New Insights into Medical Treatment of Acromegaly

Giants and Acromegalics fascinated people, since ancient times. Historical artifacts, paintings, illustrations, photographs or articles have documented many. The earliest medical reports date back to 1516. In 1864 Verga was the first to describe an acromegalic in medical literature and called it “prosopectasia”. However the article did not really characterize the disease. Pierre Marie was the first to do so and describe the disease and gave it the final name “acromegalie”, in 1886. Although Pierre Marie was aware of the enlarged pituitary gland he did not describe this as cause of the disease. In 1887 Minkowski was the first to suggest a pituitary origin of acromegaly. Later Massalongo also described the pituitary origin and additional the relationship between acromegaly and Gigantism. So at the end of the 19th century the disease and origin were unraveled. A decade later Harvey Cushing was the first to observe partial reversal of clinical symptoms after partial hypophysectomy, and the first form of effective treatment was born

Pregnancy and acromegaly

Introduction: Acromegaly is a rare disorder in which, due to the high incidence of secondary hypogonadism, pregnancies are relatively rare. However, some women with acromegaly do get pregnant, which brings along questions about medication, complications and follow-up. This review tries to address these issues and provide the reader with practical information. Methods: This review summarizes published data. Conclusions: Acromegaly is a disorder that is characterized by changes in growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin concentrations and actions. All these hormones are important in pregnancy as well. In principle, the fetal-placental collaboration between mother and child more-or-less takes over the control over GH and IGF-1, not only in normal physiology but also to a certain extend in acromegaly. When medication for the high GH levels or actions is continued during pregnancy, both dopamine agonists, somatostatin analogs and GH receptor antagonists have been used and the available data suggest that there are no adverse consequences on mother or fetus to date. However, it is strongly advised to stop any medical intervention during pregnancy until more data are available on the safety of these compounds. Also, medical treatment is not needed as tumor size and disease activity are not reported to escape

Combined treatment of somatostatin analogues with pegvisomant in acromegaly

Treatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups has recommended switching to combined treatment of LA-SSA and pegvisomant (PEGV) in patients with partial response to LA-SSAs. This combination of LA-SSA and PEGV, a growth hormone receptor antagonist, can normalize IGF-I levels in virtually all patients, requiring that the adequate dose of PEGV is used. The required PEGV dose varies significantly between individual acromegaly patients. One of the advantages of the combination therapy is that tumor size control or even tumor shrinkage can be observed in a vast majority of patients. The main side effects of the combination treatment are gastrointestinal symptoms, lipohypertrophy and transient elevated liver transaminases. In this review we provide an overview of the efficacy and safety of the combined treatment of LA-SSAs with PEGV

Unacylated ghrelin modulates circulating angiogenic cell number in insulin-resistant states

__Background:__ Type 2 diabetes (T2D) is associated with reduced numbers and impaired function of circulating angiogenic cells (CAC) which contributes to the progression of atherosclerosis and microvascular disease. Previous studies suggest that short-term infusion of unacylated ghrelin (UAG) normalizes CAC number in patients with T2D. To determine dose-dependent effects of short-term infusion of UAG in T2D patients using a cross-over model, and of long-term infusion of UAG in obese mice, on differentiation of monocyte progenitors into CAC. __Methods:__ Eight overweight T2D patients were infused overnight with 3 and 10 µg/kg/h of UAG in a double-blind, placebo-controlled cross-over study. To assess the effects of long-term UAG treatment, obese mice were infused with UAG for 4 weeks. Monocyte progenitors were assessed for their ability to differentiate into CAC in vitro. __Results:__ In T2D patients, UAG treatment caused a reduction in differentiation of CAC, dependent on UAG dose and differentiation method. However, mice treated with UAG showed a significant increase in differentiation of bone marrow progenitors into CAC. __Conclusion:__ UAG causes a minor suppressive effect on CAC development after short-term treatment in humans, but experiments in mice suggest that long-term treatment has beneficial effects on CAC formation. The Netherlands Trial Register: TC=248

Somatostatin Receptor Expression in GH-Secreting Pituitary Adenomas Treated with Long-Acting Somatostatin Analogues in Combination with Pegvisomant

Background: Growth hormone secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also down regulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. Aim of the Study: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve IGF-I normalization in relation to the SSTR expression. Materials and Methods: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenomas tissues was determined using immunohistochemistry. Results: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pre-treatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated to the required PEGV dose to achieve IGF-I normalization during post-surgical medical treatment (ρ = -0.538, p = 0.024). Conclusion: In our specific cohort, the SSTR2 expression is lower in patients pre-treated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization

Sex difference in cold perception and shivering onset upon gradual cold exposure

To maintain a thermal balance when experiencing cold, humans reduce heat loss and enhance heat production. A potent and rapid mechanism for heat generation is shivering. Research has shown that women prefer a warmer environment and feel less comfortable than men in the same thermal condition. Using the Blanketrol® III, a temperature management device commonly used to study brown adipose tissue activity, we tested whether the experimental temperature (_TE_) at which men and women start to shiver differs. Twenty male and 23 female volunteers underwent a cooling protocol, starting at 24 °C and gradually decreasing by 1–2 °C every 5 min until an electromyogram detected the shivering or the temperature reached 9 °C. Women started shivering at a higher _TE_ than men (11.3 ± 1.8 °C for women _vs_ 9.6 ± 1.8 °C for men, _P_ = 0.003). In addition, women felt cool, scored by a visual analogue scale, at a higher _TE_ than men (18.3 ± 3.0 °C for women _vs_ 14.6 ± 2.6 °C for men, _P_ < 0.001). This study demonstrate

Obesity is underestimated using body mass index and waist-hip ratio in long-term adult survivors of childhood cancer

Objective: Obesity, represented by high body mass index (BMI), is a major complication after treatment for childhood cancer. However, it has been shown that high total fat percentage and low lean body mass are more reliable predictors of cardio

The acylated/unacylated ghrelin ratio is similar in patients with acromegaly during different treatment regimens

Background: Data on plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in acromegaly are limited. High AG/UAG ratios are linked with type 2 diabetes, obesity, and hyperphagia (e.g., in Prader-Willi syndrome). Objective: To assess fasting plasma AGand UAG levels, and the AG/UAG ratio in acromegaly patients receiving combination treatment of long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV; n = 60). We used as controls acromegaly patients whose disease was controlled with PEGV monotherapy and medically näve patients with active acromegaly. Methods: Fasting venous blood samples were collected and directly stabilized to inhibit deacylation of AG. Plasma AG and UAG levels were determined by double-antibody sandwich enzyme immunoassay, and the AG/UAG ratio was calculated. Results: Plasma AG and UAG levels were significantly lower in patients with acromegaly receiving combination treatment [median, interquartile range (IQR): AG: 8.5 pg/mL, 2.9 to 21.1 pg/mL; UAG: 26.9 pg/mL, 11.2 to 42.1 pg/mL] compared with patients using PEGV alone [AG: 60.5 pg/mL (IQR, 58.8 to 77.4 pg/mL); UAG: 153.7 pg/mL (IQR, 127.3 to 196.0 pg/mL)] and medically näve patients with acromegaly [AG: 24.0 pg/mL (IQR, 12.6 to 49.7 pg/mL); UAG: 56.3 pg/mL (IQR, 43.4 to 61.5 pg/mL)]. However, AG/UAG ratios were similar in all groups. Conclusions: Although plasma AG and UAG are suppressed during combination treatment with LASSAs and PEGV, the AG/UAG ratio remained similar. This shows that SSAs decrease both AG and UAG levels, which suggests that they do not alter metabolism significantly in acromegaly patients

Inactive lifestyles and sedentary behavior in persons with chronic aneurysmal subarachnoid hemorrhage: Evidence from accelerometer-based activity monitoring

Background: Aneurysmal subarachnoid hemorrhage (a-SAH) is a potential life-threatening stroke. Because survivors may be at increased risk for inactive and sedentary lifestyles, this study evaluates physical activity (PA) and sedentary behavior (SB) in the chronic phase after a-SAH. Methods: PA and SB were objectively measured at six months post a-SAH with an accelerometer-based activity monitor, with the aim to cover three consecutive weekdays. Total time spent in PA (comprising walking, cycling, running and non-cyclic movement) and SB (comprising sitting and lying) was determined. Also, in-depth analyses were performed to determine the accumulation and distribution of PA and SB throughout the day. Binary time series were created to determine the mean bout length and the fragmentation index. Measures of PA and SB in persons with a-SAH were compared to those in sex- and age-matched healthy controls. Results: The 51 participants comprised 33 persons with a-SAH and 18 controls. None of the participants had signs of paresis or spasticity. Persons with a-SAH spent 105 min/24 h being physically active, which was 35 min/24 h less than healthy controls (p = 0.005). For PA, compared with healthy controls, the mean bout length was shorter in those with a-SAH (12.0 vs. 13.5 s, p = 0.006) and the fragmentation index was higher (0.053 vs. 0.041, p < 0.001). Total sedentary time during waking hours showed no significant difference between groups (514 min vs. 474 min, p = 0.291). For SB, the mean bout length was longer in persons with a-SAH (122.3 vs. 80.5 s, p = 0.024), whereas there was no difference in fragmentation index between groups (0.0032 vs 0.0036, p = 0.396). Conclusions: Persons with a-SAH are less physically active, they break PA time into shorter periods, and SB periods last longer compared to healthy controls. Since inactive lifestyles and prolonged uninterrupted periods of SB are independent risk factors for poor cardiovascular health, interventions seem necessary and should target both PA and SB. Study registration: Dutch registry number: NTR 2085