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Meeting Reports

92nd Annual Meeting of the Endocrine Society
June 19 - 22, 2010
San Diego, California

INTRODUCTION

The sun wasn’t shining that much despite the meeting being held in San Diego, but the interest for news on therapies for hormonal disorders more than make for it to the satisfaction of all attendees, crowding outside of the presentation rooms to at least see the discussions through TV screens when there was no sitting place left inside, which was a common occurrence. Many miscellaneous issues related to endocrine and hormonal diseases and disorders, as well as pharmacological and drug-related issues in endocrinology, were discussed and presented during this meeting, and are summarized in the next few pages. 

DIABETES

Concerning insulin and insulin analogues, three times a day administration of biphasic human insulin proved as effective as basal insulin detemir plus bolus-dose insulin aspart in poorly controlled type 2 diabetes patients, offering a novel alternative for intensified insulin therapy [Bhansali, A. et al., Abst P3-524]. Insulin glargine offered an alternative option, with maintained glycemic benefits without a risk for hypoglycemia in patients with type 2 diabetes and additional cardiovascular risk factors [Blonde, L. et al., Abst P3-256]. However, one case of persistent hypoglycemia was described in a patient undergoing hemodialysis, calling for caution even with the use of insulin analogues in high-risk subjects [Silva, A.M. et al., Abst P3-557]. Continuous subcutaneous infusion of insulin U-500 provided an additional form of intensive therapy, effective for managing obese patients with severe insulin resistance [Yuen, K.C.J. et al., Abst P3-528]. Regarding safety issues, insulin glargine was associated with a malignant glucagonoma in a woman with Prader-Willi syndrome also treated for type 2 diabetes [Noda, M. et al., Abst P1-86], but studies in experimental animals at supratherapeutical doses demonstrated no increase in the incidence of mammary neoplasms [Sandow, J. et al., Abst P3-48].

Use of metformin in the management of type 2 diabetes brought about detrimental effects on vitamin B12 levels [Plodkowski, R.A. et al., Abst P3-515] and in males, resulted in increased testosterone levels [Varanasi, A. et al., Abst P1-400]. Regarding the sulfonylureas, although a retrospective analysis could not demonstrate an increased risk of death, a trend towards increased mortality in patients with coronary artery disease was noted with glipizide and glibenclamide, but was not shared by glimepiride [Pantalone, K.M. et al., Abst P3-518]. Not specifically related to diabetes, the a-glucosidase inhibitor acarbose was effective in preventing severe postprandial hyperglycemia after gastric bypass surgery [Tabatabaeian, L. et al., Abst P1-453]. On a related topic, pramlintide was reported effective in managing glycemia without worsening hypoglycemia in patients with type 2 diabetes and gastroparesis [Houser, D.P. et al., Abst P3-564].

Besides clinical data confirming the benefit of pioglitazone on blood pressure and insulin resistance in patients with type 2 diabetes and metabolic syndrome [Hashimoto, S. et al., Abst P2-541], thiazolidinediones used alone or in combination with metformin or exenatide resulted in reductions in C-reactive protein levels [Varanasi, A. et al., Abst P2-543]. In the mechanistic arena, thiazolidinediones were noted to increase adipogenesis in the bone marrow without directly modifying osteoblastogenesis or osteoclast formation from peripheral blood stem cells [Beck, G.R. et al., Abst P2-185].

Add-on exenatide improved the glycemic control obtained with insulin therapy in type 2 diabetes with an additional trend toward lowering weight [Skugor, M. et al., Abst P3-531]. Furthermore, treatment of two patients with gastric bypass plus exenatide resulted in decreased postprandial hypertriglyceridemia and insulinemia, and reduced late hypoglycemia [Chang Figueroa, S.E. et al., Abst P3-551]. In addition, while exerting a direct effect on appetite-regulating neuropeptides [Dalvi, P.S. et al., Abst P2-252] by improving mitochondrial function and through epigenetic mechanisms, neonatal exenatide increased peroxisome proliferator-activated receptor-γ coactivator-1a (PGC-1a) expression in the liver of experimental animals [Pinney, S.E. et al., Abst OR09-1]. Moreover, a case of remission of diabetes by exenatide in a patient with late-stage morbid obesity with severe insulin resistance and minimal b-cell reserve was reported [Lee, W.A. et al., Abst P3-552].

 

In close relation with exenatide, the agent fused to a recombinant 864-amino acid polypeptide constituting an extended conformation similar to chemical polyethylene glycol, coded VRS-859, offered potential for monthly dosing resulting in glycemic benefits comparable to those obtained with weekly used incretin mimetics [Cleland, J.L. et al., Abst P3-517]. VRS-859 combined with a similar construct with glucagon coded AMX-808, resulted in improved weight and glycemic control in experimental animal models [Cleland, J.L. et al., Abst OR24-4].

In addition, an incretin-based approach and besides the effect on glycemic parameters, liraglutide offered benefits on blood pressure not explained by the effect of the agent on body weight alone [Henry, R.R. et al., Abst P3-514]. A novel glucagon-like polypeptide-1 analogue, LY-2189265 improved hemoglobin A1c levels, body weight, postprandial and fasting glucose levels with a significantly greater impact in Hispanics compared to non-Hispanic Caucasians [Bastyr, E.J. et al., Abst P3-513]. Also concerning incretin-related drugs, novel undisclosed small-molecular-weight glucagon-like polypeptide-1 receptor agonists with potential therapeutic use in diabetes, were tested positive for inducing insulin secretion in vitro [Sloop, K.W. et al., Abst P1-479].

Among the dipeptidylpeptidase-IV inhibitors, saxagliptin was noted to improve oxidative stress and inflammation in obesity, through increased nitric oxide availability and reduced soluble CD40 levels in obese experimental animals [Mason, P.R. et al., Abst P1-487].

Regarding new putative treatment options in development, the sodium-glucose cotransporter-2 inhibitor LX-4211 induced marked, rapid improvements in glycemic control in patients with type 2 diabetes [Freiman, J. et al., Abst OR24-6] (Fig. 1), and the glycogen phosphorylase inhibitor GSK-1362885 effectively suppressed glucagon-stimulated glucose rises in healthy volunteers compared to placebo [Vasist, L.S. et al., Abst OR24-5], while inducing glucose-lowering activity in patients with type 2 diabetes, especially during the night, respecting postprandial glucose excursions [Lin, J. et al., Abst P3-509].


 

Fig. 1. Change in 2-hour postprandial glucose levels in patients treated with LX-4211 or placebo [Freiman, J. et al., Abst OR24-6].

Improvements in glucose tolerance resulted from treatment with the glucosylceramide synthase inhibitor EXEL-0346 [Richards, S. et al., Abst OR06-1]. In the experimental preclinical arena, improvements of glycemic control and insulin sensitivity in models of diabetes and obesity were demonstrated with the leptin receptor agonist [d-Leu4]-OB3 [Megan, A. et al., Abst OP13-6]. Also at the preclinical level, treatment with angiotensin1-7 prevented metabolic syndrome, hepatic steatosis and adipose tissue inflammation in fructose-fed experimental animals [Marcus, Y. et al., Abst P1-419], whereas the peptides nephrilin and anephril inhibited albuminuria in experimental models of diabetic nephropathy [Singh, B.K. et al., Abst P1-488]. An interesting additional observation was that in young obese male individuals, cotreatment with dutasteride, but not anastrozole, enhanced the beneficial effect of testosterone on glucose disposal rate and fat-free mass, suggesting an insulin-sensitizing effect [Liao, P.S. et al., Abst OR42-1], whereas also in male patients, clomiphene resulted in partial sex hormone responses in the case of type 2 diabetes, while normal responses were noted in that of type 1 diabetes [van Gastel, P.M. et al., Abst P3-330]. Improvements in insulin sensitivity brought about by salicylate in animal models of obesity were related to downregulation of 11b-hydroxysteroid dehydrogenase type 1 in omental adipose tissue [Nixon, M. et al., Abst OR30-6]. In that context, the novel 11b-hydroxysteroid dehydrogenase type 1 inhibitor XL-903 was shown to improve glucose tolerance and diet-related obesity in experimental animal models [Dalgard, J. et al., Abst P1-473].

In the preclinical arena, the angiotensin AT2 receptor agonist M-024 prevented diet-induced insulin resistance and downregulated adipocyte differentiation [Shum, M. et al., Abst P1-420], whereas the melanocortin MC4 receptor agonist reduced body weight and improved glucose homeostasis [Kievit, P. et al., Abst P2-257]. The nonretinoid retinol-binding protein-4 modulator EXEL-9767 attenuated diet-induced glucose and insulin elevations, and improved glucose homeostasis [Huang, H. et al., Abst P3-446]. The peroxisome proliferator-activated receptor-δ agonist GW-501516 also improved metabolic and glycemic disturbances in obesity and the myostatin inhibitor PF-809 improved whole-body metabolism and muscle strength [Bernardo, B.L. et al., Abst P1-477]. In addition, an undisclosed dual co-glucagon-like polypeptide-1/gastric inhibitory peptide agonist improved glucose tolerance and fat mass in diet-induced obese animal models [Perez-Tilve, D. et al., Abst P2-511]. In addition, humanized antifibroblast growth factor receptor-1c monoclonal antibody prevented high-fat diet-induced obesity through an effect on hypothalamic glucose sensitivity [Isoda, F. et al., Abst P2-247]. Various additional experimental findings included a study suggesting increased basal energy expenditure with no effect on brown adipose tissue thermogenesis after a high-fat diet, but decreased energy expenditure without an effect on brown adipose tissue thermogenesis after nonfatty diet, in animals treated with dexamethasone [Poggioli, R. et al., Abst P1-36].

Regarding diabetes insipidus, the disease in infants was effectively managed by oral administration of the intranasal formulation of desmopressin [Gutmark-Little, I. et al., Abst P3-324].


 

OBESITY

Orlistat has been developed and is available as a treatment for obesity, although evidence is accumulating of a risk for severe hepatic adverse events that should be monitored [Bali, R. et al., Abst P3-438]. In the case of sibutramine, a case of induction of hyperprolactinemia was reported [Leaes, C.G.S. et al., Abst P1-293]. Effective control of body weight and the overall cardiometabolic risk profile, including lipid levels, glycemic indices and insulin sensitivity was reported with phentermine/topiramate, a fixed drug combination also developed for the treatment of obesity [Garvey, W.T. et al., Abst S19-5]. Other alternatives are available, as summarized below based on presentations and discussions at ENDO 2010.

Excess abdominal fat in patients with HIV infection was consistently reduced by treatment with tesamorelin, with a corresponding improvement in body image and lipid profiles [Falutz, J. et al., Abst OR25-5] (Fig. 2).

Fig. 2. Change in total and non-HDL-cholesterol and triglyceride levels after 26 weeks of treatment with tesamorelin or placebo [Falutz, J. et al., Abst OR25-5].

HIV-associated lipodistrophy was also improved by mecasermin, which also reduced insulin levels [Kim, R.J. et al., Abst P2-173]. Levocarnitine supplementation also improved nonesterified fatty acid levels in HIV-infected patients on highly active antiretroviral therapy [Semrad, A.S. et al., Abst P1-514].

Improvements in body weight and composition in patients with Prader-Willi syndrome were obtained with rimonabant, although such treatment resulted in psychiatric adverse events recommending against its use as a treatment of obesity in the context of that particular genetic disorder [Motaghedi, R. et al., Abst P3-422]. In relation to rimonabant used as a treatment of obesity, treatment continuation with metformin maintained the body weight and metabolic benefits obtained with the cannabinoid receptor blocker [Dawson, A.J. et al., Abst P3-423].

A specific topic related to obesity is overweight and metabolic abnormalities secondary to treatment with antipsychotics, in which respect treatment with ergocalciferol was reported as a safe tool for reducing body mass index and serum cholesterol levels in vitamin D-deficient adolescents receiving second-generation antipsychotics for psychiatric conditions [Nwosu, B.U. et al., Abst P2-726]. In that respect, olanzapine was noted to rapidly induce insulin resistance independently of weight changes in healthy volunteers [Teff, K.L. et al., Abst OR30-3]. In preclinical animal models, risperidone was also associated with metabolic syndrome and a deleterious effect on bone mass [Dick-de Paula, I. et al., Abst P2-187].

Additional miscellaneous observations related to obesity included: a study documenting benefits on angiotensin II-dependent oxidative stress, ultrastructural glomerular hypertrophy, podocytopenia and proximal tubular mitochondrial fragmentation obese animal models treated with nevibolol [Hayden, M.R. et al., Abst P3-462; Habibi, J. et al., Abst P3-464]; demonstration of direct inhibition of angiotensin II-induced oxidative stress in cardiomyocytes after treatment with nebivolol [Pulakat, L. et al., Abst P1-120], which also improved insulin resistance in the skeletal muscle of obese animals [Manrique Acevedo, C.M. et al., Abst P3-474]; and observations of the benefit of garlic on oxidative stress in obese/hypertensive animal models [Hou, D. et al., Abst P3-470]. Finally, experimental animal studies in models of high glucose-induced oxidative stress supported an antioxidant benefit for herbal therapies, including notably Bacopa moniera (brahmi), Terminalia chebula, Terminalia belerica and emblica officinalis [Desai, N.R. et al., Abst P3-472].


DYSLIPIDEMIA

While improving inflammatory responses to a high-fat/high carbohydrate meal when combined with plant polyphenols [Ghanim, H. et al., Abst P3-498], inhibition of hydroxymethylglutaryl-coenzyme A expression and cholesterol biosynthesis resulted from exposure to resveratrol in theca interstitial cells. This effect was favorably enhanced and complemented by simvastatin, which inhibited the enzyme activity while increasing its expression [Wong, D.H. et al., Abst P1-345].

In the context of hypertriglyceridemia, intravenous insulin infusion proved effective for rapidly reducing severely elevated triglyceride, levels while also inducing anti-inflammatory activity [Abdo, T. et al., Abst P1-515].

METABOLIC SYNDROME

A randomized, controlled trial in patients with type 2 diabetes and metabolic syndrome revealed rapid reductions in vascular cell adhesion molecule-1 levels after six weeks of cilostazol, a treatment duration within which no meaningful benefits could be demonstrated on other adipocytokines or arterial stiffness [Kim, H.Y. et al., Abst P2-527].

ACROMEGALY

Without a negative impact on blood glucose levels [Wangnoo, S.K. et al., Abst P3-529], somatostatin analogues such as cabergoline are effective in controlling insulin-like growth factor levels in many acromegaly. The synergistic effect occurs upon cotreatment with pegvisomant, resulting in reduced dose requirements, whereas the combination lacks significant effects on insulin sensitivity or glucose tolerance [Madsen, M. et al., Abst P3-249]. However, treatment of healthy volunteers with pegvisomant transiently elevated insulin levels to compensate for the reduced effect of insulin-like growth factor on the muscle [Berg, C. et al., Abst P3-250]. That pegvisomant was an effective therapy for acromegaly was confirmed in additional studies [Fusco, A. et al., Abst P3-275]. Add-on cabergoline also proved effective for controlling acromegaly in patients not fully responding to somatostatin analogues [Sandret, L. et al., Abst P3-268; Vilar, V. et al., Abst P3-269]. Looking for alternatives, lanreotide depot was reportedly safe and effective for controlling biochemical parameters in most patients with acromegaly [Gordon, M. et al., Abst P3-272]. Favorable pharmacokinetics were documented with a subcutaneous gel, the data supporting potential for extended dosing intervals up to 56 days [Ramis, J. et al., Abst P3-271]. Cotreatment with lanreotide subcutaneous gel and pegvisomant was a further safe alternative, according to additional trial results [van der Lely, A.J. et al., Abst P3-276]. In the mechanistic arena, the effects of lanreotide in acromegaly were mediated by aryl hydrocarbon receptor-interacting protein, the expression of which was noted to be increased in acromegaly [Chahal, H.S. et al., Abst P1-244]. As a novel addition, favorable pharmacokinetics were described in healthy volunteers and patients with acromegaly for the somatostatin receptor agonist BIM-23A760 [Ramis, J. et al., Abst P3-277].

Biochemical control and reduction in tumor volume over the long term were accomplished with pasireotide in patients with acromegaly [Farrall, A.J. et al., Abst OR16-5]. In addition, pegvisomant improved the elevated cardiovascular risk profile associated with acromegaly [Berg, C. et al., Abst OR16-6].

OTHER PITUITARY DISORDERS

Regarding pituitary neoplasms, somatostatin analogues were described effective in the treatment of clinically nonfunctioning pituitary adenomas [Kunert-Radek, J. et al., Abst P1-296]. Cabergoline was found to be effective in inducing tumor shrinkage in cases of giant prolactinoma [Kothapally, J.R. et al., Abst P1-292; Stojanovic, N.D. et al., Abst P3-316], and its use in hyperprolactinemic infertile women resulted in high pregnancy rates [Ono, M. et al., Abst P3-315], although use of the agent in patients with hyperprolactinemia resulted in valvular abnormalities [Tan, T.C. et al., Abst P3-312; Dupuis, P. et al., Abst P3-313]. However, treatment of prolactinoma with cabergoline did not result in apparent improvements in pituitary function [Karavitaki, N. et al., Abst P3-319]. Bromocriptine proved effective in controlling hyperprolactinemia in two patients with cabergoline-refractory prolactinoma [Iyer, P. et al., Abst P1-289] and induced tumor fibrosis more frequency than cabergoline [Menucci, M.B. et al., Abst P3-318]. However, a case of acromegaly acquired during bromocritine therapy for that pituitary tumor was reported [Shafiq, I. et al., Abst P3-279]. Regression of aggressive tumors was safely attained with temozolomide [Bush, Z.M. et al., Abst P1-241], which also showed clinical activity against liver metastases in a patient with a pituitary corticotroph carcinoma [Annamalai, A.K. et al., Abst P2-329]. On a related subject, aggressive pituitary tumors were effectively controlled with temozolomide independently of the degree of expression of O6-methylguanine-DNA-methyltransferase, which was a poor predictor of outcomes [Raverot, G. et al., Abst OR36-6]. In addition, rapid control of hyperthyroidism was obtained with lithium and methamizole in a patient with thyroid-stimulating hormone/growth hormone-releasing pituitary macroadenoma [Raghu, P. et al., Abst P1-294]. As an additional observation, pegvisomant did not impact on growth hormone secretion by cultured somatotroph pituitary adenoma cells [Neggers, S.J.C.M.M. et al., Abst P1-243], whereas cabergoline induced cardiac valvulopathy in a patients with prolactinoma [Siram, A.T. et al., Abst P1-291].

Concerning hypopituitarism, prasterone replacement had no effect on quality of life or insulin action [McHenry, C.M. et al., Abst P1-266], although growth hormone substitution to improve the somatotrope axis immediately after pituitary surgery improved body composition, the metabolic profile and quality of life [Aberle, J. et al., Abst P1-269].

Kisspeptin-54 administration was reported to stimulate reproductive hormone release in women with hypothalamic amenorrhea [Jayasena, C.N. et al., Abst OR39-1].

GROWTH HORMONE DEFICIENCY

Growth hormone replacement is the mainstay approach to the treatment of growth hormone deficiency, with improvements in linear growth in children (including subjects with inflammatory bowel disease) [Wong, S.C. et al., Abst P2-332; Ross, J. et al., Abst P2-336], benefits on bone mineral density in adults with lower baseline density [Tritos, N.A. et al., Abst P2-331] and protection against decline of muscular performance without actually improving muscular strength in the elderly [Gotherstrom, G.N. et al., Abst P2-342]. Nevertheless, growth hormone therapy has been associated with an increased likelihood for developing diabetes [Luger, A. et al., Abst P1-270; Child, C.J. et al., Abst P2-333]. In addition, supplementation with testosterone and growth hormone for 16 weeks in elderly males was not sufficient for improving spinal bone mineral density [Erceg, D.E. et al., Abst P3-174]. In children with growth hormone deficiency and optic nerve hypoplasia but normal height velocity, growth hormone replacement resulted in faster growth, without the slowing noted in untreated matched patients [Vedin, A.M. et al., Abst P1-688].

Early treatment of Turner’s syndrome with growth hormone resulted in increased cortical bone mineral density [Sumnik, Z. et al., Abst OR08-4]. Growth hormone replacement also demonstrated benefits in Prader-Willi syndrome, with improvements in fat and lean body composition [Sode-Carlsen, R. et al., Abst OR25-6] (Fig. 3). Treatment also improved growth in male children and adolescents with Duchenne’s muscular dystrophy and steroid-induced growth failure [Rutter, M.M. et al., Abst OR35-6].


Fig. 3. Change in fat and lean body mass after 1 year of treatment with growth hormone or placebo [Sode-Carlsen, R. et al., Abst OR25-6].

Specific data was reported on the safety and efficacy of mecasermin in prepubertal children with growth impairment. The agent was found to be safe, well-tolerated and effective in improving height velocity [Reiner, B. et al., Abst P2-705]. In addition, a study in short, prepubertal children with low insulin-like growth factor-1 levels documented the synergistic effects of coadministered recombinant human growth hormone and recombinant human insulin-like growth factor levels, without negative pharmacokinetic interactions [Reiner, B. et al., Abst P3-687]. In the context of treatment of short children born small for gestational age, growth hormone therapy improved not only body size, but also follistatin levels and insulin sensitivity, with a favorable impact on adiponectin and triglyceride levels and recovery of subcutaneous fat deposits [Ibanez, L. et al., Abst P3-690].

Besides native growth hormone, favorable pharmacokinetic/pharmacodynamic modeling was described with the pegylated, long-acting derivatives NNC-126-0083 [Klitgaard, T. et al., Abst P2-351] and ACP-001 [Beckert, M. et al., Abst P2-354] developed for weekly administration, whilst a further weekly sustained-release product LB-03002 effectively maintained insulin-like growth factor levels in adults with growth hormone deficiency [Biller, B.M.K. et al., Abst P2-352]. Looking for innovative therapies, a monthly growth hormone extended-half-life construct VRS-317, offered also a convenient, safe and effective approach to the treatment of growth hormone deficiency in preclinical animal models [Cleland, J.L. et al., Abst P2-353].

A novelty in the setting of treatments for growth hormone deficiency presented during ENDO 2010 was the description of the novel oral synthetic growth hormone secretagogue AEZS-130, which besides therapeutic usefulness also offered a diagnostic tool for the disorder [Aicher, B. et al., Abst P2-340].

As an additional issue, cotreatment with recombinant somatropin and mecasermin offered a well-tolerated approach to short stature in prepubertal children with low insulin-like growth factor levels, but normal stimulated growth hormone levels [Midyett, L.K. et al., Abst OR35-5].


VITAMIN D DEFICIENCY

Single, high oral doses of vitamin D3 effectively and rapidly restored 25-dihydroxyvitamin D levels in critically ill patients with vitamin D deficiency [Amrein, K. et al., Abst OR26-6]. Vitamin D3 supplementation also improved vitamin D deficiency in pregnant mothers and their offspring [Saadi, H.F. et al., Abst P1-177].

In addition to the prior information, over the long term, treatment of hypertensive animal models with calcitriol reduced blood pressure and prevented diet-related atherosclerosis [Karen, M. et al., Abst P1-152].

PUBERTAL DISORDERS

Metformin was effectively used for delaying menarche and improving linear growth in low-birth-weight girls with precocious puberty [Ibanez, L. et al., Abst OR43-1]. Gonadotropin-releasing hormone agonists also improved growth in children with central precocious puberty [Lee, H.S. et al., Abst P2-337], leuprorelin depot suppressing the gonadotropin-releasing hormone axis with favorable safety and tolerability [Lee, P.A. et al., Abst P1-698]. Coadministration of leuprorelin and anastrozole also improved linear growth in girls with precocious puberty and compromised growth potential [Papadimitriou, D.T. et al., Abst P3-688].

Regarding delayed puberty, estrogen patches for induction of puberty carried a risk for excess 11b-estradiol, requiring doses limited at 0.05-0.10 mg/kg [Norjavaara, E. et al., Abst P1-700].

POLYCYSTIC OVARY SYNDROME

While new studies corroborated the glycemic and bone composition benefits of metformin on polycystic ovary syndrome patients, with scarce impact on fertility [Ladson, G. et al., Abst P3-381], the positive impact of the agent on hyperandrogenism correlated with changes in salivary androstenedione levels, which arose as a marker of clinical response [Szydlarska, D. et al., Abst P3-384]. However, a survey documented the feasibility of pregnancy after treatment with metformin used alone or with ovulation inducers [Peng, S.Y. et al., Abst P3-391]. Treatment of women with polycystic ovary syndrome with rosiglitazone also brought about improvements in insulin resistance [Tao, T. et al., Abst P1-354].

Amelioration of hyperandrogenism in women with polycystic ovary syndrome with ethinylestradiol/chlormadinone resulted in reduced hirsutism without detrimental effects on glycemia, lipidemia and insulinemia [Romualdi, D. et al., Abst P3-394]. Improvements in circulating androgen levels in women with the disease resulted from supplementation with long-chain ω3-polyunsaturated fatty acids [Phelan, N. et al, Abst P2-398]. Benefits on systemic inflammation and proinflammatory cytokine levels were reported with a combination of metformin and simvastatin [Cress, A. et al., Abst P2-405]. Atorvastatin, on the other hand, reduced androstenedione and dehydroepiandrosterone levels, as well as blood pressure [Raja-Khan, N. et al., Abst P2-417], while improving 25-hydroxyvitamin D levels [Sathyapalan, T. et al., Abst P2-420]. In the in vitro scenario, inositol improved the resistance of erythrocytes from polycystic ovary syndrome patients to oxidative assault [Dona, G. et al., Abst P3-389].

MENOPAUSE

Clinical results were reported during this year’s meeting on the efficacy of bazedoxifene combined with conjugated estrogens, indicating a significant benefit on the frequency of hot flushes compared to placebo [Pinkerton, J.V. et al., Abst P2-424] (Fig. 4). In addition, there were no significant metabolic changes [Mirkin, S. et al., Abst P2-425] or an impact on breast pain [Yu, H. and Mirkin, S., Abst P2-426]. Novel experimental results with bazedoxifene in surgically menopausal animals confirmed that the agent did not attenuate the beneficial effects on concomitant conjugated equine estrogens on vaginal epithelial maturation, but prevented the uterotropic effects of estrogens administered as monotherapy, impacting on endometrial size or vaginal maturation [Ethun, K.F. et al., Abst P2-423].

Fig. 4. Change in the frequency of hot flushes after treatment with bazedoxifene/conjugated estrogens (BZA/CE) or placebo depending on the time since menopause [Pinkerton, J.V. et al., Abst P2-424].

While postmenopausal hot flushes were also improved by the micronized progesterone [Prior, J.C. et al., Abst S19-2] and luteinizing hormone-releasing hormone blocker cetrorelix [van Gastel, P.M. et al., Abst P3-330], the selective estrogen receptor modulator RAD-1901 induced benefits on menopausal symptoms, including notably hot flushes [O’Dea, L.S.L. et al., Abst P1-726] (Fig. 5). Demonstration of pharmacodynamic activity with good tolerability and optimal pharmacokinetics was demonstrated with two additional estrogen receptor modulators, MK-3984 and MK-2866 [Marcantonio, E.E. et al., Abst P2-2]. Mechanistic data with an established drug, raloxifene, demonstrated selective induction of nucleolar translocation of the estrogen receptor [Gushima, M. et al., Abst P3-8].


Figure 5. Change in the frequency of hot flushes in menopausal women receiving RAD-1901 or placebo [O’Dea, L.S.L. et al., Abst P1-726].

Ultra-low-dose estradiol replacement for treating vaginal atrophy in menopausal women did not result in changes in plasma levels of estradiol over the midterm, and did not increase the incidence of endometrial hyperplasia/carcinoma [Simon, J. et al., Abst OR07-3]. Improvements in weight gain and bone marrow adipocyte counts in ovariectomized animals were demonstrated after supplementation with vitamin D, combined with resveratrol, quercetin and genistein [Lai, C.Y. et al., Abst P2-191].


POSTMENOPAUSAL AND PRIMARY OSTEOPOROSIS

Bisphosphonates have a well established role in the treatment of postmenopausal osteoporosis, offering a cost-effective approach regardless of the patients’ age [Pham, A.N. et al., Abst P3-170]. Bisphosphonates were also an effective therapy for osteoporosis in youngsters with Duchenne’s muscular dystrophy [Sbrocchi, A.M. et al., Abst P3-176], in the case of pamidronate with efficacy reported in spastic quadriplegia and other neuromuscular disorders [Bowden, S.A. et al., Abst P3-177]. Both bisphosphonates and teriparatide also proved effective for preventing bone loss after small bowel transplantation [Gupta, N. et al., Abst P3-171]. Risedronate also showed efficacy for preventing bone loss after liver transplantation [Guadalix, S. et al., Abst P3-172]. Among the bisphosphonates, use of zoledronate to treat postmenopausal osteoporosis was associated with a risk of rhabdomyolysis [Schaefer, M.W. et al., Abst P2-205].

Treatment of postmenopausal osteoporosis with denosumab significantly improved bone mineral density and bone turnover marker levels [Miller, P.D. et al., Abst S19-1] but did not bring about negative effects on total or LDL-cholesterol [Bolognese, M.A. et al., Abst P1-513]. Mechanistic results in preclinical animal models corroborated the beneficial effect of denosumab on bone loss and vascular calcium deposition [Hofbauer, L.C. et al., Abst P2-189]. An additional putative therapy for osteoporosis, odanacatib was studied in a phase III study, the baseline demographics and design of which were presented as a poster in San Diego [Bone, H. et al., Abst P3-175].

Ethanolic extracts of undisclosed Korean plants were also demonstrated of benefit for preventing glucocorticosteroid-induced osteoporosis in in vitro and in vivo experimental models [Yoon, H.Y. et al., Abst P2-192]. Osteoprotective effects in other contexts were demonstrated in additional experimental studies with alfacalcidol in systemic chronic inflammation [Shen, C.L. et al., Abst P2-193] and nandrolone in spinal cord injury [Qin, W. et al., Abst P2-196].

In addition to the prior news on osteoporosis, teriparatide improved healing in tibial nonunion fractures in two children [Brodsky, J.L. et al., Abst P2-235].

OTHER MISCELLANEOUS NEWS ON GYNECOLOGICAL AND FEMALE SEXUAL AND HORMONAL DISORDERS

Dienogest was confirmed active in decreasing gonadotropin and estradiol levels in women with endometriosis, suggesting potential use in therapeutics [Hiraike, H. et al., Abst P3-403].

Preclinical experimental results were presented documenting the potential of the G-protein-coupled follicle-stimulating hormone receptor allosteric modulator ADX-61623, for suppressing follicle-stimulating hormone-induced progesterone production while increasing estradiol production [Dias, J.A. et al., Abst OR-LB5].

Selective activation of estrogen receptor-b was noted with the natural compound 3,3’-diindolylmethane isolated from cruciferous plants, although the effect depended on receptor recruitment and coactivation rather than direct binding to the receptor [Viva, O.I. et al., Abst P1-18].

A woman with ovarian virilization treated with long-acting leuprorelin depot showed persistent response, with decreases in testosterone levels and facial and body hair [Raj, R. et al., Abst P1-376]. Regarding feminization but in the experimental arena, testosterone improved inflammation and prevented the progression of early atherosclerosis [Kelly, D.M. et al., Abst P-519].

Independently of cholesterol levels, simvastatin directly inhibited proliferation of cells in the theca, at least in part by stimulating apoptosis [Sokalska, A. et al., Abst OR39-4]. On the contrary, metformin facilitated follicular growth by increasing glucose uptake and metabolism through an effect on insulin signaling [Rice, S. et al., Abst OR-39-5].

As miscellaneous additional information regarding female hormones, metformin enhanced luteal body emergency during hypernadrogenic conditions [Mahamed, R.R. et al., Abst P1-353] while tacrolimus and sirolimus were shown to reduce the activity of estradiol in normal female animals [Shivaswamy, V. et al., Abst P1-336].

ADRENAL DISORDERS

Although with a risk for chronic hypercortisolism [Petersenn, S. et al., Abst P1-273], pasireotide has been effective in the treatment of Cushing’s disease [Boscaro, M. et al., Abst P1-274], and a stepwise approach to the treatment of the disease with pasireotide, cabergoline and ketoconazole was proposed that resulted in biochemical remission in almost 90% of patients [Feelders, R.A. et al., Abst OR14-6]. In addition, observations in one patient suggested potential for add-on mifepristone against refractory Cushing’s disease [Dunnigan, E.E. et al., Abst P2-326]. Note that pasireotide had no effect on hyperglycemic responses to stress [Guimaraes, J. et al., Abst P1-198]. In the preclinical scenario, experimental results suggested potential for inhibition of epithelial growth factor receptor signaling, for controlling adrenocorticotropin in Cushing’s syndrome, was demonstrated in vitro with gefitinib [Fukuoka, H. et al., Abst P1-613]. In the treatment of nonmalignant macronodular adrenocortical hyperplasia with subclinical Cushing’s syndrome, propranolol with hemiadrenalectomy was reported effective in at least one case [Mouri, M. et al., Abst P3-677]. As an additional topic related with Cushing’s disease, etomidate was reported effective in the management of a child with severe disease resulting in hypercortisolemia-triggered acute psychosis [Chan, L.F. et al., Abst P2-738], and was also a feasible option in a patient with ectopic adrenocorticotropic syndrome with disseminated Nocardia farcinica infection [Kiseljak-Vassiliades, K. et al., Abst P3-98].

Concerning Addison’s disease, increases in bioavailable cortisol were noted after consumption of grapefruit and licorice because of inhibition of CYP3A4, reducing 11b-hydroxysteroid dehydrogenase activity and/or increasing absorption [Methlie, P. et al., Abst P2-669]. Overall, cortisol replacement in adrenal insufficiency with doses adjusted based on body weight and individual pharmacokinetic profiling was described as an effective therapeutic strategy [Simonsson, U.S.H. et al., Abst P2-677].

Regarding suprarenal tumors, while use of mitotane in the treatment of adrenocortical carcinoma was associated with impaired platelet aggregation [Hahner, S. et al., Abst P2-663], clinical data was reported suggesting a benefit of [131I]-metaiodobenzylguanidine in the treatment of pheochromocytoma [Soggia, A.P. et al., Abst OR14-3]. In the preclinical arena, results suggesting growth-inhibitory potential for the cytotoxic somatostatin analogues AN-238 and AN-162 [Moreno, M. et al., Abst P1-63; Ziegler, G.C. et al., Abst P1-65], and methoxyestradiol and its analogue ENMD-1198 [Casula, S. et al., Abst P1-67] against pheochromocytoma and adrenal carcinoma were shown. On related subjects, [131I]-iobenguane offered a well tolerated palliative management in a patient with recurrent paraganglioma in the urinary bladder [Ko, S.H. et al., Abst P1-88].

Miscellaneous additional news on adrenal function and disease included a report suggesting enhanced leptin-induced inhibition of steroidogenic acute regulatory protein and adrenocorticotropin receptor expression after prenatal exposure to betamethasone [Su, Y. et al., Abst P1-615]. On a related topic, usual doses of hydrocortisone used for preventing adrenal crisis during surgery-related stress were suggested to be excessively high for the actual cortisol demands [Karavitaki, N. et al., Abst P3-647].

THYROID DISORDERS

Levothyroxine replacement in elderly patients with hypothyroidism was associated with an increased risk for nontraumatic fractures, suggesting the need to avoid overdosing [Turner, M.R. et al., Abst P2-597], whereas absorption of the hormone was impaired in patients taking calcium supplements [Zamfirescu, I. et al., Abst P3-586]. Precipitation of overt hypothyroidism was described in patients with subclinical thyroid failure receiving dietary soy phytoestrogens [Sathyapalan, T. et al., Abst P3-584].

Randomized data confirmed the ablative activity of radioiodine against differentiated, thyroglobulin-positive thyroid cancer [Bal, C.S. et al., Abst OR22-3; Ali, S. et al., Abst P1-564], although severe hyponatremia following low-iodine diet prior to radioiodine therapy was described [Al Nozha Alzoghaibi, O.M. et al., Abst P1-611]. Furthermore, sorafenib was described as a feasible option as demonstrated in a case of hypoxemia and severe diffuse nodular respiratory failure due to metastatic papillary thyroid carcinoma, without negatively affecting uptake of subsequent radioiodine [Iyer, P. et al., Abst P3-93].

As miscellaneous news, a case of ipilimumab-related Graves’ ophthalmopathy [Min, L. et al., Abst P2-606] and one of carbimazole-induced myositis in a patient with Graves’ disease [Lim, A.Y.Y. et al., Abst P2-613] were reported. While amiodarone in patients with congenital heart disease was associated with thyrotoxicosis [Stan, M.N. et al., Abst P3-598], sunitinib [Muralidhara, K. et al., Abst P3-587] and thalidomide [Haase, A.Q. et al., Abst P3-589] used for treating malignant diseases and glatiramer/interferon b in the treatment of multiple sclerosis [Cheng, V. et al., Abst P3-590] were related with thyroid dysfunction. In addition, lansoprazole was causally related with hypocalcemic seizures in a patient with a history of thyroidectomy [Milman, S. et al., Abst P2-206], while a case of hepatotoxicity after therapeutic doses of paracetamol in a patient with severe hypothyroidism was reported [Ayoub, W.A. et al., Abst P1-607].

MALE HYPOGONADISM

Testosterone gel offered a pharmacokinetically feasible, safe option for the treatment of male hypogonadism, according to studies reported during ENDO2010 in San Diego [Kaufman, J.M. et al., Abst P2-442; Kaufman, J.M. et al., Abst P2-443; Miller, J. et al., Abst P2-447] (Fig. 6). However, additional explorations indicated lower bioavailability with the gel applied on the abdomen compared to upper arm or shoulder [Miller, J. et al., Abst P2-444]. The exposure was increased by concomitant application of moisturizers or sunscreen [Miller, J. et la., Abst P2-445], and minimally reduced by washing of the application area 2-10 hours after treatment [Miller, J. et al., Abst P2-446].

Fig. 6. Eugonadal testosterone rates during 182 days of treatment with testosterone gel or placebo [Kaufman, J.M. et la., Abst P2-443].

Intramuscular testosterone decanoate also proved safe and feasible for treating male hypogonadism, with a notable positive impact on the patients’ cardiovascular risk [Zitzmann, M. et al., Abst P2-448; Zitzmann, M. et al., Abst P2-449]. Over the long term, such treatment resulted in an increase in prostate size and prostate-specific antigen levels, but not urinary tract symptom-related bother [Saad F. et al., Abst P2-450]. A new oral testosterone undecanoate formulation was also developed, with effective bioavailability after twice-daily dosing even if taken in a fasted state, although dietary fat improved absorption [Yin, A. et al., Abst P2-451].

Additional observations on testosterone for hypogonadism indicated an inverse correlation between serum levels and concentrations of cardiovascular risk markers, but not cytokines [Dillon, E.L. et al., Abst P2-452], while used with growth hormone, co-supplementation resulted in sustained benefits on body composition and muscle strength in elderly males [Sattler, F.R. et al., Abst P2-453], especially if obese, in whom metabolic improvements were also noted [Allan, C.A. et al., Abst P2-455]. However, the benefits of testosterone on muscle strength, lean mass and quality of life in frail elderly people were not maintained six months post-treatment [O’Connell, M.D.L. et al., Abst P3-336]. Testosterone supplementation also improved both hypogonadism and Crohn’s disease activity in patients with said comorbidity [Haider, A. et al., Abst P2-106]. Indeed, testosterone replacement in hypogonadic men resulted in improvements in total and LDL-cholesterol, but not HDL-cholesterol levels, blood pressure or body weight [Muraleedharan, V. et al., Abst P1-397]. On the other hand, testosterone supplementation for up to five years was not associated with an increased risk of prostate cancer [Yassin, A.A. et al., Abst P2-456].

Improvements in prostate size and prostate-specific antigen levels in hypogonadal males with benign prostatic hyperplasia receiving testosterone replacement were obtained with dutasteride [Hirano, L.A. et al., Abst OR17-4]. Similarly, improvements in erectile function in males with hypogonadism were safely attained by cotreatment with vardenafil and testosterone [Yassin, A.A. et al., Abst P1-385].


MALE REPRODUCTIVE ORGANS AND DISORDERS

Studies in experimental animals indicated that ganciclovir induced apoptosis of Sertoli and germ cells [Iino, K. et al., Abst P3-338]. In that context, exposure to curcumin resulted in inhibited testicular 17b-hydroxysteroid dehydrogenase-3 activity [Hu, G.X. et al., Abst P3-347]. Furthermore, perinatal exposure to soy isoflavones in male animals resulted in elevated adiponectin levels during adulthood, with the consequent negative impact on Leydig cell testosterone output [Thomas, T. et al., Abst P2-77], whereas in the postnatal period, treatment of young animals with exemestane translated into reduced testicular weight and Sertoli cell numbers [Cappon, G.D. et al., Abst P2-748]. Disruption of reproductive tract gene expression during pregnancy resulted from prenatal exposure to genistein [Jefferson, W.N. et al., Abst P2-76].

TRANSSEXUALITY

Treatment with testosterone improved physical strength and tended to increase lean mass, while decreasing waist circumference in female-to-male transsexuals [Pelusi, C. et al., Abst P2-107], without modifying insulin resistance. Cotreatment with dutasteride had no impact on the effects of testosterone [Armillotta, F. et al., Abst P2-105].

NONGLANDULAR MALIGNANCIES

While aromatase inhibitors such as letrozole and anastrozole, with proven benefits on breast cancer, were associated with frequent bone loss [Taxel, P. et al., Abst P2-56]. However, with this therapy frequent resistances were predicted by a novel gene microarray signature [Moy, I. et al., Abst P2-57], whereas coexposure to tamoxifen and metformin improved the degree of inhibition of aromatase, expanding the activity to tamoxifen-resistant breast cancer cells [Berstein, L.M. et al., Abst P3-52]. Note that by reducing estradiol levels, the drop in negative feedback on the hypothalamic-pituitary axis brought about by letrozole resulted in increased amplitude, but not frequency, of the hypothalamic-pituitary drive in healthy women [Kucherov, A. et al., Abst OR07-5].

Future improvements in breast cancer therapy were suggested based on demonstration of the effects of small-molecular-weight progesterone receptor blockers [Aninye, I.O. et al., Abst P1-20] and the phytoestrogen fisetin [Sanchez, A.L. et al., Abst P2-49] on cultured tumor cells, and the effect of ALK5 inhibitors on tumor spreading and metastasis formation [Son, J.Y. et al., Abst P1-57]. Moreover, through upregulation of cyclic AMP levels and activation of AMP-dependent kinases, exenatide also inhibited breast cancer cell growth [Rubinek, T. et al., Abst P3-45]. In addition, demonstration that ulipristat decreased epithelial growth factor-mediated tyrosine activation of epithelial growth factor receptor and downstream components in breast cancer, but not normal human mammary epithelial cells, suggested potential health benefits that should be explored in future studies [Hwang, K. et al., Abst P2-52]. Opposed effects on malignant and normal breast cancer cells were also demonstrated with progesterone and medroxyprogesterone, which had mild proliferative activity on healthy cells but antiproliferative activity on malignant cells, suggesting additional potential use in therapeutics and chemoprevention [Courtin, A. et al., Abst P2-53]. Finally, by interfering with insulin pathways through inhibition of mammalian target of rapamycin, sirolimus prevented breast tumor cell progression in animal models of type 2 diabetes, further expanding new avenues for research [Fierz, Y.C. et al., Abst OR12-4].

Prostate cancer is also a candidate for hormonal intervention, and the novel antiandrogenic compound DIMN showed activity in vitro suggesting potential for chemoprevention to delay development and progression of such tumors [Song, C.H. et al., Abst P2-38]. Activity in preclinical models of prostate cancer was also reported with a combination of pasireotide and everolimus [Schmid, H.A. et al., Abst P2-39], the 17b-hydroxysteroid dehydrogenase type 3 inhibitor STX-2171 [Day, J.M. et al., Abst P2-41] and undisclosed 17,20-lyase inhibitors [Rafferty, S.W. et al., Abst P2-43]. Against prostate cancer bone metastases, a glyceric acid-alendronate conjugate was described [Weinstein, B.M. et al., Abst P2-40]. A pharmacological characterization of androsta-1,4,6-triene-3,17-dione as an aromatase inhibitor with potential as an antiandrogen agent was also reported during the meeting [Parr, M.K. et al., Abst P3-39].

Regarding complications of androgen deprivation in prostate cancer, contrary to testosterone, the selective androgen receptor modulator MK-0773 did not overcome leuprorelin-based, chemical castration-induced loss of bone mineral density in healthy elderly men, suggesting no potential for avoiding testosterone in patients at risk for bone loss during androgen deprivation therapy [Stoch, S.A. et al., Abst OR08-5]. Binding of the selective androgen receptor modulator LGD-4033 to the androgen receptor ligand-binding domain resulted in conformational changes that alter the protein-protein interactions of the receptor and its activity [Marschke, K.B. et al., Abst ORO01-3]. Novel undisclosed small-molecules, androgen receptor blockers, acting outside from the ligand-binding pocket were announced [Cherian, M.T. et al., Abst P2-6]. As an additional topic, high-dose isoflavone supplementation did not improve the metabolic abnormalities resulting from androgen deprivation in patients with prostate cancer [Napora, J. et al., Abst P3-51]. In that context, comparing three natural isoflavones, luteolin showed higher affinity for the estrogen receptor-b compared to -a, whereas spinacetin and patuletin showed poor binding affinity for both estrogen receptors [Starkey, N.J.E. et al., Abst P3-71].

Regarding other malignancies, adjunctive intranasal calcitonin was reported effective in the management of giant cell tumors of the jaw [Harindhanavudhi, T. et al., Abst P2-226]. In the case of colon cancer, preclinical observations suggested potential for a Laminaria japonica glycoprotein [Go, H. et al., Abst P1-71], while other in vitro studies revealed the proapoptotic activity of Hizikia fulvescens glycoprotein in hepatoma cells [Ryu, J.A. et al., Abst P1-72]. As an additional note, the activity of the histone deacetylase inhibitor MS-275 against hepatoblastoma cells involved downregulation of insulin-like growth factor-binding protein-3-mediated signaling [Lin, W.H. et al., Abst P3-118]. Miscellaneous anticancer activity was attributed to metformin and acadesine through activation of AMP-dependent protein kinase and inhibition of p70S6K [Ooi, M. et al., Abst P1-524], and to 20S-hydroxyvitamin D3, which showed antiproliferative activity against various malignant cells without causing hypercalcemia [Li, W. et al., Abst P3-43].

MISCELLANEOUS

Treatment of anorexia nervosa with selective serotonin reuptake inhibitors negatively affected bone mineral density in adolescent and young adult women [Misra, M. et al., Abst OR08-3]. By exerting mixed agonist and antagonist activity on estrogen-b receptors, ICI-182780 decreased serotonin transporter and 5-HT1B receptor expression in serotonergic neurons [Hengen, N. et al., Abst P1-11].

Upregulation of epithelial growth factor receptor expression and inhibition of estrogen receptor-related receptor-a resulted from treatment with the cannabinoid receptor type 1 blocker AM-251 [Fiori, J.L. et al., Abst P1-3].

Mifepristone was mechanistically shown to stabilize the serine249-phosphorylated progesterone receptor, preventing degradation and cycling, hence impacting on target gene promoter activation [Ali-Khan, J. et al., Abst P1-22].

A protective effect of nandrolone against denervation-induced atrophy was related with upregulation of Wnt activity and inhibition of Notch signaling, resulting in accumulation of myogenic differentiation factor D [Liu, X.H. et al., Abst P1-41].

As opposed to younger patients with spinal cord injuries, baclofen did not increase insulin-like growth factor-1 levels in healthy elderly individuals [Tsitouras, P.D. et al., Abst P2-174].

Studies in pregnant animals demonstrated the teratogenesis of propylthiouracyl and methimazole, which resulted in skull and cardiac defects in the offspring [Benavides, V.C. et al., Abst P2-595].

Fludrocortisone was effective in the management of a case of postural orthostatic tachycardia syndrome [Maaske, J. et al., Abst P2-661], whereas fluticasone propionate use in a child with asthma triggered an acute adrenal crisis [Santiago, A.E. et al., Abst P2-736].