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.
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
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].
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
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
Fig. 1. Change in 2-hour postprandial
glucose levels in patients treated with LX-4211 or placebo [Freiman, J. et al.,
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].
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
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
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.,
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].
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].
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
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
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
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].
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].
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].
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
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
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].
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
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].
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
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].
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.,
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].
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
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].
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].
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
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
which showed antiproliferative activity against various malignant cells without
causing hypercalcemia [Li, W. et al., Abst P3-43].
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].