Hormonal Patchwork: A Report from the 91st Annual Meeting of the Endocrine Society

Growth hormone replacement therapy was confirmed to be useful and safe in the management of growth hormone deficiency [Aragon-Alonso, A. et al., Abst P2-748; Peter, F. et al., Abst P1-725; Scalco, R.C. et al., Abst P1-734], and was also effective and safe in the treatment of Prader-Willi syndrome [Sode-Carlsen, R. et al., Abst P1-732; Hoybye, C. et al., Abst P1-733] and in a patient with 46,Y,r(X) kariyotypic abnormality [Salehi, P. et al., Abst P2-722]. In adults with growth hormone deficiency, low-dose growth hormone improved lipid profiles, but did not fully normalize body composition or insulin-like growth factor levels [Frisch, K.A. et al., Abst P2-745]. Favorable growth responses were likewise documented at 2 years of age in children born small for gestational age treated with either individualized or fixed-dose growth hormone replacement [Jung, H. et al., Abst P1-728]. Similarly, recombinant human insulin-like growth factor-1 administration was effective for managing and improving height in prepubertal children with primary insulin-like growth factor-1 deficiency [Midyett, L.K. et al., Abst P1-742]. Furthermore, growth hormone replacement therapy increased prolactin levels in children with growth hormone deficiency after surviving acute lymphoblastic leukemia [Follin, C. et al., Abst P1-731]. In the case of Turner’s syndrome, delayed therapy or inadequate growth hormone doses had a major impact on outcomes, calling for the need for early diagnosis and treatment at younger ages in order to attain adequate adult height [Pienkowski, C. et al., Abst P2-720].

A pegylated formulation of the hormone proved safe and well tolerated while exhibiting potential in adults with growth hormone deficiency [Hansen, B.S. et al., Abst P2-735]. No differences in the pharmacokinetic/pharmacodynamic profile of tesamorelin were apparent when comparing patients with HIV infection on antiretroviral therapy and healthy volunteers [Michaud, S.E. et al., Abst P3-641], whereas pharmacokinetic and pharmacodynamic validation of weekly injection of a novel long-acting crystalline formulation of somatropin was obtained in healthy adults [Attie, K.M. et al., Abst P1-722]. A further human growth hormone construct with a prolonged half-life enabling weekly administration was described: VRS-317 [Cleland, J.L. et al., Abst P1-720].

A number of observations related to wasting and muscular hypo/atrophy were discussed during this year’s meeting, including observations that treatment with soluble activin receptor type II_B prevented androgen deprivation-induced atrophy [Lachey, J.L. et al., Abst OR16-5] and nandrolone protected against experimental denervation atrophy [Qin, W. et al., Abst P1-19]. In addition, patients with osteoarthritis undergoing total hip replacement showed markedly improved lean body mass and decreased fat mass after three weeks of treatment with ghrelin [Iwakura, H. et al., Abst P2-188]. Besides the above reports, miscellaneous news related to muscular body composition included a study that concluded on a muscular hypertrophy effect of follistatin through induction of satellite cell proliferation [Gilson, H. et al., Abst P1-229].

Somatostatin analogs are the mainstay in the treatment of acromegaly, although with a risk of effects on glucose metabolism that cannot be predicted by clinical or biochemical parameters [Mazziotti, G. et al., Abst P3-674]. In the case of long-acting octreotide, a higher dose was concluded to offer a safe and successful alternative for patients not responding to conventional therapy [Giustina, A. et al., Abst P1-662] (Fig. 1), whereas extending the administration interval without loss of insulin-like growth factor-1 response was deemed possible in selected patients [Shimizu, C. et al., Abst P3-680]. An octreotide-releasing implant was also tested for pharmacokinetic and pharmacodynamic feasibility in acromegalic patients, with favorable results after monthly utilization [Kuzma, P. et al., Abst P3-675].

Self- (or partner-) administration of extended-release lanreotide proved safe and well tolerated and resulted in effective suppression of insulin-like growth factor and growth hormone in patients with acromegaly [Salvatori, R. et al., Abst P3-682]. Use of lanreotide autogel proved effective for normalizing insulin-like growth factor-1 levels many patients not previously controlled by pegvisomant [Birman, P. et al., Abst P3-688]. Initial evidence of the ability of the dopamine/somatostatin receptor agonist BIM-23A760 to inhibit growth hormone secretion in patients with acromegaly was described [Lesage, C. et al., Abst P3-673], while studies in healthy volunteers confirmed the pharmacokinetic and pharmacodynamic feasibility of the agent [Froehlich, J. et al., Abst P3-685].

Pegvisomant was another effective option for the treatment of acromegaly according to studies discussed during this year’s meeting, with changes in NT-pro-brain natriuretic peptide levels and body weight as markers for improved quality of life after therapy [Neggers, S.J.C.M.M. et al., Abst P3-689]. Furthermore, pegvisomant combined with octreotide was not superior to pegvisomant monotherapy regarding control of insulin-like growth factor-1 levels and symptoms [Zdunowski, P. et al., Abst P3-686], and in fact two cases of acromegaly resistant to high-dose pegvisomant combined with somatostatin analogs were reported [Morin, E. et al., Abst P1-683]. However, reversible cases of pegvisomant-related lypohypertrophy were reported [Rochira, V. et al., Abst P3-687].

Hypothyroidism

Although symptomatically effective as previously demonstrated, thyroxine replacement therapy did not improve growth in children with subclinical hypothyroidism [Zen, V.L. et al., Abst P3-700]. Furthermore, withdrawal was recommended for young children with inadequate thyrotropin-stimulating hormone responses or who continue to receive a smaller dose than normal for their age [Kaplowitz, P.B. et al., Abst P3-704]. Variable absorption of levothyroxine in fasting conditions resulted in higher but inconsistent serum thyrotropin levels, suggesting preference for nonfasting administration [Bach-Huynh, G. et al., Abst P3-527], but pharmacokinetics during pregnancy showed reduced clearance and increased exposure [Soldin, O.P. et al., Abst P1-507]. Regarding time of administration, better gastrointestinal absorption, although without an impact on quality of life or plasma lipid outcomes, was noted upon bedtime dosing of levothyroxine, which could also be related to the fasting nocturnal period [Kelderman-Bolk, N. et al., Abst S21-6]. As an additional comment, levothyroxine replacement in patients with subclinical hypothyroidism was associated with improvements in endothelial function and lipid levels [Samitin, W. et al., Abst OR27-4], whereas an effect of coffee impairing intestinal absorption of levothyroxine was described [Sindoni, A. et al., Abst P1-541].

Other thyroid disorders

Isolated news was discussed on treatment issues related to thyrotoxicosis, goiter and Graves’ disease. Carbimazole with thyroxine was not able to normalize thyroid function after ¹³¹I therapy for thyrotoxicosis [Goss, L. et al., Abst P3-545]. Thyroid-stimulating hormone-guided levothyroxine replacement proved feasible as a treatment for nodular goiter [Grussendorf, M. et al., Abst P3-544]. Through activation of peroxisome proliferator-activated receptor-alpha, ciprofibrate, fenofibrate and gemfibrozil inhibited self-perpetuating proinflammatory cytokine release from thyrocytes and retrobulbar cells from Graves’ ophthalmopathy patients [Antonelli, A. et al., Abst P1-555].

While a combination of cabergoline and low-dose ketoconazole was shown to be clinically effective and safe in patients with Cushing’s disease partially responding to cabergoline monotherapy [Pivonello, R. et al., Abst P1-616], growth-suppressing and proapoptotic activity of diferoyloylmethone from curcumin against adrenocorticotropin-producing Cushing’s disease cells was reported, suggesting potential for the treatment of the disease [Bangaru, M.L.Y. et al., Abst P3-577].

Nocturnal treatment with dexamethasone effectively suppressed the hypothalamus-pituitary-adrenal axis in children with congenital adrenal hyperplasia [Dauber, A.N. & Majzoub, J.A., Abst P2-612]. In that context, a study suggested better control of corticosteroid therapy by monitoring urinary 17-hydroxyprogesterone levels compared to serum androstenedione [Krone, N. et al., Abst P2-613]. Also in case of adrenal hyperplasia, reports of an effect for tamsulosin in modulating luteinizing hormone, follicle-stimulating hormone and testosterone production in a patient treated with hydrocortisone were discussed [O’Riordan, S. et al., Abst P1-347].

Regarding primary adrenal insufficiency, dual-release hydrocortisone was able to normalize the circadian cortisol profile as effectively upon single daily dosing as thrice-daily treatment with the standard formulation [Johannsson, G. et al., Abst P3-614].

As an additional issue, no overt effects on the testes or suprarenal glands resulted from in utero exposure to flutamide, although permanent effects were noted on accessory sex organs [Adamsson, A. et al., Abst P1-360].

The selective estrogen receptor modulator GSK-232802 offered a well-tolerated approach to the treatment of vasomotor symptoms in otherwise healthy menopausal women [Clark, R.V. et al., Abst P1-316]. Improvements in wellbeing, anxiety, depression and overall quality of life through shiatsu (finger pressure and massage) in menopausal women were paralleled by moderate increases in salivary cortisol levels [Lewicka, S. et al., Abst P1-310].

Secondary precocious puberty in patients with congenital adrenal hyperplasia was successfully controlled with cyproterone without altering adult height in an open-label study [Brito, V.N. et al., Abst P2-697]. On the other hand, stimulation of precocious puberty in experimental animals resulted from acute exposure to genistein [Lee, S.Y. et al., Abst P3-44].

While effective against endometriosis, the gonadotropin-releasing hormone antagonist elagolix had no negative impact on bone mineral density [OBrien, C.F. et al., Abst P3-281]. Efficacy against endometriosis-related dysmenorrhea and dyspareunic and nonmenstrual pelvic pain was reported with a novel progesterone receptor modulator: CDB-4124 [Ruiz, J. et al., Abst OR06-4].

While testosterone replacement has been effective in the management of hypogonadism, with additional benefits on metabolic syndrome [Saad, F. et al., Abst P3-308], oral testosterone supplementation combined with dutasteride improved testosterone availability with low levels of dihydrotestosterone in hypogonadic men [Clark, R.V. et al., Abst P2-355], and pharmacokinetic feasibility was also demonstrated with oral testosterone undecanoate given twice daily [Htun, M. et al., Abst P2-357]. However, other studies suggested preference for transdermal testosterone patches for improving clinical signs and symptoms of hypogonadism [Raynaud, J.P. et al., Abst P2-356], and efficacy was also reported with long-acting testosterone undecanoate injection [Wang, C. et al., Abst P2-358; Zitzmann, M. et al., Abst P3-307]. Note that testosterone undecanoate therapy was further shown to improve exercise-induced cardiac ischemia in patients with stable angina [Malkin, C.J. et al., Abst P3-306]. In addition, novel formulations of external-matrix testosterone for oral delivery were validated, with favorable pharmacokinetics and pharmacodynamic activity in healthy men with experimental hypogonadism [Snyder, C.N. et al., Abst P2-354].

In subjects with persistent hypogonadism and treated macroprolactinoma, clomifene emerged as an alternative to testosterone replacement regarding improvements in sexual function [Formiga-Bueno, C.B. et al., Abst P3-660].

Although diabetes was more specifically addressed during the American Diabetes Association (ADA) scientific sessions held immediately prior to ENDO in New Orleans, as reviewed and summarized in the corresponding report within this website, a number of presentations covering therapeutic issues in diabetes were also discussed during ENDO in Washington.

Although no major news related to insulin therapy for diabetes was presented during this year’s ENDO, intensive insulin therapy in critically ill infants increased resistance to growth hormone [Gielen, M. et al., Abst P3-416], but glucose-targeted intensive insulin therapy was associated with reduced risk for death in the pediatric intensive care unit [Vlasselaers, D. et al., Abst S21-2]. Regarding insulin analogs, mechanistic studies suggested a role for insulin detemir in modulating proglucagon gene expression through interactions with the Wnt signaling pathway [Song, L. et al., Abst P1-437].

While early initiation of therapy in children with newly diagnosed type 2 diabetes was associated with a reduced need for insulin [Raman, S. et al., Abst P3-409], an insulin-sensitizing effect of metformin was related to improvements in insulin-mediated suppression of free fatty acid, without affecting free fatty acid mobilization [Bos, P.R. et al., Abst P2-431]. The agent was noted to revert the antiosteogenic effects of rosiglitazone in experimental animals [Sedlinsky, C. et al., Abst P2-209], and to improve erectile function in nondiabetic patients with insulin resistance [Knoblovits, P. et al., Abst P2-347]. From a mechanistic point of view, metformin was shown to increase sirtuin 1 (SIRT1) and general control of amino acid synthesis-5 (GCN5) levels in obese animal models [Caton, P.W. et al., Abst P2-432].

Hypersensitivity to glipizide in the form of leukocytoclastic vasculitis was noted in one patient [Patel, R.R. et al., Abst P1-138]. Also regarding toxicity of sulfonylureas, severe recalcitrant neuroglycopenia after overdose of glibenclamide was reverted by octreotide therapy [Khor, H.T. et al., Abst P1-132], and the agent also helped in reverting sulfonylurea-induced hypoglycemia in a renal failure patient [Bichala, S. et al., Abst P1-439] as well as profound trimethoprim/sulfamethoxazole-induced hypoglycemia refractory to dextrose administration [Sindler, C.J., Abst P1-440], suggesting potential for related emergency situations.

According to gene mapping studies, coadministration of pioglitazone and metformin could facilitate fat consumption and antiobesity effects in skeletal muscle [Shimizu, H. et al., Abst P2-433] and in fact pioglitazone per se was noted to increase ghrelin secretion after a high-fat meal [Greeley G.H. & Englander, E.W., Abst P3-494]; however, pioglitazone, although not sitagliptin, exacerbated ovariectomy-induced bone loss in experimental animals [Kimmel, D.B. et al., Abst P1-165]. At equivalent glycemic control, pioglitazone, but not metformin increased epicardial and abdominal subcutaneous fat deposits in patients with type 2 diabetes [Jonker, J.T. et al., Abst P1-454], and overall use of thiazolidinediones brought about improvements in hemoglobin A1c levels and blood pressure, but increased body mass index [Satkus, J. et al., Abst P1-455]. Compared to pioglitazone, metformin and sulfonylureas, retrospective real-life data could not attribute an increased risk for coronary artery disease or congestive heart failure-related mortality in patients treated with rosiglitazone [Pantalone, K.M. et al., Abst P1-456].

The benefits of exenatide on glycemic control and body weight in patients with type 2 diabetes were confirmed in new clinical studies [Yarlagadda, M.Y. et al., Abst P1-452]. A further incretin mimetic, liraglutide also demonstrated metabolic benefits in type 2 diabetes patients, with improvements in total cholesterol levels and the prevalence of metabolic syndrome [Pratley, R.E. et al., Abst P3-431].

Experimental results suggesting benefits of dapagliflozin on pancreatic function [Macdonald, R.F. et al., Abst OR24-1] and mechanistic and theoretical rationale for the use of glucokinase activators in the treatment of diabetes [Grimsby, J., Abst S61-1; Akiyama, T.E. et al., Abst P2-429] were discussed, with favorable results in experimental models reported with GSK-1362885 [Thomson, S.A. et al., Abst P2-430]. Also in the experimental arena, inhibition of 11-hydroxysteroid dehydrogenase type 1 with the compound A1 was shown to improve insulin sensitivity in the muscle, offering putative new targets for intervention in diabetes [Morgan, S.A. et al., Abst P3-451].

Additional information related to diabetes and metabolic syndrome included a report according to which testosterone replacement therapy improved hepatic fatty infiltration in type 2 diabetes [Dugdale, C.A. et al., Abst P3-286], a further study that indicated improvements in insulin sensitivity and cholesterol levels in metabolic syndrome patients receiving dietary phytosphingosine supplementation [Snel, M. et al., Abst P2-481] and a report that described spironolactone/hydrochlorothiazide as a beneficial combination for the treatment of nephrogenic diabetes insipidus [Somuri, S. et al., Abst P1-134]. From another perspective, reversal of long-standing type 2 diabetes by caloric restriction was reported in two obese subjects, although durability of such reversal could not be confirmed [Lee, W. et al., Abst P1-467].

Very high doses of intramuscular cholecalciferol (10 MIU/kg) were shown to be safe but effective in the management of vitamin D deficiency in infants and toddlers, with biochemical and radiological normalization of signs [Soliman, A.T. et al., Abst P3-171]. However, prenatal vitamin D supplementation was suggested as an optimal approach for preventing hypovitaminosis [Saadi, H.F. et al., Abst P3-173]. On the other hand, vitamin B₁₂ and folate supplementation were found to effectively prevent bone mineral abnormalities during levodopa therapy for Parkinson’s disease [Lee, S.H. et al., Abst P1-185].

In diabetic patients with hypertension, carvedilol showed superiority over diuretic therapy in lowering blood pressure while also reducing the insulin resistance index [Yanagi, K. et al., Abst P1-447] (Fig. 2). Improvements in oxidative stress and insulin-stimulated skeletal muscle glucose uptake resulted from treatment with nebivolol in experimental animal models [Lastra-Gonzalez, G. et al., Abst P1-592], while the agent was associated with increased myocardial endothelial cell transcytotic vesicle density and reduced mitochondrial biogenesis through anti-oxidative stress activity in additional experimental obesity models [Hayden, M.R. et al., Abst P3-426; Hayden, M.R. et al., Abst P3-428].

Compared to other angiotensin receptor blockers, telimsartan offered greater nephroprotective activity in hypertension and diabetes, with significant decrease in the urinary excretion of liver-type fatty acid-binding protein [Ikeda, S. et al., Abst P2-496]. An anti-stress effect of angiotensin receptor blockers was identified, which was related to regulatory effects on the pariventricular nucleus, pituitary and adrenal gland [Honda, M. et al., Abst P1-583]. On the other hand, experimental results with these agents (candesartan) and with eplerenone (aldosterone receptor blocker) in models of diabetic nephropathy demonstrated similar beneficial effects [Takeda, Y. et al., Abst P1-596]. However, treatment with enalapril was related to a neuroglucopenic stress profile, lowering glucose and triglyceride levels, in experimental animals [Miranda, P.A.C. et al., Abst P1-608].

Antiatherosclerosis activity was reported with calcitriol in experimental animal models [Ish-Shalom, M. et al., Abst P3-162]. Further experimental studies revealed potential for FT-061452, an antioxidant glutathione precursor, in preventing vascular smooth muscle cell apoptosis trough suppression of oxidative stress and c-Jun N-terminalkinase pathway signaling [Sinha-Hikim, I. et al., Abst P1-606], while an additional study with spironolactone revealed protection against myocardial infarction in diabetic, hypertensive animals [Mihailidou, A.S. et al., Abst P3-430].

Although remarkably effective, poor adherence with the guidelines for prescription of statins was suggested in patients with type 2 diabetes, resulting in undertreatment in the vast majority of patients, who according to a Swedish National Registry are not at the recommended LDL-cholesterol target levels for primary or secondary prevention [Berthold, H.K. et al., Abst P1-463].

No effect of simvastatin on apolipoprotein B₁₀₀ could be demonstrated in fasting, nonobese, moderately hypercholesterolemic patients [Berthold, H.K. et al., Abst P1-418].

Extended-release niacin brought about increases in body mass index and fasting blood glucose levels, increasing the likelihood for new-onset diabetes [Swislocki, A.L.M. et al., Abst P1-464].

A number of observations on the effect of pharmacotherapies in obesity and obesity-related cardiometabolic disease were discussed this year at ENDO. Sibutramine induced a preferential effect on perirenal fat, increasing adiponectin levels without modifying resistin or leptin [Xagorari, A. et al., Abst P3-334]. Premeal orlistat markedly reduced postprandial peaks in triglycerides and VLDL after high-fat meals in healthy volunteers [Gabriel, F.S. et al., Abst P3-386]. Administration of rosiglitazone to obese patients improved insulin resistance and adiponectin levels but had no impact on visceral fat inflammation, sleep apnea or resulting sleepiness [Pejovic, S. et al., Abst P3-397]. Compared to placebo, the ghrelin mimetic ibutamoren did not impact on muscular or hepatic insulin resistance or glucose-induced insulin secretion in healthy older volunteers [Nass, R. et al., Abst P3-496]. Cotreatment with bupropion and naltrexone improved the cardiometabolic profile in obese individuals, with rapid weight loss and good tolerability [Pi-Sunyer, F.X. et al., Abst OR18-5].

In experimental studies, the agouti-related protein inhibitor TTP-2515 reduced food intake, body weight gain and adiposity while improving responses to tetraiodothyroxine [Dutia, R. et al., Abst P3-374] while, through inhibition of 11beta-hydroxysteroid dehydrogenase, PF-877423 improved the lipogenic-modulating activity of dexamethasone through interaction with insulin activity on adipocytes [Gathercole, L.L. et al., Abst P3-346]. Interestingly, activation of the cholinergic inflammatory pathway in obesity by the nicotinic alpha₇ receptor agonist GTS-21 reversed obesity-induced insulin resistance in additional animal models [Harris, Y.T. et al., Abst P2-382]. On the other hand, an insulin-mediated effect against preadipocyte mitosis was demonstrated with (-)-epigallocatechin gallate [Ku, H.C. et al., Abst P2-474]. In addition, orexigenic effects resulted from treatment with a pegylated leptin antagonist [Gertler, A. et al., Abst P2-379]. In the in vitro area, the ghrelin receptor blocker JMV-2959 blocked the antilipolytic effect of parent, but not unacylated ghrelin [Mulumba, M. et al., Abst P3-352]. As additional news, a long-acting leptin agonist produced using ligand-receptor fusion techniques was described [Carpenter, B. et al., Abst P1-560] and reported to be undergoing further testing and pharmacokinetic feasibility.

Additional miscellaneous information related to appetite and obesity was presented in a report describing reduction of basal and endotoxin-stimulated ghrelin levels by systemic oxytocin administration [Vila, G. et al., Abst P1-377].

Despite improvements in metabolic parameters and body weight, metformin, orlistat and pioglitazone failed to reduce oxidative stress in obese women with polycystic ovary syndrome [Cho, L.W. et al., Abst P2-314]. However, combinations of metformin with oral contraceptives improved insulin responses to glucose while inducing a more favorable impact on HDL-cholesterol and triglyceride levels [Essah, P.A. et al., Abst P2-231; Baatar, T. et al., Abst P2-323], and oral contraceptives per se improved hirsutism [Mattiello, S. et al., Abst P2-322]. Furthermore, a direct link between the insulin-sensitizing activity of metformin and testosterone levels was demonstrated in postmenopausal women without diabetes [Patel, S.M. et al., Abst OR19-5]. In addition, the activity of metformin on insulin sensitivity and testosterone levels was enhanced by pretreatment with atorvastatin [Sathyapalan, T. et al., Abst P2-318].

Although suppressing insulin secretion in women with polycystic ovary syndrome or obesity, diazoxide had no immediate impact on urinary d-chiro-inositol levels, a marker of insulin action [Wickham, E.P. et al., Abst P2-301].

Potential in polycystic ovary syndrome was suggested for resveratrol, which showed an effect in modulating gene expression in theca-interstitial cells [Wong, D.H. et al., Abst P1-301]. Through activation of AMP-dependent protein kinase, resveratrol stimulated hypothalamic-mediated food intake [Li, B. et al., Abst P1-379].

In postmenopausal osteoporosis, annual intravenous zoledronate treatment was effective in improving and maintaining bone mineral density [Black, D.M. et al., Abst P1-177] and no differences in efficacy were apparent comparing yearly treatment with patients who failed to receive a dose at 12 months [Signore, C.M. et al., Abst P1-176]; zoledronate furthermore offered beneficial effects on bone structure in men on gonadotropin-releasing hormone analog therapy for prostate cancer [Gupta, A. et al., Abst P1-175], and was also related to reduced likelihood for fractures when administered after healing and stabilization of a prior hip fracture in men [Boonen, S. et al., Abst P2-242]. Benefits on bone mass and mineralization resulted from treatment with risedronate in postmenopausal women with primary hyperparathyroidism [Desmukh, M. et al., Abst P1-199]. A fixed combination of alendronate and calcitriol was as effective as alendronate/cholecalciferol in patients with osteoporosis, although the former better lowered parathyroid hormone levels and the latter had a more prominent effect on 25-hydroxyvitamin D₃ levels [Kim, E.K. et al., Abst P1-179]. In the negative side, a recognized risk of jaw osteonecrosis is attributed to bisphosphonates, but according to observations reported during ENDO’09 this could be more frequent in older patients, females and subjects with certain comorbidities, including notably diabetes, those receiving corticosteroids or undergoing dental procedures [Lee, M.S. et al., Abst P1-186].

Denosumab offered a valid alternative to bisphosphonates, with benefits on bone mineral density in bisphosphonate-naive postmenopausal patients or those switching from alendronate [Bone, H.G. et al., Abst OR13-1; Bolognese, M.A. et al., Abst OR13-2].

As a putative alternative, beneficial effects on postmenopausal bone were demonstrated with nitroglycerin [Hoover, D.R. et al., Abst P1-183]. In addition, plyometric exercise improved bone turnover in young men with low energy availability (imbalance between dietary intake and energy expenditure) [Loucks, A.B. et al Abst P2-200].

However, adequate calcium and vitamin D intake remains essential for the control of bone structure, mineralization and turnover, to which extent cholecalciferol was noted to significantly increase serum 25-hydroxyvitamin D in schoolchildren, although not enough to correct seasonal deficiencies during fall and winter, especially in girls [Mirsaeidghazi, S. et al., Abst P3-172].

As an additional comment, a retrospective study confirmed a risk for osteoporosis during treatment with proton pump inhibitors [Gonzales, T. et al., Abst P2-220].

Breast cancer

Tamoxifen was among the hormonal therapies considered in the treatment of estrogen receptor-positive breast cancer [Fourati, S. et al., Abst P2-77], but use of aromatase inhibitors in women with breast cancer was associated with a deterioration of cognitive performance, with loss of delayed memory for word recognition and subjective memory [Mirza, F.S. et al., Abst P1-322]. Mechanistic insight into tamoxifen activity revealed antiestrogenic effects of a metabolite, 4-hydroxy-N-demethyltamoxifen, on the pituitary, with such an effect depending on the activity of CYP2D6 [Gjerde, J. et al., Abst P1-97]; however, resistance to tamoxifen was also considered, and according to new studies was related to alterations in mitochondrial estrogen receptor gamma signaling [Riggins, R.B. et al., Abst P1-47; Pedram, A. et al., Abst P2-82]. As additional comments, tamoxifen and raloxifene, like estradiol, modulated estrogen receptor function in isolated skeletal muscle cells [Dieli-Conwright, C.M. et al., Abst P1-3], whereas experimental in vitro studies in granulose cells revealed noncompetitive aromatase inhibition by rosiglitazone and competitive inhibition by pioglitazone [Araki, T. et al., Abst P3-268]. Additionally, the related peroxisome proliferator-activated receptor-gamma blocker GW-9662 had no effect on estradiol production, but prevented its inhibition by mono-(2-ethylhexyl)-phthalate [Reinsberg, J. et al., Abst P2-67].

In the in vivo experimental setting, prevention of progression of preneoplastic lesions was demonstrated with norgestrel [Benakanakere, I. et al., Abst P1-82]. Chemoprevention in experimental animals was also suggested feasible with the somatostatin analog SOM-230 [Lutitz, S.E. et al., Abst P1-96]. Also in the preclinical arena, different effects were noted for letrozole and alfacalcidol on bone in experimental animals, with the aromatase inhibitor increasing body weight, tibial bone length and longitudinal growth rate, but decreasing total bone volume in the proximal tibial metaphysis, and alfacalcidol having no effect on bone length but increasing trabecular bone volume, osteoblast counts and mineralized surface, with an antiremodeling effect [Yeh, J. et al., Abst P1-170]. Furthermore, nonantiestrogen effects of fulvestrant on matrix metalloproteinase-7 and cysteine-rich secretory protein-1 were identified [Gomes, G.R.O. et al., Abst P3-295]. As a mechanistic side comment, fulvestrant was shown to interfere with embryo implantation in the placenta of COUP-TFII-deficient animal models, revealing a role for estrogen receptors in the control of placentation [Lee, D.K. et al., Abst P2-283].

In the in vitro laboratory, the progesterone receptor blocker RU-486 [Chen, C.C., Abst P1-91], the prolactin receptor blocker G129R [Middleton, L.A. et al., Abst P3-76] and undisclosed ALK5 inhibitors [Kim, D.K. et al., Abst P2-145] suppressed breast cancer stem cells.

Additional studies related to breast cancer demonstrated an effect of rosiglitazone in blocking leptin signaling while inducing direct antiproliferative effects, suggesting beneficial effects especially in obese women with breast malignancies [Ando, S. et al., Abst P1-93].

Adrenal cancer

While benefits on catecholamine levels were attributed to chemotherapy with cyclophosphamide/vincristine/dacarbazine in patients with malignant pheochromocytoma [Tanabe, A. et al., Abst P2-608], activity against somatotroph adenomas was reported with octreotide, E-cadherin levels being related to responsiveness to treatment [Fougner, S.L. et al., Abst P3-693]. In vivo activity against adrenocortical carcinoma xenografts was shown with rosiglitazone [Luconi, M. et al., Abst P3-574] and in vitro activity against adrenocortical carcinoma cell proliferation was demonstrated with the steroidogenic factor-1 inverse agonist 4-(heptyloxy)-phenol [Doghman, M. et al., Abst OR20-5]. Moreover, radiosensitizing potential was shown with mitotane [Stigliano, A. et al., Abst P2-99].

Prostate cancer

Findings in middle-aged men (mean age 59 years) ruled out an effect of transdermal dihydrotestosterone on prostate growth, treatment being devoid of any beneficial or adverse effects on the gland, but revealed consistent decreases in spinal, but not hip bone mineral density [Handelsman, D.J. et al., Abst OR42-5].

In the laboratory, acquired resistance of prostate cancer cells to dexamethasone was related to increased transitional activity of Stat_5a/b signaling proteins involved in the prolactin signaling pathway [Liao, Z. et al., Abst P3-56].

High-dose soy isoflavone supplementation had no impact on cognition, vasomotor symptoms or the quality of life in prostate cancer patients on androgen deprivation therapy [Basaria, S. et al., Abst P1-107].

In vitro activity against prostate cancer cells was demonstrated with the camptothecin analog NSC-606985 [Tan, C. et al., Abst P3-63], while, also in the in vitro area, curcumin was shown to enhance responses to androgen receptor-directed anticancer agents, with potential for reverting castration resistance [Shah, S.A. et al., Abst P1-367].

Thyroid cancer

Radioiodine therapy remains standard for thyroid cancer [Sujana, S. et al., Abst P2-533], but alternatives have been sought. The in vitro activity of everolimus against medullary thyroid carcinoma cell proliferation was documented [Grozinsky-Glasberg, S. et al., Abst P1-517]; similarly, pulsatile treatment with vandetanib and sunitinib induced cytotoxic activity without the need for continuous exposure, suggesting preserved activity with low likelihood for adverse events during clinical treatment [Charalambous, E. et al., Abst P2-519], and in vitro data also suggested potential for tyrosine kinase inhibitors combined with conventional cytotoxic chemotherapy [Charalambous, E. et al., Abst P2-520]. Putative activity in mechanistic experimental studies was suggested for lanreotide and cabergoline [Pivonello, R. et al., Abst P2-103]. A redifferentiation effect of rosiglitazone in restoring radioiodine uptake by radioiodine-negative thyroid carcinoma metastases [Kuhne-Eversmann, L. et al., Abst P2-539] and a cell cycle arresting effect of metformin in thyroid cancer cells [Ooi, M. et al., Abst P2-521] were reported. Activity against follicular thyroid carcinoma cells was demonstrated with tetraiodothyroacetic acid nanoparticles [Yalcin, M. et al., Abst P1-72].

Pituitary tumors

Octreotide induced no effect on residual tumor size in patients with nonsecreting pituitary adenomas after partial surgical resection [Fusco, A. et al., Abst P1-661], and both octreotide and cabergoline induced a fibrotic transformation of invasive Nelson’s tumor resulting in significant reduction of adrenocorticotropin hormone release without inducing effective tumor shrinkage [Abelev, Z. et al., Abst P1-685]. Furthermore, treatment of pituitary adenomas with cabergoline was reported to improve outcomes compared to immediate surgery, while better controlling remaining tumor growth [Attanasio, R. et al., Abst P1-674]. Note that concomitant use of octreotide and long-acting pasireotide in experimental animals prevented hyperglycemia and escape insulin-like growth factor-1 production that occur during octreotide [Schmid, H.A., Abst P2-168]. In the in vitro setting, antiproliferative effects in human pituitary tumor cells were demonstrated with the dopamine-somatostatin chimeric agent BIM-23A760 [Peverelli, E. et al., Abst OR15-4], while everolimus was noted to block insulin-like growth factor-1 effects on tumor cell viability [Zatelli, M.C. et al., Abst P2-113].

Neuroendocrine cancer

Inhibition of cell proliferation and cholecystokinin release by neuroendocrine cancer cells were demonstrated with the somatostatin analog SOM-230 [Dalino Ciaramella, P. et al., Abst P2-102]. Rationale was also provided during the meeting for somatostatin receptor-targeted photodynamic therapy with chlorin e₆-coupled octreotate [Hofland, L.J. et al., Abst OR15-5].

Other malignancies

Scattered experimental information on a number of other types of cancer discussed during ENDO’09 is very briefly summarized in the following patchwork-like section. In vitro effects of everolimus on bronchial carcinoma cell viability were reported [Zatelli, M.C. et al., Abst P2-106]. Activity against renal-cell carcinoma in experimental animal models was demonstrated with tetraiodoacetic acid nanoparticles [Yalcin, M. et al., Abst P1-72]. Suppression of constitutive STAT-3 activation in ovarian and endometrial cancer cells by curcumin was noted [Saydmohammed, M. et al., Abst P2-278]. A glycoprotein extracted from dried Laminaria japonicus showed proapoptotic and antimitotic effects on colorectal cancer cells in vitro in studies that were related to activity on the nuclear factor κ_b/Wnt signaling pathways [Go, H. et al., Abst P1-217; Go, H. et al., Abst P2-139], but stimulated growth of normal gastrointestinal IEC-6 cells in vitro through activity on the mitogen-activated and inositol triphosphate kinase pathways [Go, H. et al., Abst P2-138]. Although without any information related to therapy and outcomes, a theoretical preclinical research study revealed reduced effect of tamibarotene compared to isotretinoin on CD38-mediated leukemia cell adherence to endothelium through delaying CD38 expression [Uruno, A. et al., Abst P1-46].

As an additional issue, glucagon infusion was suggested as an effective approach to hypoglycemia in patients with metastatic insulinoma [Briggs, E. et al., Abst P1-124].

Immunomodulatory effects of Angelica gigas were demonstrated in ovalbumin-sensitized experimental animals [Jung, D.Y. et al., Abst P1-572]. In that same context, potential activity of Cudrama tricuspidata was shown in models of atopic dermatitis [Lee, H.Y. et al., Abst P1-574].

Alterations in uterine gene expression and estrogen receptor-modulating properties were documented after intake of isoflavone-rich diet, without an impact on cell proliferation [Moller, F.J. et al., Abst P3-45]. Further observations in experimental animals suggested potentiation of uterine estradiol activity by exposure to triclosan [Stoker, T.E. et al., Abst P3-54].

Inhibition of neurohypophyseal release of oxytocin and vasopressin resulted from treatment with anandamine in the experimental arena [De Laurentiis, A. et al., Abst P1-640].

Although scarce, low-quality data is available, steroid use in gender transition programs was suggested to cause cardiovascular harm in a meta-analysis of clinical trails [Elamin, M.B. et al., Abst P2-727]. More specifically, androgen use in female-to-male transition was reported as safe, whereas estrogen use for male-to-female transition was confirmed harmful regarding ischemic heart disease and cerebrovascular disease in a further analysis [Asscheman, H. et al., Abst P3-314].

The 11beta-hydroxysteroid deoxygenase inhibitor CC-1961 improved spatial memory in aged animals, suggesting potential for the treatment of cognitive impairment [Sooy, K. et al., Abst OR02-5].

Add-on letrozole improved final height in an adolescent with Behçet’s disease showing steroid-induced growth retardation who was also treated with growth hormone [Kon, Y.C. et al., Abst P1-751].