New and old therapies for endocrine diseases: A report from the annual meeting of the Endocrine Society

INTRODUCTION

By X. Rabasseda

Shortly after the American Diabetes Association, San Francisco was again the site for this year’s meeting of the U.S. Endocrine Society, during which not only diabetes, but other endocrine diseases captured the attention of scientists worldwide seeking improved therapies for very common diseases.

DIABETES

Insulin is the mainstay in the treatment of diabetes, with data to suggest safety and efficacy at a lower cost than insulin analogs when used as a treatment for type 1 diabetes [Guevara-Aguirre, J. et al., Abst OR56-3]. Insulin is also used in hospitalized patients to control for hyperglycemia, even in non-critically-ill situations [Pietras, S.M. et al., Abst P2-398], but intensive therapy has been associated with severe hypoglycemia, although improvements in glycemic control with lower risk of hypoglycemia can be obtained with controlled continuous subcutaneous insulin infusion [Fatourechi, M.M. et al., Abst OR26-6]. Low risk of hypoglycemia has also been attributed to insulin analogs, including insulin glargine, which was successfully used with evening dosing for preoperative glycemic control in diabetic patients scheduled for surgery [Dukatz, T. et al., Abst OR56-6]. However, insulin therapy may be related to an increased risk for hypoglycemia, and even when using insulin glargine, hypoglycemia should be anticipated in cases of prolonged, sustained exercise [Dawrant, J.M. et al., Abst P1-276]. Using mealtime insulin lispro, lower reductions in hemoglobin A_1c were obtained in Hispanic and South Asian individuals compared to Caucasian patients, but the effect could be dependent on baseline factors such as age and prior glycemic control [Davidson, J.A. et al., Abst P2-392].

However, oral medications to avoid injection of insulin have been developed that offer improvements in glycemic control over the long term with less tendency for obesity [Swislocki, A.L.M. et al., Abst P1-328]. Even in nondiabetic, overweight children, metformin was associated with decreased hunger, resulting in body weight loss and decreased insulin resistance [Sorg, R.A. et al., Abst P3-228; Yanovski, J.A. et al., Abst OR25-5] (Fig. 1); reduced food intake was confirmed in a retrospective analysis of 32 nondiabetic men with hyperinsulinemia [Mogul, H.R. & Peterson, S.J., Abst P3-229] and additional experimental animal studies, in which it was related to interferences with the regulation of hypothalamic neuropeptide Y [Aubert, G. et al., Abst P3-190]. Furthermore, while experimental results suggested an effect of metformin in improving bone marrow mesenchymal progenitor cell differentiation to osteoblasts [Molinuevo, M.S. et al., Abst P3-392], the combination with rosiglitazone improved the negative adipogenic effects on bone of the thiazolidinedione [Sedlinsky, C. et al., Abst P3-391]. Additionally, metformin showed activity in improving autoimmune hypoglycemia, through an effect on circulating free insulin levels [Miranda, L.M. et al., Abst P1-321]. However, lactic acidosis associated to metformin has been reported, which pathophysiologically was related to pancreatitis [Innerfield, R.J., Abst P1-323].

Fig. 1. Change in the HOMA insulin resistance index in overweight, insulin-resistant children treated with metformin or placebo for 6 months [Yanovski, J.A. et al., Abst OR25-5].

Among the sulfonylureas, repaglinide showed efficacy in correcting glucose homeostasis in a diabetic woman with Turner’s syndrome [La Rosa, C. & Conway, G., Abst P1-264].

The benefits of pioglitazone in the treatment of diabetes have been further confirmed in studies and registries reported this year at ENDO [Mundi, M.S. et al., Abst Ps-396]. Furthermore, while improving insulin sensitivity, decreasing VLDL and increasing adiponectin levels in obesity [Florez-Villavicencio, Y. et al., Abst P2-529], low-dose pioglitazone was related to improved body adiposity in women with androgen excess [Ibanez, L. et al., Abst P1-587]. Experimental studies confirmed a role in diminishing abdominal adiposity [Whigham, L.D. et al., Abst P2-488]. In relation to that, studies with pioglitazone, rosiglitazone and troglitazone revealed no effect on fat deposition in lipodystrophic areas in patients with familial partial lipodystrophy, but exacerbation of fat deposition in nonlipodystrophic regions [Simha, V. et al., Abst P1-326]; on the other hand, troglitazone and rosiglitazone induced apoptosis and inhibited hormonal secretion in pituitary tumor cells [Feelders, R.A. et al., Abst P3-770], while rosiglitazone lowered serum alkaline phosphatase levels and hematocrit [Padmanabhan, H. et al., Abst P1-508] and increased bone resorption in women [Ghayee, H.K. et al., Abst OR47-1].

With similar improvements in the overall glycemic control, exenatide improved acute-phase insulin responses to a meal [Maggs, D. et al., Abst OR56-5] and lowered postprandial glucose excursions more effectively than biphasic insulin aspart in a cohort of 463 patients with type 2 diabetes [Brodows, R.G. et al., Abst P1-262], and in patients with metabolic syndrome induced benefits on weight, abdominal girth and the overall cardiovascular risk profile [Bhushan, R. et al., Abst P1-261]. In mechanistic studies, the glucagon-like polypeptide-1 analog normalized epigenetic modifications at the proximal PDX-1 promoter, which has been linked to the increased risk for type 2 diabetes after intrauterine growth retardation [Pinney, S. et al., Abst OR37-2]. A pegylated formulation of exenatide showed potential as a treatment for metabolic syndrome in experimental animals [Choi, M.C. et al., Abst P1-207]. A further incretin analog, liraglutide also improved glycemic control in patients on oral antidiabetic therapy [Ratner, R.E. et al., Abst OR56-4] (Fig. 2). Regarding alternative incretin mimetic options, a glucagon-like polypeptide-1_7-36 amide offered activity in decreasing interleukin-6 without altering leptin and adiponectin levels in type 2 diabetes, obese patients [Daousi, C. et al., Abst P3-458], CNTO-736 improved insulin resistance and the lipid profile in high fat-fed experimental animals [Parlevliet, E.T. et al., Abst OR5-3] and exendin(9-39) corrected fasting hypoglycemia in animals lacking the sulfonylurea receptor through a direct effect on insulin secretion [De Leon, D.D. et al., Abst OR37-4].

Fig. 2. Change in hemoglobin A1c levels upon addition of liraglutide, rosiglitazone or placebo to glimepiride in the LEAD studies [Ratner, R.E. et al., Abst OR56-4].

Miscellaneous information on antidiabetic-like activity of other drugs and drug families included a report on improvements in glycemic control and reduced insulin requirements in a man with type 1 diabetes receiving octreotide long-acting injection [Bonucchi, J.T. et al., Abst P1-304] and results of an experimental study in which the immunomodulator oligonucleotide IMT-504 improved hyperglycemia, polyphagia, polydipsia and islet morphology [Bianchi, M.S. et al., Abst P2-373]. On the other hand, miglitol showed usefulness for postgastrectomy dumping syndrome in type 2 diabetes patients [Fujimoto, M. & Tanaka, Y., Abst P2-379] and phenylmethimazole was shown to reverse plasminogen activator inhibitor-1 overexpression in experimental diabetic animals [Monaco, F. et al., Abst P2-538]. Further experimental studies suggested activation of insulin receptor signaling with 6Cl-TGQ, an antidiabetic-like drug currently under preclinical research [Cao, Y. et al., Abst P1-119].

Regarding additional issues, insulin increase in diabetes has been related to body mass gains which, according to observations in four female patients, were attenuated by oral leucine supplementation [Desikan, V. et al., Abst P1-278].

DYSLIPIDEMIA AND METABOLIC SYNDROME

Fibrates are effective in controlling lipid levels, and addition of fenofibrate to rosiglitazone in type 2 diabetes patients already on statin therapy brought about decreases in triglyceride and non-HDL- and total cholesterol levels compared to placebo [Dhindsa, S. et al., Abst P2-326] (Fig. 3).

Fig. 3. Change in HDL-, LDL-, VLDL- and total cholesterol levels after 16 weeks of adding fenofibrate or placebo, combined with rosiglitazone, in patients already on statin therapy [Dhindsa, S. et al., Abst P2-326].

The lipid benefits of statins are known, and statins are currently widely used in people at increased cardiovascular risk, including notably the diabetic population, although real-world data suggest suboptimal lipid control due mostly to lack of treatment reviews by health care professionals [Santosh, H.S. et al., Abst P2-335]. Data on the pleiotropic effects of statins discussed during ENDO ‘08 included positive modulation of plasminogen activator inhibitor-1 levels by rosuvastatin and pitavastatin [Monden, T. et al., Abst P2-325] and anabolic effects of simvastatin in bone through antagonism of tumor necrosis factor-α-mediated inhibition of bone morphogenic protein-2-induced osteoblast differentiation [Otsuka, F. et al., Abst P3-389]. Specific studies with pitavastatin also revealed an effect in increasing the high-molecular-weight:total adiponectin ratio, further adding to the antiatherogenic properties of the agent [Yoshioka, K. et al., Abst P2-322].

Exploratory data reported during the meeting suggested age-, race- and baseline LDL-cholesterol-, triglyceride- and non-HDL-cholesterol-dependent activity of ezetimibe/simvastatin and atorvastatin on LDL-cholesterol levels regardless of the presence of metabolic syndrome [Goldberg, R.B. et al., Abst P2-327], with ezetimibe/simvastatin offering greater reductions in all LDL subparticles than equivalent doses of atorvastatin [Mazzone, T. et al., Abst P2-328].

Other agents able to improve lipid profile include the bile acid sequestrant colestilan, which regardless of lipid changes also decreased free triiodothyronine [Domeki, N. et al., Abst P2-241]. The liver-selective thyromimetic agent sobetirome substantially lowered LDL-cholesterol levels in healthy volunteers without effects on heart rate or thyroid axis [Lin, V.H. et al., Abst OR36-3]. In the experimental setting, benefits on atherogenic diet-induced dyslipidemia were reported with Cnidium monnieri rhizome [Lee, H.Y. et al., Abst P2-345] and Paeonia root [Ha, H. et al., Abst P2-346] extracts.

Agents improving obesity and adiposity

New data was reported on orlistat, which was shown to abolish postprandial hyperlipidemia in healthy volunteers [Abejuela, Z.R. et al., Abst P2-323], and cetilistat, which compared to placebo offered significant reductions in body weight and improvements in glycemic control similar to those obtained with orlistat with a superior gastrointestinal adverse event profile [Murray, F.T. et al., Abst OR25-6] (Fig. 4). Additional observations suggested benefits on fat meal-induced increased expression of toll-like receptor-4 and plasma endotoxin levels with orange juice [Ghanim, H. et al., Abst P3-427]. In that context, pycnogenol, an extract from Pinus maritima bark, suppressed toll-like receptor-4-mediated adipose differentiation-related protein expression in macrophages [Ikuyama, S. et al., Abst P2-353], suggesting potential for fat-related disorders. Similarly, cotreatment with glycyrrhetinic acid reduced intra-abdominal compared to total body fat, offering a potential further alternative against central obesity [Esfandiari, N.H. et al., Abst P3-225]. On the other hand, testosterone supplementation improved body composition but not insulin sensitivity in obese males with low normal testosterone [Peng, S.Y. et al., Abst P1-667], with an effect in decreasing carotid intima-media thickness [Zitzmann, M. et al., Abst OR24-5], and significantly improved lipid levels and other risk factors in hypogonadal men with metabolic syndrome [Saad, F. et al., Abst P2-270].

Fig. 4. Change in body weight after 12 weeks of treatment with cetilistat, orlistat or placebo [Murray, F.T. et al., Abst OR25-6].

In the experimental arena, rimonabant was shown to reduce growth hormone levels [Al-Massadi, O. et al., Abst P3-152]. Further advances in research have resulted in new putative antiobesity agents, as exemplified by the following examples reported during this year’s meeting: the nonpeptide growth hormone secretagogue receptor blocker JMV-2959 was demonstrated to reduce body weight gain in experimental models of high fat diet-induced obesity [Roy, M.C. et al., Abst P1-204]. Also as an experimental finding, upregulation of resistin expression in white adipose tissue of obese, diabetic animals resulted from administration of caffeine, linking obesity and insulin resistance [Kogure, A. et al., Abst P2-89].

Regarding other therapies with an impact on obesity-related parameters, the antihypertensive agents telmisartan and valsartan, and to a lesser extent lisinopril, induced release of visfatin from adipocytes and skeletal myocytes [Storka, A. et al., Abst P1-452]. Aliskiren, a direct renin inhibitor, showed benefits on blood pressure but also adipose tissue weight and leptin levels in experimental models of obesity [Stucchi, P. et al., Abst P1-152]. Darusentan effectively lowered trough sitting and mean 24-hour systolic and diastolic blood pressure in diabetic individuals with resistant hypertension [Warren, M.L. et al., Abst P1-463] while the imidazoline agonist moxonidine was shown to activate the insulin cascade through increased phosphorylation of substrates [Tesfai, J. & Edwards, L.P., Abst P1-196]. Independent observations suggested a link between obesity and higher cardiac work and fatty acid oxidation and depressed stroke volume, which were improved by treatment with trimetazidine [Bucci, M. et al., Abst P2-330]; in that respect, improvements in obesity and glucose intolerance in experimental animals were also obtained with eplerenone [Takeda, Y. et al., Abst P1-163]. Further studies revealed improved circadian growth hormone secretion and  attenuation of augmented circadian thyroid-stimulating hormone secretion in obese premenopausal women treated with bromocriptine [Kok, P. et al., Abst P1-218; Kok, P. et al., Abst P1-219].

Other compounds

While benefits of allopregnenolone were reported on the neuroinflammatory status in patients with Niemann-Pick type C disease [Gong, W. et al., Abst P2-703], eicosapentaenoate improved arterial stiffness and increased adiponectin levels in patients with metabolic syndrome [Satoh, N. et al., Abst P2-332]. Also regarding natural compounds, virgin coconut oil showed benefits on lipid profile and weight in healthy overweight individuals [Pollisco, C.C. & Raboca, J.C., Abst P2-324].

GROWTH HORMONE DEFICIENCY

Growth hormone replacement remains the mainstay in the treatment of growth hormone deficiency [Lee, P. et al., Abst P2-560], with long-term benefits on growth and quality of life [Shimatsu, A. et al., Abst P1-807; Fuhr, U. et al., Abst P2-567; Fuhr, U. et al., Abst P2-568; Romer, T. et al., Abst P2-566], and was reported safe regarding the risk for craniopharyngioma recurrence in childhood [Muller, H.L. et al., Abst P3-677]. Somatostatin replacement improved voluntary physical activity in adults with growth hormone deficiency, bringing about increases in hunger and reductions in eating disinhibition without a marked effect on overall calorie intake [Deepak, D.S. et al., Abst P1-796]; furthermore, growth hormone replacement was associated with benefits on C-reactive protein levels and cardiovascular risk, despite a modest increase in blood pressure and left ventricular mass [Deepak, D.S. et al., Abst P1-802; Conceicao, F.L. et al., Abst P1-795], and improvements in cognition and quality of life [Madrazo-Atutxa, A. et al., Abst P1-806]. In addition to somatostatin, growth hormone-releasing factor analogs have been developed, including tesamorelin, which significantly decreased triglycerides and improved glucose parameters in HIV-positive patients with abdominal fat accumulation [Falutz, J. et al., Abst OR41-4]. On the other hand, growth hormone replacement after prior treatment for acromegaly was reported to improve the quality of life in a retrospective analysis of 10 patients diagnosed with growth hormone deficit after treatment for acromegaly [Higham, C.E. et al., Abst P1-803].

Besides growth hormone, insulin-like growth factor-1 has also been used in the treatment of growth failure, and a registry of 237 children confirmed the favorable safety and tolerability profile of mecasermin [Kuntze, J. et al., Abst P2-564], a compound that was also described as effective in treating severe short stature in twins with the mitochondrial DNA A3243G mutation [Ma, N. et al., Abst P1-759]. On the other hand, recombinant insulin-like growth factor-1, but not growth hormone, was reported effective in the treatment of the profound growth failures seen in patients with X-linked severe combined immune deficiency [Rezvani, G. et al., Abst P3-682].

Regarding novel therapies, a pharmacokinetic assessment concluded on the reduced bioavailability of the novel oral growth hormone secretagogue ARD-07 when taken with food [MacLean, C.M. et al., Abst P3-764]. A further analogue, LAB GNRH, proved superior to placebo in reversing wasting syndrome in 26 patients with chronic kidney disease [Wiecek, A. et al., Abst S68-1].

ACROMEGALY

Treatment of acromegaly patients with long-acting octreotide injection resulted in impaired glucose tolerance and transient reductions in insulin secretion that was suggested to depend upon prior degree of insulin resistance [Yoshida, M. et al., Abst P2-729]; octreotide showed efficacy against acromegaly in a pregnant woman, without a negative impact on her baby’s growth and development [Iwabuchi, M. et al., Abst P2-773]. While showing efficacy against signs and symptoms of acromegaly [Higham, C.E. et al., Abst OR41-6] and improving glucose metabolism and, at least in part, the lipid profile [Maffei, P. et al., Abst P2-724], there was no evidence that pegvisomant increases the rate of pituitary tumor growth in 307 patients [Buchfelder, M. et al., Abst OR8-1]. Meanwhile, add-on cabergoline was reported effective for rescuing patients with active acromegaly despite treatment with octreotide long-acting injection [Jallad, R.S. et al., Abst P1-809] and lanreotide was confirmed effective over the long term in a cohort of 49 patients [Toledano, Y. et al., Abst P2-739]. Potential for the treatment of acromegaly was suggested for a long-acting release formulation of pasireotide based on the results of a phase I study in 18 patients [Petersenn, S. et al., Abst OR41-5] (Fig. 5), and switch to pasireotide overcame insulin-like growth factor-1 tachyphylaxis in animals previously treated with octreotide [Schmid, H.A., Abst P2-635]. Oral estrogens, alone or combined with octreotide long-acting injection, also normalized insulin-like growth factor-1 levels, being as effective in monotherapy as octreotide or pegvisomant [Vallette, S. et al., Abst P2-726].

Fig. 5. Growth hormone, insulin-like growth factor-I and total response rates in patients receiving increasing doses of pasireotide long-acting release [Petersenn, S. et al., Abst OR41-5].

Independently of acromegaly but in relation with pituitary adenoma, antitumor activity in experimental models was reported with BIM-23A760, a somatostatin SST2 and SST5 and dopamine D2 receptor agonist [Hochgeschwender, U. et al., Abst P3-758], and with curcumin [Miller, M.L. et al., Abst OR33-6].

THYROID ABNORMALITIES

Levothyroxine replacement was reported feasible during pregnancy with careful control of dose requirements from the second trimester [Loh, J.A. et al., Abst OR42-6], and bioequivalence was demonstrated comparing levothyroxine and liothyroxine in hypothyroid patients [Zemskova, M. et al., Abst OR11-3]; absorption of levothyroxine was improved by vitamin C [Antunez, P.B., Abst P2-240]. Regarding liothyroxine, an open-label study in 28 women with primary autoimmune hypothyroidism already on adequate thyroxine replacement demonstrated improvements in clinical outcomes [Tevaarwerk, G.J.M., Abst P2-243]. To note that cotreatment with colesevelam or lanthanum carbonate reduced levothyroxine absorption [Weitzman, S.P. et al., Abst P2-239]. Treatment of subclinical hypothyroidism with high-dose soy phytoestrogens significantly reduced insulin resistance and blood pressure without an effect on thyroid function [Sathyapalan, T. et al., Abst P1-102]. In the opposite range of hypothyroidism severity, a case of myxedema coma was effectively recovered with increasing doses of oral levothyroxine in an elderly woman with cardiovascular compromise [Fonte, J.S. et al., Abst P3-353]. To note that according to a retrospective review of 549 inpatients in medical wards, levothyroxine was frequently administered with compounds and/‌or supplements that have been shown to interfere with its absorption, which was the basis for recommending bedtime administration of the thyroid hormone in inpatient medical units when required [Alshehri, B. et al., Abst P2-242].

Radioiodine was further confirmed as an effective approach to the treatment of Graves’ disease in a series of 125 patients [Sanyal, D. et al., Abst P2-188], but the disease was also safely and efficiently managed by low-dose methimazole [Villagelin, D.G.P. et al., Abst P2-187] and rituximab [Heemstra, K.A. et al., Abst P2-192]. Mechanistic experimental data regarding thyrocyte and CD4-positive T-cell activation suggested potential for elocalcitol in the treatment of Graves’ disease [Sottili, M. et al., Abst P1-392], while report from a patient suggested potential for adjuvant lithium to enhance radioiodine uptake [Macaballug, A.G. et al., Abst P2-201].

Regarding pregnancy and postpartum thyroiditis, selenium supplementation was reported to inhibit progression of autoimmune chronic thyroiditis and protect postpartum thyroid gland function [Negro, R., Abst S70-1].

While showing benefits on metabolic status and body weight [Ladenson, P.W. et al., Abst S68-2], studies in an experimental model suggested potential for DITPA, a thyroid hormone agonist, as a treatment for monocarboxylate transporter-8 gene mutations (a inborn disorder that causes severe mental and neurological impairment in males) [Di Cosmo, C. et al., Abst OR23-1].

Regarding thyroid malignancies, while patient data confirmed the feasibility of sunitinib [Catargi, B. et al., Abst P3-332] (although with a risk for thyrotoxicosis at least in patients with renal cell carcinoma [Grossmann, M. et al., Abst P2-212]), vandetanib [Lodish, M.B. et al., Abst P3-316] and romidepsin [Piekarz, R.L. et al., Abst P2-255] against refractory advanced thyroid cancer, methoxyestradiol showed inhibitory potential against anaplastic thyroid cancer cells [Wang, S.H. et al., Abst P1-350]. On the other hand, the feasibility of recombinant human thyroid-stimulating hormone in patients with differentiated thyroid carcinoma and end-stage renal disease was confirmed in two cases using doses of 0.9 and 0.45 mg, respectively, but the high exposure after half-dose administration suggested the need for adjusting doses in case of renal failure [Pitoia, F. et al., Abst P3-328]. Multinodular lymphocytic thyroiditis in a young woman was reportedly treated with ¹³¹iodine, resulting in improved clinical and laboratory parameters and regression of nodules [General, E.R. & Mercado-Asis, L.B., Abst P2-219].

PARATHYROID ABNORMALITIES

Cinacalcet was reported effective and well tolerated in the treatment of intractable align="center"hypercalcemia and multiple endocrine neoplasia type 1-associated primary hyperparathyroidism-related hypercalcemia [Moyes, V.J. et al., Abst P3-524; Padmanabhan, H. & Iranmanesh, A.S, Abst P1-541] with minimal impact on meal-induced gut hormone responses in dialysis patients [Diaz, J.J. et al., Abst P3-457], but was reported ineffective in improving clinical outcomes in 90 patients with primary hyperparathyroidism, while significantly accelerating bone loss over the long term [Norman, J. & Politz, D., Abst OR14-4]. Results in three postmenopausal women with primary hyperparathyroidism suggested benefits of zoledronate on serum calcium without lowering intact PTH levels [Wang, X. et al., Abst P2-311]. In relation to that, pamidronate was reported as an option for thyrotoxicosis-related hypercalcemia in severe cases resistant to conventional therapy [Antal, Z. et al., Abst P2-706].

Regarding hypoparathyroidism, hypocalcemia was effectively managed by teriparatide in three children and an adult woman [Newfield, R.S. et al., Abst PS2-599; Jacob, K.N. et al., Abst P3-411].

POLYCYSTIC OVARY SYNDROME

While improving the HDL-cholesterol levels and inflammatory status in women with polycystic ovary syndrome (PCOS) with or without metabolic syndrome [Cheang, K. et al., Abst P1-592; Yu, J. et al., Abst P1-591], metformin had no negative impact on body weight compared to placebo in obese adolescents with PCOS on a lifestyle modification program [Hoeger, K.M. et al., Abst OR28-6], and mechanistically an effect in inhibiting human granulosa cell aromatase expression and activity was documented [Rice, S. et al., Abst OR1-2]. Insulin sensitization with metformin or rosiglitazone markedly improved endothelial function in 26 women with PCOS [Jensterle, M. et al., Abst P1-584], while metformin, orlistat and especially pioglitazone showed further cardiovascular benefits by modulating fibrinolysis [Ajjan, R.A. et al., Abst OR28-4].  To note: experimental studies revealed improved insulin sensitivity and reproductive cycles with rosiglitazone in female animals exposed prenatally to testosterone [Veiga-Lopez, A. et al., Abst P2-495]. Furthermore, combined treatment with metformin and exenatide markedly improved menstrual cyclicity, body weight, abdominal circumference, hyperandrogenism and metabolic profile, with superiority over the respective monotherapies [Elkind-Hirsch, K.E. et al., Abst OR28-2]. Simvastatin also improved insulin sensitivity, decreased prolactin levels and improved inflammation markers and endothelial function in women with polycystic ovary syndrome, with superiority over metformin in controlling the metabolic profile [Banaszewska, B. et al., Abst OR28-1]. Benefits in women with polycystic ovary syndrome were also reported with rimonabant, which reduced free androgens more effectively than metformin in 20 patients [Sathyapalan, T. et al., Abst P1-590].

Regarding hormonal interventions, concomitant use of estradiol/drospirenone and spironolactone in 23 lean women with polycystic ovary syndrome and normal glucose tolerance effectively improved the androgen imbalance without negative effects on adiposity, glucose tolerance or the lipid profile, but increased C-reactive protein and homocysteine levels [Harmanci, A. et al., Abst P1-585]. On the other hand, ovarian responses to human chorionic gonadotropin were preserved in women with polycystic ovaries [Coffler, M.S. et al., Abst P1-594].

FEMALE HYPOGONADISM

Intravenous better than subcutaneous pulsed gonadotropin-releasing hormone administration offered potential for ovulation induction in 23 women with hypogonadotropic hypogonadism [Pesant, M.H. et al., Abst P2-528]. In young women with primary ovarian insufficiency, transdermal testosterone treatment resulted in additional benefits by lowering subcutaneous fat [Popat, V.B. et al., Abst OR53-3].

MALE HYPOGONADISM

Testosterone replacement is a known approach to the treatment of male hypogonadism [Band, M.M. et al., Abst P3-657], which according to the TIMES 2 study can be successfully accomplished over the long term with transdermal testosterone in patients with type 2 diabetes or metabolic syndrome without negative impact on diabetes control or insulin sensitivity [Jones, T.H. et al., Abst P3-422]. In older males with late-onset hypogonadism testosterone replacement brought about additional benefits on anthropometric parameters, inflammation markers and metabolic parameters [Tishova, Y.A. et al., Abst P3-364; Tishova, Y.A. et al., Abst P2-272]. A novel transdermal cream formulation of testosterone proved very well tolerated in healthy volunteers [Ruiz, C. et al., Abst P3-664]. Furthermore, depot intramuscular testosterone was reported safe with favorable pharmacokinetics in groups of 130 adult and 146 elderly men [Gooren, L. et al., Abst P2-274; Swerdloff, R.S. et al., Abst P3-654], and in independent studies resulted in improvements in lower urinary tract symptoms and metabolic parameters [Saad, F. et al., Abst P3-365]. On the other hand, bioavailability of oral testosterone was enhanced by concomitant treatment with dutasteride [Clark, R.V. et al., Abst P3-640]. Additional related information on enclomiphene was reported, with results suggesting decrease of serum glucose levels compared to placebo in 199 subjects with idiopathic hypogonadotrophic hypogonadism [van As, A., Abst P3-641] (Fig. 6), while according to results in 140 patients a combination of topical nestorone and testosterone gel is able to suppress gonadotropins in healthy men [Mahabadi, Y. et al., Abst P3-661]. Improvements in a patient with Kennedy’s disease, an X-linked spinal and bulbar muscular atrophy, were also noted with testosterone gel [Koch, C.A. et al., Abst P3-673].

Miscellaneous experimental observations related to testicular steroidogenesis suggested protection against germ cell death and steroidogenesis during cadmium poisoning with vitamin C supplementation [Kim, J. et al., Abst P1-664].

MENOPAUSAL DISORDERS

Topical estradiol and conjugated estrogens used for prevention and treatment of vaginal atrophy in menopause were associated with significant increases in serum estradiol and estrone levels, suggesting systemic exposure and possibility for systemic effects [Labrie, F. et al., Abst OR53-6]. Considering such systemic effects, data on the effect of estradiol in elevating overnight plasma acylated ghrelin levels without altering its metabolic clearance was reported in healthy women [Paulo, R. et al., Abst P2-743]. On the other hand, high-dose isoflavones offered no marked benefits on inflammation or metabolic parameters in healthy, normal-weight postmenopausal women [Charles, C. et al., Abst P2-507], but a combination of genistein and quercetin showed potential antiobesity activity against adipogenesis in in vitro studies [Rayalam, S. et al., Abst P2-93]. Administration of soy isoflavones to peri- and post-, but not premenopausal women decreased morning cortisol levels and offered benefits on the quality of life [von Salza, A. et al., Abst P2-506]. To note, isoflavones showed complex effects on bone marker expression, with bone-protective effects related to modulation of osteoclast and osteoblast activity [Hertrampf, T. et al., Abst P2-288], while genistein stimulated proliferation and development of Leydig’s cells in experimental animals [Shernill, J.D. et al., Abst P1-112].

HORMONAL ENDOMETRIAL DISORDERS

Gonadotropin-releasing hormone agonists are useful in the treatment of endometriosis, but results in gonadal function suppression that may recover faster when goserelin is used compared to leuprorelin [Aisaka, K. et al., Abst P2-523].

SEX HORMONE DISORDERS

Female sexual dysfunction improved with transdermal testosterone, with favorable results over the long term, and the cardiovascular safety is being currently investigated in over 3,000 postmenopausal women [Snabes, M. et al., Abst P2-512].

Transdermal estradiol was suggested as more effective than oral estrogen replacement therapy in 12 girls with Turner’s syndrome, with faster spinal bone accrual and uterine growth [Nabhan, Z.M. et al., Abst P1-747], although low-dose estrogen replacement also improved pubertal development and adult height in 149 girls with the disease compared to placebo [Ross, J.L. et al., Abst OR22-1]. On the contrary, oxandrolone showed no benefit compared to placebo when used in monotherapy in 76 girls, at least regarding growth velocity and height [Zeger, M.P.D. et al., Abst S68-6]. In the experimental arena, kisspeptin-10 analogs have been developed and will be tested for their effect on pubertal development and adult reproductive function [Curtis, A.E. et al., Abst P1-637]. Similarly, G protein-coupled receptor GPR54 blockers have been developed as potential agents for pubertal failure [Kuohung, W. et al., Abst P1-669].

Regarding precocious puberty, anastrozole showed no activity in a case of McCune-Albright disease, while tamoxifen significantly decreased pubertal manifestation, slowed bone age advancement and improved final height [Cohen, D. & Gottschalk, M.E., Abst P2-592]. On the other hand, treatment with metformin in low-birth weight girls with precocious pubarche resulted in improvements in total and visceral fat while delaying menarche without a negative impact on linear growth [Ibanez, L. et al., Abst OR22-4].

On the other hand, mechanistic data from postmenopausal women suggested a link between estrogen supplementation and enhanced hypothalamo-pituitary sensitivity to ghrelin [Kok, P. et al., Abst P3-761].

CONTRACEPTION

Scarce news were reported this year on contraception, with the exception of confirmation of renal safety and male contraception potential for 7α-methyl-19-nortestosterone [Prasad, P.V. et al., Abst P1-453], observations on the lack of delay of follicle rupture by cetrorelix administered during the luteinizing hormone surge in healthy women [Busquets, M. et al., Abst P3-351], effect of ganirelix in increasing activin levels in pubertal boys and girls [Foster, C.M. et al., Abst P1-738] and experimental results that demonstrate a role of testosterone in tyrosine tubulin, Fas, integrin-β₁ and γ-laminin in the irreversible infertility caused by the nonhormonal oral male contraceptive agent l-CDB-4022 [Koduri, S. et al., Abst P1-639].

BREAST CANCER

Although with a risk for hypertension, namely increased nighttime and 24-hour blood pressure in postmenopausal women [Mirza, F.S. et al., Abst OR12-5], aromatase inhibitors are used extensively in the treatment of breast cancer. The activity of tamoxifen against cancer cell growth was decreased by growth factor activation and related to mutations of estrogen receptor α [Giordano, C. et al., Abst P1-88]. In mechanistic studies, tamoxifen, but not mifepristone, inhibited the neuronal nitric oxide synthase system [Ota, F.H. et al., Abst P1-697]. Using raloxifene, reduction in fat oxidation and leucine incorporation was demonstrated in hypopituitary women, suggesting a marked effect on protein anabolism [Birzniece, V. et al., Abst P1-791], while compared to tamoxifen the agent showed direct protective effects on human osteoblasts mediated by both estrogen receptor-dependent and ‑independent mechanisms [Miki, Y. et al., Abst P1-50]. Comparing novel options for estrogen receptor modulation, acolbifene was suggested as more potent than bazedoxifene in inhibiting estrogen-induced cell growth while being devoid of estrogenic activity [Martel, C. et al., Abst P1-98].

• Regarding new compounds, the dual aromatase/sulfatase inhibitor STX-681 showed potential in experimental xenograft models of breast cancer [Foster, P.A. et al., Abst P1-95] and the antiestrogen ICI-182780 was shown to penetrate into the central nervous system and reach the hypothalamus, partially inhibiting central estrogenic activity in ovariectomized animals [Alfinito, P.D. et al., Abst P1-731] whilst inducing gene expression changes in the epididymus [Shayu, D. et al., Abst P1-649]. TPBM, a novel small molecular blocker of estrogen receptor α, was able to inhibit gene expression and growth in tamoxifen-resistant breast cancer cells [Patterson, N.M. et al., Abst OR4-3]. On the other hand, the selective androgen receptor modulator-like profile of MKI-0773, an agent developed for the treatment of sarcopenia, was characterized in healthy postmenopausal women [Stoch, S.A. et al., Abst OR35-3], while tissue selectivity and reduced activity on the clitoral gland was demonstrated with LGD-3303, a further selective androgen receptor modulator [Lopez, F.J. et al., Abst P2-3]. The safety and favorable pharmacokinetic profile of another selective androgen receptor modulator, LGD-2941, after oral administration were demonstrated in healthy men [Gunawardhana, L. et al., Abst P1-517]. On the contrary, artemisinin ablated estrogen responsiveness in human breast cancer cells through disruption of estrogen receptor α-mediated gene expression [Sundar, S.N. et al., Abst OR6-6]. On the other hand, fulvestrant induced abnormalities in epididymide diameter and sperm motility in animals [Shayu, D. et al., Abst P1-649]. In the experimental arena, liver receptor homologue-1 was identified as a target for intervention, with nondisclosed selective inhibitors inhibiting promoter-mediated aromatase expression in adipose stromal cells [Chand, A.L. et al., Abst OR32-4]. Ganoderma extract showed protection against p,p’-DDE disruption in experimental models of breast cancer [Qin, J. et al., Abst P1-105] while compound α-PGG induced apoptosis of breast and cervical cancer cells [Cao, Y. et al., Abst P1-104].

Other news regarding treatment for breast cancer included reports on the antimetastatic activity of the activin receptor-like kinase 5 inhibitors IN-1130 and IN-1233 [Sheen, Y.Y. et al., Abst P1-96].

PROSTATE CANCER

Prostate malignancies are also hormone-dependent, and a number of hormone modulators have been developed and tested positive for treating early-stage disease. To the known androgen deprivation therapies, prolactin receptor blockers may be added, with initial research on engineered molecules suggesting downregulation of tumorigenic pathways and inhibition of tumor growth [Rouet, V. et al., Abst OR59-6]. Experimental data with ciglitazone suggested potential for reducing androgen receptor activity in androgen-dependent prostate cancer cells through activation of peroxisome proliferator-activated receptor-γ [Moss, P.E. et al., Abst P2-47].

Regarding the bone in prostate cancer, addition of a luteinizing hormone-releasing hormone agonist to low-dose estramustine prevented the adverse effects of estramustine on bone resorption, resulting in a net increase in bone mineral density [Yajima, A. et al., Abst P1-518].

OVARIAN CANCER

Most women receiving high-dose chemotherapy for ovarian cancer develop alterations of follicle-stimulating hormone and anti-Mullerian hormone levels, resulting in ovarian failure, amenorrhea and low follicle counts at a young age [Frey, M.A. et al., Abst P2-250]. In the experimental arena, bortezomib induced apoptosis and decreased proliferation of ovarian granulosa cell tumors [Chu, S. et al., Abst P2-435] and metformin antagonized valproate-induced HSD17B5 expression in ovarian cancer cells [Du, X. et al., Abst OR55-4].

UTERINE CANCER

Fibroid shrinkage, increased apoptosis and decreased proliferation were noted during ulipristat therapy in women with uterine leiomyomas [Wei, Q. et al., Abst P2-444] (Fig. 7).

Fig. 7. Change in total fibroid volume in women receiving ulipristat or placebo [Wei, Q. et al., Abst P2-444].

PITUITARY TUMORS

Although prolonged dopamine agonist therapy has been related to increased prevalence of aortic valve calcification and mild tricuspid regurgitation without clinically relevant valvular heart disease [Kars, M. et al., Abst OR27-3], cabergoline was reported effective in the treatment of prolactinoma (tumor shrinking and control of hyperprolactinemia) without negative effects on valvular thickening or regurgitation, mitral valve tenting area or height or overall valvular disease risk [Herring, N. et al., Abst OR27-4; Bhansali, A. et al., Abst P3-156; Delorme, S. et al., Abst P3-747; Kharlip, J. et al., Abst OR27-5]. Response to cabergoline in aggressive tumors was enhanced by tamoxifen through an effect on mitochondrial estrogen receptor-β [Auchus, R.J. et al., Abst P2-762]. However, cabergoline, but not bromocriptine, may trigger cluster headaches in patients with macroprolactinoma [Pineyro, M.M. et al., Abst P2-788]. On the other hand, marked hyperprolactinemia due to metoclopramide was described in a young woman [Ginsburg, K.C. et al., Abst P2-790]. On the other hand, while temozolomide, but not cabergoline, offered potential as a treatment for refractory Nelson’s syndrome [Bramswig, J.H. et al., Abst P2-129], treatment with retinoic acid in a pet animal resulted in Nelson’s syndrome [De Marco, V. et al., Abst P2-786].

Also related to the pituitary, a case of aggressive, recurrent lymphocytic hypophysitis responding to rituximab was reported [Postema, P.T.E. et al., Abst P1-394].

MISCELLANEOUS INFORMATION ON OTHER MALIGNANCIES

A number of reports regarding pharmacological intervention for miscellaneous tumors were reported during the various oral and poster sessions, and are listed here:

• Adjuvant mitotane offered benefits to patients with advanced adrenocortical cancer by prolonging survival and reducing the risk of relapse independently of the secretory activity of the tumor [Terzolo, M. et al., Abst P1-490; Daffara, F.C. et al., Abst P1-491], but can result in permanent adrenal dysfunction [Paulo, R.C. et al., Abst P2-595]; in vitro results in the same form of cancer revealed potential for cetrorelix [Young, L. et al., Abst P2-422]. On the other hand, potent inhibition of aldosterone synthesis and release in adrenocarcinoma cells was demonstrated with the calcium channel blocker azelnidipine [Isaka, T. et al., Abst P1-450].
• Diminished tumor load and reduced enterochromaffin-like cell density in patients with gastric carcinoid were noted after treatment with long-acting formulations of the somatostatin analogs octreotide or lanreotide [Grozinsky-Glasberg, S. et al., Abst P1-497], and reduced carcinoid cell viability was demonstrated with pasireotide [Zatelli, M.C. et al., Abst P2-425].
• Fluorouracil/epigallocatechin gallate combination showed antitumor activity against pancreatic cell lines [Benghuzzi, H.A. et al., Abst P2-428].
• Cotreatment with the histone deacetylase inhibitor trichostatin A and 1,25-dihydroxyvitamin D3 induced mitotic failure in poorly differentiated squamous cell carcinoma cells [Tavera, L.E. et al., Abst P3-379].
• Use of imatinib in cancer therapy induced permanent alterations in testicular development and gonadal function, according to experimental animal studies [Nurmio, M. eta l., Abst P1-658].
• Anastrozole protected spermatogenesis and allowed full adult height over the long term in a child with Peutz-Jeghers large-cell, calcifying Sertoli’s cell tumor [Bouvattier, C. et al., Abst P2-584].
• Inhibition of colon cancer cell growth was demonstrated with MLS-128 via downregulation of insulin-like growth factor-1 receptor [Fujita-Yamaguchi, Y. et al., Abst P3-636]. The histone deacetylase inhibitors trichostatin A, apicidin and sodium butyrate also induced apoptosis of colon cancer cells [Law, Y.S. et al., Abst P2-551].
• A case of succinate dehydrogenase subunit B-related paraganglioma was successfully treated with cyclophosphamide/vincristine/dacarbazine [He, J. et al., Abst P2-165].
• The growth hormone-releasing hormone antagonist JV-1-36 inhibited proliferation  and secretion of vascular endothelial growth factor from neuroendocrine tumor cells [Sacewicz, M. et al., Abst P2-427].
• Monthly ibandronate offered a well-tolerated option for the treatment of symptomatic Paget’s disease of bone [Castellanos, M. et al., Abst P3-419].

Regarding other aspects of cancer therapy, experimental studies confirmed a role of ghrelin administration in preventing cisplatin-induced cachexia and testicular toxicity [Whirledge, S.D. et al., Abst OR52-5]; improvements in survival and quality of life in pets with cancer were obtained with a growth hormone-releasing hormone plasmid-based therapy [Draghia-Akli, R. et al., Abst P2-620]; similar treatment during pregnancy improved body weight and lean body mass in offspring [Person, R. et al., Abst P1-168]. In the experimental arena, oxypurinol and allopurinol improved survival and reduced wasting in models of cancer cachexia [Springer, J. et al., Abst P2-88], whereas no effect on experimental cancer cachexia was noted during administration of spironolactone [Springer, J. et al., Abst P1-717].

POSTMENOPAUSAL OSTEOPOROSIS

Bisphosphonates remain a major option for the prevention and treatment of postmenopausal osteoporosis, and new data discussed this year suggested superiority over risedronate in preventing fractures [Bergman, G.J.D. et al., Abst P1-514] and significant increases in calcium absorption [Shapses, S. et al., Abst P1-509] with weekly alendronate plus vitamin D, while being the most active bisphosphonate in preventing fractures according to some evidence [Jansen, J.P. et al., Abst P1-513]. New data from the HORIZON-PTF trial confirmed the benefits of zoledronate on bone mineral density and fracture risk with a favorable safety and tolerability profile [Reid, D.M. et al., Abst P1-512]; skeletal responses to the bisphosphonate were unaffected by renal impairment [Miller, P. et al., Abst P1-511]. Mechanistic studies with alendronate revealed an effect in inducing apoptosis of macrophages through interference with RAS signaling and alterations in cytokine production [Benghuzzi, H.A. et al., Abst P2-282].

Teriparatide, a recombinant parathyroid hormone (PTH), is another option for increasing bone mineral density, as confirmed in a real-life retrospective analysis of 100 patients [Sood, A. & Armas, L., Abst P1-515], and a further PTH analog, PTH_1-84 offered benefits on urinary bone markers during pregnancy [Muse, K.N. et al., Abst P3-533].

Through inhibition of the nuclear factor κ_b, its ligand and osteoprotegerin triad, Cimicifuga racemosa extracts improved bone homeostasis in experimental ovariectomized and orchidectomized animals [Seidlova-Wuttke, D. et al., Abst P2-286]. The extract potentiated bone nodule formation in further experimental studies [Chan, B.Y. et al., Abst P2-292]. Potential in the prevention of postmenopausal bone loss was attributed to turmeric and ginger extracts in further studies in animals [Wright, L.E. et al., Abst P2-283], while further Asian plant extracts, especially HL39, were shown to promote osteoblast and suppress osteoclast differentiation [Yoon, H.Y. et al., Abst P2-284].

Regarding other forms of osteoporosis, single intravenous zoledronate infusion was found significantly more effective than daily risedronate therapy in increasing bone mineral density in patients with glucocorticosteroid-induced osteoporosis [Reid, D.M. et al., Abst OR14-2] (Fig. 8), and zoledronate was also tested positive in the management of osteopenia in children and adolescents with Crohn’s disease [Sbrocchi, A.M. et al., Abst P1-510]. Glucocorticosteroid-induced osteoporosis also improved with strontium ranelate in experimental animal studies [Yilmaz, N. et al., Abst P1-516].

Fig. 8. Change in lumbar spine bone mineral density after single zoledronate infusion (5 mg) or daily oral risedronate (5 mg/‌day) in patients with or at risk for glucocorticosteroid-induced osteoporosis [Reid, D.M. et al., Abst OR14-2].

Referring to other bone mineralization disorders, mecasermin was well tolerated but did not improve bone mineralization in a child with hypophosphatasia, but extraskeletal anabolic gains contributed to clinical stabilization [Van Sickle, B.J. et al., Abst P2-600].

CUSHING’S SYNDROME

Cabergoline resulted in complete or partial urinary cortisol responses in 29 patients with Cushing’s syndrome within 3-6 months of starting therapy [Godbout, A. et al., Abst P2-130]. Although a weak effect in lowering urinary cortisol levels was noted with octreotide or cabergoline in patients with Cushing’s syndrome, greater efficacy was reported with the combination in six patients [Romanholi, D.J.P.C. et al., Abst P2-128]. Potential for the treatment of Cushing’s disease was also suggested for a combination of metformin and rosiglitazone, with suppression of adrenocorticotropin hormone and urinary free cortisol levels [Adiraju, R. et al., Abst P2-781].

MISCELLANEOUS

A number of mechanistic and physiological observations regarding estrogen pathways were reported:

• Amplification of both weak and strong sex steroid hormones but induction of hyperplasia of accessory male sex organs was noted with the antimicrobial agent triclocarban [Chen, J. et al., Abst P1-120; Ahmed, M.I. et al., Abst OR6-4].
• Interference with androgen binding to aromatase by thiazolidinediones resulted in reduced estrone and estradiol production [Avtanski, D.B. et al., Abst P2-44].
• Induction of adverse growth and skeletal effects in peripubertal males by the aromatase inhibitor letrozole, although with preservation of bone mineral density [Bajpai, A. et al., Abst P3-382].
• Inhibition of steroid production in granulosa-luteal cells by mono-(2-ethylhexyl)-phthalate [Reinsberg, J. et al., Abst P1-106].
• A tissue-selective anabolic steroid, bolandiol showed weak activity on androgen and progesterone receptors and no aromatization to estradiol [Attardi, B.J. et al., Abst P1-644].

Triptorelin offered long-lasting benefits to men with severe paraphilias on supportive psychotherapy [Rosler, A. et al., Abst P2-674].

Prasterone was reported to act as an antiglucocorticosteroid on proliferation, differentiation and insulin sensitization of human preadipocytes [McNelis, J.C. et al., Abst P1-141], and induced differentiation of pheochromocytoma cells towards a more neuroendocrine phenotype in the presence of nerve growth factor [Ziegler, C.G. et al., Abst P2-11].

Prednisolone inhibited pulsatile hypothalamic-pituitary-adrenal axis activity in healthy men [Russell, G.M. et al., Abst P3-272].

An effect of resveratrol in repressing follicle-stimulating hormone-b gene expression [Lan, D. et al., Abst P2-461] and suppressing proinflammatory genes causing insulin resistance [Dandona, P. et al., Abst P3-428] was described.

Prenatal betamethasone exposure increased adrenal corticotrophin receptor and steroid acute regulatory protein expression in animals [Su, Y. et al., Abst P3-286]; prenatal dexamethasone had no impact on weight and length of experimental animals, but induced redistribution of fat depots without increasing the risk for metabolic-like syndrome [Seidlova-Wuttke, D. et al., Abst P2-291].

Neonatal administration of bisphenol A had negative effects on the hypothalamic-pituitary-ovarian axis and altered reproductive parameters in pre- and postpubertal animals [Fernandez, M.O. et al., Abst P1-107].

The fatty acid synthase inhibitor C-75 antagonized growth hormone-releasing hormone-induced growth hormone secretion [Ishii, S. et al., Abst P3-147].

The frequency of adrenal insufficiency caused by inhaled corticosteroid therapy was established at over 100 cases per year using retrospective data from 11,783 French pediatricians, endocrinologists, pulmonologists and intensive care physicians [Molimard, M. et al., Abst P2-135]. Regarding the opposite issue, extended-release hydrocortisone was suggested as a promising new treatment for congenital adrenal hyperplasia [Verma, S. et al., Abst OR13-3], but was related to increases in phosphotyrosine phosphatase-1B and S-6-kinase expression in circulating mononuclear cells in healthy volunteers [Patnaik, P. et al., Abst P2-97].

Exposure to morphine modulated the expression of genes involved in food intake (neuropeptide Y, agouti-related protein, cocaine and amphetamine-regulated transcript) in the hypothalamus and/or pituitary of experimental animals [Anghel, A. et al., Abst P1-171].

MOERAS-115, a novel aldosterone synthase inhibitor, lowered aldosterone levels but had no marked effect against cardiac fibrosis in experimental animal models [Emmen, J.M.A. et al., Abst P1-479]. No effect of doxycycline against hyperthyroidism-induced cardiac hypertrophy was demonstrated in experimental studies [Konar, A. et al., Abst P1-393].

Tacrolimus and sirolimus caused hyperglycemia, but only sirolimus induced hyperinsulinemia, and both compounds decreased estradiol, preovulatory follicle formation and uterine weight in experimental animals [Ochsner, L.D. et al., Abst P2-459].

Conivaptan showed efficacy in the treatment of hyponatremia in patients with or without heart failure [Ghali, J.K. et al., Abst OR8-2].

Tadalafil improved sleep-related tumescence and erections in normal men [Granata, A.R.M. et al., Abst P3-663]. On the other hand, a case of severe headache and nausea after taking sildenafil in a patient treated for hypertension, migraine and depression was related to reduction in blood pressure resulting in pituitary gland infarction [Kamaruddin, M.S. et al., Abst P3-789].

Through an effect on mitogen-activated protein kinase pathways, the green alga Capsosiphon fulvescens stimulated proliferation of gastrointestinal cells in vitro [Go, H. et al., Abst P1-34].

Increases in breast milk volume were obtained with a recombinant prolactin in mothers with lactation insufficiency [Powe, C.E. et al., Abst P3-749].

Immunomodulatory activity was reported with Dioscorea rizhoma, suggesting potential for the treatment of tumors, allergy and possibly other immune-mediated diseases [Lee, H.Y. et al., Abst P3-610].