, but not all cases [Ah-Lan, J. et al., Abst P1-433; Moura, L.T. et al., Abst P3-336], the agent combined with a somatostatin analogue also offering potential as a treatment for acromegaly in patients not willing to undergo surgical resection [Tutunku, Y.A. et al., Abst P3-287]. Therapeutic responses in patients with aggressive pituitary adenoma were also reported for temozolomide [Cozzi, R. et al., Abst P2-377]. Not a tumor, but a case of lymphocytic hypophysitis resulting in pan-hypopituitarism responding to high-dose pulsed methylprednisolone was likewise reported [Shen, S. et al., Abst P2-406]. Improved bone remodeling in an additional study in patients with hypopituitarism was observed after treatment with low-dose hydrocortisone [Behan, L.A. et al., Abst P2-411].

Regarding prolactinoma, the prolactin-lowering activity of aripiprazole offered a therapeutic option for the treatment of psychosis while reducing tumorigenic hyperprolactinemia [Moin, T. et al., Abst P3-313], whereas cabergoline was at least as effective as bromocriptine as a treatment for prolactinoma [Vilar, L. et al., Abst P3-325], but resulted in hypersexuality in a patient [Gupta, A. & Zimmerman, R.S., Abst P3-312].

As a side comment, in two patients undergoing transsphenoidal pituitary surgery, tolvaptan was an effective treatment for delayed hyponatremia [Auchus, R.J. et al., Abst P2-379].

PRECOCIOUS PUBERTY

While a histrelin implant effectively suppressed puberty in male children [Silverman, L.A. et al., Abst P3-717], triptorelin [Freire, A.V. et al., Abst P3-714] and leuprorelin [Sathasivam, A. et al., Abst P3-716] challenge were effective tests for the early diagnosis of precocious puberty in girls. Early intervention with metformin in girls with low body weight and precocious puberty improved visceral and hepatic fat levels and reduced the prevalence of polycystic ovary syndrome in later adolescence [Ibanez, L. et al., Abst OR45-1]. It should be noted that an inhibitory effect of metformin on follicle-stimulating hormone and anti-Müllerian hormone production in the granulose may represent an additional benefit on polycystic ovaries [Pellat, L.J. et al., Abst P1-303; Rice, S. et al., Abst P1-297]. In addition, metformin inhibited insulin-driven endometrial epithelial cell proliferation, indicating putative benefits against endometrial hyperplasia in women with insulin resistance and/or hyperinsulinemia [Flannery, C.A. et al., Abst P3-179].

POLYCYSTIC OVARY SYNDROME

Metformin treatment of polycystic ovary syndrome resulted in additional benefits on gallbladder motility, which is impaired in women with the disease [Isik, S. et al., Abst P2-221], and the use of metformin combined with pioglitazone and flutamide exerted favorable effects on lean mass, visceral fat, hepatic fat and vascular inflammation in girls with androgen excess [Ibanez, L. et al., Abst P2-247], the benefits of metformin on precocious pubarche depending on a number of single-nucleotide polymorphisms and repeats in the organic cation transporter 1 (OCT1), serine/threonine-protein kinase 11 (STK11), androgen receptor (AR), sex hormone-binding globulin (SHBG) and fat mass and obesity-associated protein (FTO) genes [Diaz, M. et al., Abst P2-246].

Treatment of women with polycystic ovary syndrome with atorvastatin brought about decreases in dehydroepiandrosterone and androstenedione levels, suggesting a beneficial effect on hyperandrogenemia [Sathyapalan, T. et al., Abst P2-230]. In a similar way, treatment of patients with the disease with spironolactone reduced estradiol levels through an effect on ovarian estrogen synthesis [Fiore, C. et al., Abst P2-248]. On the contrary, exenatide improved body weight, but not hyperandrogenemia, in overweight women with polycystic ovaries [Dawson, A.J. et al., Abst P2-242]. In the pre-clinical stage, the apolipoprotein A-I mimetic 4F improved fat deposition and glucose and cholesterol levels in animal models of polycystic ovary syndrome, without restoring estrous cycles [Nedorezov, L.B. et al., Abst P1-307].

MENOPAUSE

A combination of bazedoxifene and conjugated estrogens exhibited no untoward impact on breast density in postmenopausal women [Harvey, J.A. et al., Abst P1-79].

Oral micronized progesterone safely improved hot flushes in menopausal women, without untoward cardiovascular effects [Hitchcock, C. & Prior, J., Abst P1-312], although discontinuation resulted in return to pretreatment vasomotor symptoms [Prior, J.C. & Hitchcock, C., Abst P1-311]. Improvements in women with moderate to severe vasomotor symptoms were also demonstrated with desvenlafaxine, which showed a rapid onset of action [Guico-Pabia, C.J. et al., Abst P1-310].

A novel para-quinol derivative of 17beta-estradiol showed particular efficacy for controlling hot flushes, depression and anxiety in ovariectomized animal models [Merchenthaler, I. et al., Abst P1-15]. Also in animal models of surgical menopause, bazedoxifene exhibited antiproliferative effects on the mammary glands and was able to antagonize the proliferative and transcriptional effects of conjugated equine estrogens if used concomitantly [Ethun, K.F. et al., Abst P1-16]. Prevention of estrogenic proliferation also resulted from chemical modifications of estradiol, including the 18-methyl and 17-hydroxy inversion [Ayan, D.P. et al., Abst P1-17]. As an additional preclinical mechanistic observation, the metastin analogue TAK-683 attenuated gonadotropin-releasing hormone pulse generation but induced gonadotropin-releasing and luteinizing hormone secretion in the pituitary portal circulation after ovariectomy [Wakabayashi, Y. et al., Abst P2-264; Ohkura, S. et al., Abst P2-273].

With reassuringly low rates of cardiovascular events and breast cancer [Snabes, M.C. et al., Abst P1-313], testosterone administration in postmenopausal women not receiving hormone replacement therapy brought about improvements in verbal learning and memory [Davidson, S.L. et al., Abst P1-314].

AMENORRHEA


Effective control of exercise-induced hypothalamic amenorrhea, menstrual restoration and increase in lumbar spinal bone mineral density were demonstrated over a 2-year period in women treated with metreleptin [Aronis, K.N. et al., Abst LB-3].

HYPOGONADISM

Over the long term, testosterone replacement was associated with reduced mortality in men with low testosterone levels [Shores, M.M. et al., Abst P1-772] and counteracted the increased mortality observed in men with type 2 diabetes and hypogonadism [Muraleedharam, V. et al., Abst OR35-2], with oral testosterone therapy in hypogonadic men resulting in beneficial effects on leptin and LDL cholesterol levels, despite untoward effects on resistin and HDL cholesterol levels [An, J.H. et al., Abst P1-349]. Compared to placebo, testosterone replacement in older men also resulted in reduced levels of C-reactive protein and soluble tumor necrosis factor receptor 1 [Maggio, M. et al., Abst P3-209], indicating reduced inflammation, which, in subjects with metabolic syndrome, brought about significant cardiometabolic benefits [He, J. et al., Abst P3-208]. A modified slow-release oral formulation tested positive for restoring testosterone levels in men with experimental hypogonadism [Lee, A.P. et al., Abst P1-346].

In relation to testosterone, a gel formulation provided relevant exposure with normal physiological levels [Dobs, A. et al., Abst P1-354], regardless of alternating or concomitant application on the abdomen and upper arm/shoulders [Stahlman, J. et al., Abst P1-344], although clothing or washing was recommended before intimate contact resulting in transfer of testosterone to female partners [Stahlman, J. et al., Abst P1-351; Stahlman, J. et al., Abst P1-350]. Feasible pharmacokinetics and safety in androgen-deficient men were also demonstrated with a testosterone solution applied to the armpits [Wang, C. et al., Abst P1-352].

Intramuscular long-acting testosterone depot proved to be a safe, feasible modality for androgen substitution in male hypogonadism, with a favorable impact on metabolic and cardiovascular risk factors [Zitzmann, M. et al., Abst P1-348; Zitzmann, M. et al., Abst P1-347].

Regarding other treatment options, although letrozole normalized serum testosterone in men with obesity-related hypogonadotropic hypogonadism, it failed to induce clinical benefits on somatic or psychological signs and symptoms [Loves, S. et al., Abst P1-473]. On the other hand, in addition to hypogonadism, topical dihydrotestosterone tested positive for increasing penile size when initiated at an early age, with the only untoward effect of promoting pubic hair growth [Silva, R.B. et al., Abst P2-185]. As a final comment, the selective androgen receptor modulator LGD-4033 proved to be safe and well tolerated in healthy men, and studies were announced to determine its impact on body composition, muscle strength and physical function [Basaria, S. et al., Abst P3-207].

BREAST CANCER

In vitro data indicated a proapoptotic effect for tamoxifen on human breast cancer cells mediated by monocytes [Ramzy, M. et al., Abst P1-55]. However, resistance to tamoxifen was described, mediated by switch to insulin-like growth factor-binding protein 2-dependent PTEN modulation for cell survival [Foulstone, E.J. et al., Abst P1-143]. It should be noted that tamoxifen, but not raloxifene, decreased growth hormone secretion and whole-body fat oxidation in healthy women, suggesting a risk for metabolic disturbance [Birzniece, V. et al., Abst P2-368]. Activity against breast cancer cells, but mediated by downregulation of estrogen receptor-alpha and upregulation of tumor suppressor protein p53, was also demonstrated with 2-methoxyestradiol [Siebert, A.E. et al., Abst P1-63]. Proapoptotic activity against breast cancer cells was similarly reported with combinations of salirasib and estradiol or CMH [Aiyar, S.E. et al., Abst P1-72]. In addition, a novel 17beta-hydroxysteroid dehydrogenase type 1 inhibitor, PBRM, effectively inhibited estradiol production in breast cancer cells [Ayan, D.P. et al., Abst P1-68]. On the other hand, the phosphatidylinositol 3-kinase inhibitor BKM-120 and the phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ-235 reduced breast cancer development and progression, but induced hyperglycemia in diabetic animal models [Gallagher, E.J. et al., Abst P2-29].

Also in the context of breast cancer, phenolic curcuminoids from Curcuma longa (turmeric) with preventive activity against osteolytic bone metastases from breast cancer were described [Wright, L.E. et al., Abst P1-71]. Additional mechanistic observations indicated efficacy for the proteasome inhibitor MG-132 in abolishing the suppressive effect of steroid hormones on parathyroid hormone production by bone-metastasizing cancer cells [Kajitani, T. et al., Abst P3-17]. Antimetastatic activity in animal models of breast cancer was also revealed for the TGF-beta receptor type-1 inhibitor EW-7179 [Son, J.Y. et al., Abst P3-39] and the tyrosine-protein kinase JAK2 inhibitor NIM-811 [Clevenger, C.V., Abst S67-2]. On the contrary, eicosapentaenoic acid did not inhibit progestin-induced invasiveness of breast cancer cells [King, R.A. et al., Abst P1-85].

DIABETES

Whether using insulin glargine or human insulin, decreased insulin-like growth factor I bioactivity was noted in type 2 diabetes patients on insulin replacement therapy [Varewijck, A.J. et al., Abst OR39-5], but children with type 1 diabetes receiving long-acting insulin glargine or insulin detemir showed better control of glycated hemoglobin A1c levels than children receiving long-acting human insulin [Bang, P. et al., Abst P3-478]. It should be noted that treatment of type 1 diabetes with insulin glargine enhanced growth velocity in prepubertal girls [Moll, G.W. et al., Abst P1-764].

Additional evidence discussed in Boston corroborated the reduced likelihood of cancer in diabetic patients receiving metformin, already suggested by prior observations [Lega, I.C. et al., Abst P2-40]. Furthermore, in the experimental laboratory, metformin prevented the deleterious effects of metabolic syndrome on bone trabecular microarchitecture [Felice, J.I. et al., Abst P1-218], while effectively reverting sirolimus-induced hyperglycemia and normalizing islet insulin content [Clure, C. et al., Abst P1-501]. It should be noted that bone-promoting effects in type 1 diabetes were also attributed to recombinant insulin-like growth factor I [Fowlkes, J. et al., Abst P1-215]. On the other hand, balaglitazone also proved effective for lowering glucose and hemoglobin A1c levels in patients with type 2 diabetes, but was less potent than pioglitazone in a randomized trial [Henriksen, K. et al., Abst P3-467] (Fig. 2).

Fig. 2. Change in hemoglobin A1c levels after 26 weeks of treatment with balaglitazone or pioglitazone [Henriksen, K. et al., Abst P3-467].

Among the thiazolidinediones, pioglitazone improved beta cell function and insulin sensitivity in patients with ketosis-prone diabetes [Smiley, D. et al., Abst P3-495], while experimental observations with the agent indicated an antiinflammatory effect by repressing TNF-alpha transcription in mesangial cells [Milton, F.A. et al., Abst P2-525]. A novel partial peroxisome proliferator-activated receptor-gamma agonist, GQ-16, tested positive in preclinical assays, with insulin-sensitizing activity but no weight gain [Neves, F.A.R. et al., Abst OR23-6].

While inducing long-lasting benefits on glycemic control, C-reactive protein levels, body weight and the lipid profile [Gupta, M. et al., Abst P3-492], and also protecting beta cells against apoptosis secondary to endoplasmic reticulum stress [Chen, W. et al., Abst P2-502] and inducing antiinflammatory and antiatherosclerotic effects [Chaudhuri, A. et al., Abst P3-389] in diabetic conditions, experimental findings related to prenatal exposure to exenatide indicated long-term effects on body weight regulation and adipose balance, which were possibly related to central effects on energy expenditure and locomotor activity [Babu, D.A. et al., Abst P2-437]. In addition, direct effects of exenatide on isolated hepatocytes were demonstrated, resulting in decreased gluconeogenesis and lipogenesis through an effect on as yet unidentified receptors [Samson, S.L. et al., Abst P2-483].

New clinical studies and observations confirmed the benefit of liraglutide in the treatment of type 1 diabetes, the addition of the agent to continuous subcutaneous insulin infusion significantly lowering fasting and overall glucose levels and glycemic oscillations, while reducing insulin dose requirements. Furthermore, add-on liraglutide reduced hemoglobin A1c levels and body weight [Varanasi, A. et al., Abst OR07-5].

With a documented beneficial effect on fasting plasma glucose and hemoglobin A1c levels and the proinsulin:insulin ratio indicating improved pancreatic insulin secretion [Sue, M. et al., Abst P1-509] and clinical efficacy comparable to bedtime insulin in patients not responding to metformin and sulfonylureas [Nogueira, K.C. et al., Abst P3-482], treatment of type 2 diabetes with sitagliptin resulted in antiinflammatory effects that translated into reductions in C-reactive protein and interleukin-6 levels; decreases were also noted in free fatty acid levels [Dandona, P. et al., Abst OR26-1]. However, two cases of sitagliptin-induced acute hepatitis were described, suggesting the need for periodic liver function testing [Patel, K. et al., Abst P1-566]. On the other hand, the benefits and tolerability of linagliptin on glycemic control in patients with type 2 diabetes were independent of the patients' age and gender [Rendell, M. et al., Abst P3-483; Rendell, M. et al., Abst P3-497].

Additional clinical trial data discussed during ENDO 2011 indicated beneficial C-peptide responses in patients with type 1 diabetes treated with the anti-CD3 monoclonal antibody otelixizumab, suggesting potential for beta cell preservation [Donner, T. et al., Abst P3-474].

Potent antidiabetic effects in experimental animal models were demonstrated with the novel peroxisome proliferator-activated receptor-gamma ligand SR-1664, which, without acting as an agonist, inhibited cyclin-dependent kinase 5-mediated phosphorylation [Banks, A.S. et al., Abst LB-1]. Also in the preclinical arena, blockade of the cannabinoid CB1 receptor resulted in improved incretin-mediated secretion of insulin by beta cells [Kim, W. et al., Abst OR01-4], suggesting putative new therapies for type 2 diabetes to be further explored.

In the preclinical arena, the mesenchymal cell-stimulating oligonucleotide IMT-504 improved metabolic disturbances in animal models of type 1 diabetes, supporting a putative role in therapeutics [Bianchi, M.S. et al., Abst P1-502]. Also as preclinical findings, but related to islet transplant, clinically relevant doses of tacrolimus, but not sirolimus, impaired beta cell function without affecting cell mass in human islet xenografts [Robledo Reyes, A.M. et al., Abst P2-484]. On the other hand, antiinflammatory and beta cell-protective activity was demonstrated with dextran sulfate in nonobese diabetic animal models, suggesting potential as a treatment for type 1 diabetes [Valle, S. et al., Abst P2-481]. As a complementary finding, undisclosed small molecules targeting adenylate cyclase and phosphodiesterase were able to restore beta cell function in islets isolated from patients with type 2 diabetes, also suggesting new putative treatment strategies to be explored [Balhuizen, A. et al., Abst P2-473].

In addition to diabetes, a patient with Donohue's syndrome (a severe form of congenital insulin receptor dysfunction) was effectively treated with subcutaneous insulin-like growth factor I replacement therapy, resulting in improved glycemic control [Stanescu, D.E. et al., Abst OR07-1]. Also in relation to nondiabetic glycemic abnormalities, improved insulin sensitivity in patients with lipodystrophy resulted from leptin replacement therapy [Lungu, A.O. et al., Abst OR07-2]. In that context, glycemic and hypertriglyceridemic disturbances in patients with lipodystrophy were also effectively managed with metreleptin [Amarnath, S.L. et al., Abst OR07-3].

Diabetes complications

At least in experimental animal models, tretinoin increased nerve growth factor levels, improving nerve cell regeneration, suggesting potential to be explored as a treatment for diabetic neuropathy [Park, J.S. et al., Abst P1-507].

Hypertension is a common co-occurrence in patients with diabetes that was effectively managed by carvedilol and metoprolol, neither agent affecting endothelial function, although both improved arterial elasticity in large arteries, but metoprolol had a negative effect on small vessel elasticity [Mahajan, G. et al., Abst P2-532]. In addition, add-on nebivolol was well tolerated in patients with hypertension, without the untoward effects on glucose levels and insulin sensitivity observed with hydrochlorothiazide in subjects with metabolic syndrome [Deedwania, P. et al., Abst P2-567] (Fig. 3). Using a different approach, azelnidipine also exerted beneficial effects on hypertensive patients with type 2 diabetes, lowering aldosterone and plasminogen activator inhibitor 1 levels, as well as blood pressure [Ikeda, K. et al., Abst P2-617]. On the other hand, angiotensin-converting enzyme inhibitors lowered albuminuria more effectively than angiotensin receptor blockers in type 2 diabetes patients [Al-Sayed, N.A. et al., Abst P2-616], whereas a particular angiotensin receptor blocker, olmesartan, decreased blood pressure without inducing escape aldosterone breakthrough [Hiroi, N. et al., Abst P2-618].

Fig. 3. Change in the Homeostasis Model Assessment (HOMA) insulin resistance index after 12 weeks of adding nebivolol, hydrochlorothiazide or placebo to prior therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers [Deedwania, P. et al., Abst P2-567].

Diabetes insipidus

A case of diabetes insipidus resulting from central nervous system lymphoma and effectively treated with high-dose methotrexate was described [Sarkar, M.M. & Chin, E., Abst P2-408].

HYPERCHOLESTEROLEMIA

Benefits on LDL cholesterol levels without an apparent risk for myalgia or creatine kinase elevation were reported in three patients with prior statin-induced myalgia receiving ezetimibe/simvastatin [Hoang, T.D. et al., Abst P1-609]. Sequential administration of cholestyramine after priming with simvastatin effectively normalized LDL cholesterol levels in children with severe hypercholesterolemia [Lek, N. et al., Abst P2-467]. In vitro observations indicated potential prevention of statin-induced myopathy by calcidiol and calcitriol [Gannon, A.W. et al., Abst P1-208].

Improvements in LDL particle size and triglyceride levels in patients with diabetic dyslipidemia resulted from omega 3-polyunsaturated fatty acid supplementation [Kim, D. et al., Abst P1-608], while dietary omega 3- and omega 6-polyunsaturated fatty acids improved metabolic and hormonal imbalances in high-fructose-fed animals [Malaisse, W.J. et al., Abst P3-446], and poly- but not monounsaturated fatty acids also showed potential for preventing obesity, insulin resistance and hepatic steatosis [Spicer, E.G. et al., Abst P3-363].

OBESITY, ATHEROSCLEROSIS AND METABOLIC SYNDROME

Although topiramate effectively induced weight loss in obese individuals, unpleasant adverse events limiting its use, including paresthesias, taste disturbance and psychomotor abnormalities, remained a concern [Kramer, C.K. et al., Abst P1-471]. Sibutramine has also been reported to be effective for weight loss, although synergistic effects of spironolactone and fluoxetine exceeded the effect of sibutramine on central obesity and body mass index outcomes [Sakkal, S. et al., Abst P1-474] (Fig. 4).

Fig. 4. Percent change in body weight after 3 months of treatment with spironolactone, fluoxetine and/or sibutramine [Sakkal, S. et al., Abst P1-474].

While a double-blind study indicated benefits for growth hormone on the cardiovascular risk profile and body composition in women with visceral obesity, at the cost of reduced glucose tolerance in a subgroup of patients [Bredella, M.A. et al., Abst OR27-5], a finding that matched observations of increased hepatic but not muscular insulin resistance in healthy men and women receiving the agent [Lee, H.W. et al., Abst OR27-4], an additional randomized, controlled trial confirmed that consumption of a fruit and vegetable concentrate in obese children brought about improvements in glucose disposal and serum retinol levels [Canas, J.A. et al., Abst OR19-4]. According to additional evidence, resveratrol improved glucose metabolism and reduced adipose tissue inflammation in overweight, insulin-resistant patients [Bursheh, S.S. et al., Abst OR40-5]. In a not dissimilar way, formoterol administered to men resulted in increased energy expenditure, fat utilization and protein anabolism, without undue tachycardia, suggesting benefits on obesity and sarcopenia [Lee, P. et al., Abst P1-472]. Recombinant somatropin also improved visceral fat and waist girdle in adult men and women, suggesting benefits to be explored, particularly in elderly women [Hong, J.W. et al., Abst P1-470].

In the experimental arena, low-dose paracalcitol lowered blood pressure in hypertensive animal models without causing hypercalcemia or hypercalciuria [Torjman, K.M. et al., Abst P1-201]. Paracalcitol also reduced the atherogenic burden in apolipoprotein E-deficient animals [Ish-Shalom, M. et al., Abst P1-199]. In addition, oral but not injectable salmon calcitonin improved insulin sensitivity and glucose homeostasis in obese animals [Feigh, M.J. et al., Abst P3-399]. Also as preclinical observations related to obesity, (-)-epigallocatechin gallate was demonstrated to inhibit insulin-like growth factor II-induced preadipocyte proliferation through an effect on laminin receptors [Ku, H.C. et al., Abst P2-79], whereas peptide YY(3-36) was noted to decrease food intake without apparent adverse cardiovascular events or nausea [Qadri, A. et al., Abst P2-434]. Finally, berberine was shown to improve metabolic disturbances and insulin resistance related to obesity through an effect on 11beta-hydroxysteroid dehydrogenase 1 in adipose tissue [Du, H. et al., Abst P3-444].

THYROID AND PARATHYROID DISORDERS

While levothyroxine was corroborated to be effective in the management of hypothyroidism, even in patients with multidrug resistance [Yoshida, T. et al., Abst P3-621] or myxedema coma [Zainah, H. et al., Abst P3-624], propranolol used as a treatment for infantile hepatic hemangioma also brought benefits on consumptive hypothyroidism [Emerick, J.E. et al., Abst OR24-5].

Among scarce news on hypoparathyroidism, continuous subcutaneous infusion of recombinant parathormone 1-34 proved effective in three children with the disease [Roth-enbuhler, A. et al., Abst OR29-5], whereas teriparatide improved calcium and phosphate levels in patients with symptomatic, difficult-to-treat hypoparathyroidism [Jung, M. et al., Abst P3-107]. In addition, radioiodine preceded by thyrotropin alfa offered a safe option for the treatment of nontoxic multinodular goiter in the elderly, even in patients at high cardiovascular risk [Oliveira, R.A. et al., Abst P2-700]. Moreover, thyrotropin alfa combined with lithium improved low radioiodine uptake during treatment with amiodarone in a patient with thyrotoxicosis [Laplano, N.E.R. & Asis, L.M., Abst P2-691]. Regarding hyperparathyroidism, favorable preclinical pharmacokinetics were demonstrated in experimental animals with the novel peptidic calcimimetic KAI-4169 [Walter, S. et al., Abst P1-198; Baruch, A. et al., Abst P2-98], an agent that also exhibited favorable pharmacokinetics in healthy volunteers, with a predictable exposure-response relationship [Shen, J. et al., Abst P1-236]. Also referring to hyperparathyroidism, vitamin D replacement was safe in patients with concomitant vitamin D deficiency, and helped to lower parathormone levels, without excessive calcium elevations [Wagner, D. & Hou, R., Abst P3-96], whereas denosumab effectively managed hypercalcemia associated with hyperparathyroidism in patients previously resistant to cinacalcet and bisphosphonates [Varughese, A. et al., Abst P3-91]. However, cinacalcet was as effective as parathyroidectomy for controlling intact parathormone, calcium and phosphate levels in dialysis patients with secondary hyperparathyroidism not responding to alfacalcidol, although the surgical procedure was associated with better control of bone resorption [Egshatyan, L.V. et al., Abst P3-97].

Concerning thyroid malignancies, cyclophosphamide/vincristine/dacarbazine was well tolerated, but resulted in low tumor response rates, although with long-lasting stabilization, in patients with advanced medullary thyroid carcinoma or malignant pheo-chromocytoma [Deutschbein, T. et al., Abst P1-719]. Percutaneous ethanol injection also offered a useful approach to the treatment of thyroid nodules [Paz Filho, G. et al., Abst P1-710], and was also found to be effective as a treatment for cervical lymph node metastases from papillary but not medullary thyroid carcinoma [Abate, E.G. et al., Abst P1-720]. Based on in vitro results, potential as a treatment for thyroid cancer was suggested for dasatinib [Chan, C.M. et al., Abst P2-669] and an N-tert-butyl­oxy­carbonyl­hexyl­ene­di­amine derivative of 7-O-carboxymethyl-daidzein [Somjen, D. et al., Abst P2-675], whereas additional in vitro observations indicated potential primary resistance to vemurafenib by receptor tyrosine kinase overexpression [Montero-Conde, C. et al., Abst P2-668].

As a final comment, an additional case report suggested potential for sorafenib as a treatment for parathyroid cancer [Etzrodt-Walter, G. et al., Abst P3-53].

CUSHING’S SYNDROME AND OTHER SUPRARENAL DISORDERS AND CANCER

Significant clinical and metabolic improvements in patients with refractory Cushing's syndrome were demonstrated with the somatostatin analogue pasireotide [Colao, A. et al., Abst OR09-6; Varewijck, A.J. et al., Abst P3-535], which in in vitro studies moderately enhanced adrenal corticosteroid output [Pecori Giraldi, F. et al., Abst P2-590], the glucocorticosteroid receptor blocker mifepristone [Fleseriu, M. et al., Abst OR09-5] and ketoconazole, at least in the preoperative stage [Correa-Silva, S.R. et al., Abst P3-337], but not long-acting injectable octreotide, which reduced corticotropin output in a patient with Nelson's syndrome, but failed to do so in two patients with Cushing's syndrome, possibly because of the interference of concomitant glucocortico-steroids [Arregger, A.L. et al., Abst P3-339]. Because of its potent anticorticosolic activity, 1-ortho-1-para'-dichloro-diphenyl dichloroethane also offered potential therapeutic use as a first-line alternative to transphenoidal surgery or as salvage after failed surgery in patients with Cushing's disease [Baudry, C. et al., Abst OR09-4]. Also in the setting of Cushing's syndrome, significant benefits in postoperative hyponatremia were reported with conivaptan [Rowland, N. et al., Abst P3-533].

Regarding suprarenal malignancies, while sunitinib demonstrated modest single-agent activity in patients with refractory adrenocortical carcinoma [Quinkler, M. et al., Abst OR13-1] and exhibited activity against pituitary lesions in a patient with renal cell carcinoma [Srikugan, L. & Powrie, J., Abst P2-378], a combination of sorafenib and everolimus exerted activity in animal models of adrenal tumors by antiangiogenic and direct antitumor effects [Mariniello, A. et al., Abst OR13-3]. In addition, sunitinib was reported to be feasible in patients with pheochromocytoma or paraganglioma, resulting in improvements in symptoms and reduction in tumor size [Ayala-Ramirez, M. et al., Abst P2-633]. On the other hand, mitotane inhibited cytochrome P450 CYP3A4 and 5alpha-reductase, interfering with glucocorticosteroid and androgen metabolism, but also downregulated total steroid output, indicating potential as a treatment for adrenocortical carcionoma, as well as testicular Leydig cell carcinoma and prostate cancer [Chortis, V. et al., Abst P1-620].

OVARIAN CANCER

In vitro observations indicated potential for small-molecule tyrosine kinase inhibitors such as SU-6656 against particular forms of granulosa cell ovarian tumors [Jamieson, S. et al., Abst P2-214].

A cancer vaccine targeted against the zona pellucida glycoprotein 3 proved to be a feasible option for ovarian cancer in in vitro and in vivo studies [Rahman, N.A. et al., Abst P1-770].

PROSTATE CANCER

In preclinical animal models, GTx-758, a selective estrogen receptor-alpha agonist, reduced testosterone levels to castrate levels without inducing fatty mass increases [Jones, A. et al., Abst P2-26]. In models of prostate cancer, treatment with simvastatin significantly prevented progression to aggressive, advanced cancer [Drenkhahn, S.K. et al., Abst P2-25]. As a further potential therapy, N-phenylanthranilic acid derivatives inhibiting testosterone production via aldo-keto reductase family 1 member C3 were described [Adeniji, A.O. et al., Abst P2-581]. Also in the preclinical stage, prevention against bone metastases was demonstrated with two alendronate conjugates that target prostatic acid phosphatase [Levine, A.C. et al., Abst P2-21]. In vitro activity against prostate cancer cell proliferation was demonstrated with novel small-molecule androgen receptor blockers, including IN-19 [Cherian, M.T. et al., Abst P2-37]; in vitro antitumor activity was likewise demonstrated with the estrogen receptor-beta blocker 8beta-VE2 [Balanathan, P. et al., Abst P2-30] and the heat shock protein HSP 90 inhibitors ganetespib, NVP-AUY-922 and HSP-990 [Butler, L.M. et al., Abst P2-28; He, S. et al., Abst P2-84]. In addition, mechanistic studies with the metastin analogues KiSS1-305, TAK-448 and TAK-683, revealing potential for testosterone depletion, indicated promise as a treatment for prostate cancer and other hormone-related conditions [Matsui, H. et al., Abst P3-148].

OSTEOPOROSIS

Bisphosphonates have an essential role in the management of osteoporosis, although atypical transverse or oblique subtrochanteric or femoral shaft fractures during treatment with alendronate and other agents have raised concerns. In that sense, long-term follow-up of a patient cohort indicated the benefit of drug holidays after 5 years of treatment with bisphosphonates, at least in patients at low risk for fractures [Padilla, F.A. et al., Abst P1-232]. In addition, teriparatide and strontium ranelate were both associated with bone anabolic effects on unhealed bisphosphonate-related atypical fractures [Carvalho, N. et al., Abst P3-112]. Among the bisphosphonates, ibandronate was also reported to be effective for improving bone pain and metabolism in patients with Paget's disease of bone [Voss, L. et al., Abst P2-148].

The results of a randomized, controlled trial corroborated the antiresorptive benefits of yearly intravenous zoledronate even at doses of 1 or 2.5 mg, resulting in anti-fracture activity approaching the efficacy of the 5-mg yearly dose [Grey, A. et al., Abst OR29-3].

Teriparatide has also been an effective therapy for osteoporosis, although greater responses were documented in bisphosphonate-naive compared to recently pretreated patients [Dahl, P. et al., Abst P1-230].

Maintained efficacy, safety and tolerability of denosumab as a treatment for postmenopausal osteoporosis were observed in the 5-year open-label extension of the FREEDOM trial [Bone, H.G. et al., Abst OR29-1]. The agent proved active at reducing cortical porosity and bone morphology [Boyd, S.K. et al., Abst OR29-4]. However, at least one case of denosumab-induced hypocalcemia was described in a very elderly woman [Mamish, Z.M. et al., Abst P1-233] (symptomatic hypocalcemia was also reported in a patient with metastatic bone cancer receiving oral ibandronate [Chen, D.L.T. et al., Abst P2-144]), although the agent was effectively used in another patient with lymphoma-associated hypercalcemia [Makonnen, E. & Styner, M. et al., Abst P1-231].

Benefits were demonstrated for alendronate on bone mineral density in HIV-infected patients, without an impact on inflammation markers [Brown, T. et al., Abst OR29-6].

Additional miscellaneous information on osteoporosis indicated a direct osteoclast-activating effect for thiazolidinediones, resulting in inhibited osteoprotegerin production [Suwandhi, P. et al., Abst P1-189], whereas strontium ranelate protected osteoblasts against the deleterious effects of advanced glycation end products on proliferation and inflammatory cytokine production [Sedlinsky, C. et al., Abst P1-184]. Additional pre-clinical mechanistic findings included a study that indicated suppression of receptor activator of nuclear factor NF-kappaB ligand-stimulated osteoclast differentiation by pycnogenol [Watanabe, H. et al., Abst P1-191].

In addition to therapies for osteoporosis, a new meta-analysis further indicated a negative association between proton pump inhibitor but not histamine H2 receptor blocker use and an increased risk of fractures [Yu, E.W. et al., Abst P3-122]. Also regarding bone health, a study in HIV-positive patients with lipodystrophy did not reveal an effect for rosiglitazone on bone mineral density or bone resorption and formation, whereas metformin was associated with a significant decrease in bone formation marker levels [Walker Harris, V. et al., Abst P3-121].

MISCELLANEOUS CANCERS

Tamoxifen showed antitumor activity against a number of malignant mesothelioma cell lines, but exhibited tumor-promoting activity when used in combination with cisplatin [Jennings, C.J. et al., Abst P3-23]. Tamoxifen also exhibited anticarcinogenic activity against bladder cancer [Konnath George, S. et al., Abst P3-41]. Antiproliferative activity against intestinal epithelial and colon cancer cells was also demonstrated with a hot water extract of Chlorella vulgaris [Song, S.H. et al., Abst P1-158] and laminarin from Laminaria digitata [Park, H.K. et al., Abst P1-157], respectively, whereas tetra-iodothyroacetic acid nanoparticles exerted activity against colorectal cancer growth in animal models comparable to that of cetuximab [Yalcin, M. et al., Abst P3-38]. Additional in vitro studies in melanoma cell lines suggested potential for 20-hydroxy- and 20,23-dihydroxyvitamin D3 as nuclear receptor NF-kappaB-targeted therapies for melanoma [Janjetovic, Z. et al., Abst P1-211].

Compared to cytotoxic chemotherapy, everolimus alone or combined with octreotide was associated with mostly mild to moderate adverse events only in patients with pancreatic neuroendocrine tumors [Horsch, D. et al., Abst OR25-2; Gross, D. et al., Abst OR25-1]. However, used as a treatment for renal cell carcinoma, everolimus was associated with hyperthyroidism in one patient [Abou Assi, H.N. et al., Abst P1-683].

Regarding leiomyoma, experimental findings were presented on the negative impact of the Akt inhibitor MK-2206 on cancer cell survival and proliferation [Sefton, E. et al., Abst P2-75].

CACHEXIA


Nandrolone and 1alpha,25-dihydroxyvitamin D3 synergistically induced skeletal muscle cell proliferation [Kloosterboer, H.J. et al., Abst P1-210], the effect of nandrolone against muscle atrophy in experimental animals depending upon induction of the expression of the notch signaling inhibitor protein numb homolog by inhibition of Mdm2 [Liu, X.H. et al., Abst P2-63]. Additional mechanistic findings indicated an enhancing effect of nandrolone on the transcriptional coregulator PGC-1-alpha and genes related to oxidative metabolism in muscles paralyzed after spinal cord injury [Cardozo, C.P. et al., Abst P3-88]. Improvements in muscle mass in experimental animals were demonstrated with ACE-031, the soluble form of activin receptor type-2B fused to immunoglobulin G1 [Attie, K.M. et al., Abst P1-229].

MISCELLANEOUS

An experimental study in male animal models indicated rapidly reversible inhibition of spermatogenesis by oral administration of the retinoic acid receptor blocker BMS-189453 [Chung, S.S.W. et al., Abst LB-4], indicating potential for male contraception.

Parenteral nutrition substituting olive for a soybean oil-based emulsion had a favorable impact on blood pressure and endothelial function [Smiley, D. et al., Abst OR04-6], although both oils were associated with comparable rates of infectious and noninfectious complications and benefits on metabolic, inflammatory and oxidative markers [Umpierrez, G. et al., Abst P1-610].

A selective glucocorticoid receptor modulator, compound A, was described, which exhibited potent antiinflammatory activity without untoward effects on the bone [Rauner, M. et al., Abst P1-19].

Spironolactone protected against ischemia/reperfusion-induced myocardial apoptosis by restoring the antioxidant balance [Le, T.Y.L. et al., Abst P1-25]. The agent also improved renal function independently of blood pressure in renin-overexpressing animal models [Whaley-Connell, A. et al., Abst P1-26].

Exposure to triclosan enhanced uterine responses to ethinylestradiol in experimental animals [Louis, G.W. et al., Abst P1-103].

In vitamin D-deficient individuals, ergocalciferol normalized 25-hydroxyvitamin D levels without improving insulin sensitivity or secretion [Burnett-Bowie, S.A.M. et al., Abst OR26-2].

Treatment of hepatitis C with interferon alfa was associated with inflammatory cytotoxic thyroiditis [Akeno, N. et al., Abst OR30-5].

The 11beta-hydroxysteroid dehydrogenase type 1 inhibitors RO-838 and RO-151 did not induce adrenal insufficiency, but the latter, which was more potent against the enzyme, upregulated the hypothalamus-pituitary-adrenal axis [Fuerst-Recktenwald, S. et al., Abst OR39-4].

Sodium thiosulfate improved calcium balance in a patient with normophosphatemic familial tumoral calcinosis [Yalla, N.M. et al., Abst OR44-3].

Comparable effects for estradiol valerate/dienogest and etihylestradiol/levonorgestrel on the libido were demonstrated in women seeking contraception, both combinations improving desire, lubrication, orgasm, satisfaction and pain during intercourse [Nappi, R.E. et al., Abst P1-315].

Observations in a patient with neurocysticercosis indicated benefits for raloxifene [Sacerdote, A.S. et al., Abst P1-327].

Severe hypocalcemia in a patient with chronic kidney disease was restored by adding cholecalciferol to ongoing calcitriol and calcium treatment [Amrein, K. et al., Abst P2-123]. In a related way, single-dose intramuscular vitamin D3 improved vitamin D stores in patients with tropical chronic pancreatitis [Bhatia, E. & Reddy, S.V.B., Abst P2-122].

Compared to valproate and carbamazepine, levetiracetam was not associated with negative effects on bone health in patients with epilepsy [Hakami, T. et al., Abst P2-145].