This review summarizes 10 years experience with male abusers of anabolic androgenic steroids (AAS). The typical user of AAS is male, aged between 20 and 40 and lifting weights. Illegal AAS are cheap and easily obtained via internet or local suppliers. AAS are mostly used in cycles with a duration between 6 and 18 weeks. Most AAS cycles contain multiple agents, used simultaneously in a dose vastly exceeding a substitution dose. A variety of other performance and image-enhancing drugs are commonly used, including human growth hormone, thyroid hormone, tamoxifen, clomiphene citrate and human chorionic gonadotrophin. Short-term clinical and biochemical side effects are well established. Long-term side effects are uncertain, but may include heart failure, mood-and anxiety disorders, hypogonadism and subfertility. We share our views on the management of common health problems associated with AAS abuse.
Willem de Ronde and Diederik L Smit
Michael Ulm, Arvind V Ramesh, Keely M McNamara, Suriyan Ponnusamy, Hironobu Sasano, and Ramesh Narayanan
Hormonal cancers affect over 400,000 men and women and contribute collectively to over 100,000 deaths in the United States alone. Thanks to advances in the understanding of these cancers at the molecular level and to the discovery of several disease-modifying therapeutics, the last decade has seen a plateauing or even a decreasing trend in the number of deaths from these cancers. These advanced therapeutics not only effectively slow the growth of hormonal cancers, but also provide an insight on how these cancers become refractory and evolve as an altogether distinct subset. This review summarizes the current therapeutic trends in hormonal cancers, with focus on prostate, breast and ovarian cancers. The review discusses the clinical drugs being used now, promising molecules that are going through various stages of development and makes some predictions on how the therapeutic landscape will shift in the next decade.
Shruti Khare, Anurag R Lila, Hiren Patt, Chaitanya Yerawar, Manjunath Goroshi, Tushar Bandgar, and Nalini S Shah
Macroprolactinomas are the most common functional pituitary tumours. Hypotheses proposed to explain predominance of large tumours in males are: i) diagnostic delay, as hyperprolactinaemia remains under recognised in males and ii) gender-specific difference in tumour proliferation indices. Our study objectives are to compare gender differences in clinical, biochemical, radiological features, management outcomes and cabergoline responsiveness in macroprolactinomas. Drug resistance was defined as failure to achieve prolactin normalisation and >50% reduction in tumour volume with cabergoline (3.5 mg/week dose for minimum 6 months duration). The baseline characteristics of 100 patients (56 females and 44 males) with macroprolactinoma were analysed. Drug responsiveness was analysed in 88 treatment naive patients, excluding 12 post-primary trans-sphenoidal surgery cases. We found that females (30.29±10.39 years) presented at younger mean age than males (35.23±9.91 years) (P<0.01). The most common presenting symptom was hypogonadism (oligo-amenorrhoea/infertility) in females (96.15%) and symptoms of mass effect (headache and visual field defects) in males (93.18%). Baseline mean prolactin levels were significantly lower in females (3094.36±6863.01 ng/ml) than males (7927.07±16 748.1 ng/ml) (P<0.001). Maximal tumour dimension in females (2.49±1.48 cm) was smaller than males (3.93±1.53 cm) (P<0.001). In 88 treatment naïve patients, 27.77% females and 35.29% males had resistant tumours (P=0.48). On subgrouping as per maximum tumour dimension (1.1–2 cm, 2.1–4 cm and >4 cm), gender difference in response rate was insignificant. In conclusion, macroprolactinomas are equally prevalent in both sexes. Macroprolactinomas in males predominantly present with symptoms of mass effects, as against females who present with symptoms of hypogonadism. Males harbor larger tumours but are equally cabergoline responsive as those in females.
Enrique Soto-Pedre, Paul J Newey, John S Bevan, and Graham P Leese
High serum prolactin concentrations have been associated with adverse health outcomes in some but not all studies. This study aimed to examine the morbidity and all-cause mortality associated with hyperprolactinaemia.
A population-based matched cohort study in Tayside (Scotland, UK) from 1988 to 2014 was performed. Record-linkage technology was used to identify patients with hyperprolactinaemia that were compared to an age–sex-matched cohort of patients free of hyperprolactinaemia. The number of deaths and incident admissions with diabetes mellitus, cardiovascular disease, cancer, breast cancer, bone fractures and infectious conditions were compared by the survival analysis.
Patients with hyperprolactinaemia related to pituitary tumours had no increased risk of diabetes, cardiovascular disease, bone fractures, all-cause cancer or breast cancer. Whilst no increased mortality was observed in patients with pituitary microadenomas (HR = 1.65, 95% CI: 0.79–3.44), other subgroups including those with pituitary macroadenomas and drug-induced and idiopathic hyperprolactinaemia demonstrated an increased risk of death. Individuals with drug-induced hyperprolactinaemia also demonstrated increased risks of diabetes, cardiovascular disease, infectious disease and bone fracture. However, these increased risks were not associated with the degree of serum prolactin elevation (P trend > 0.3). No increased risk of cancer was observed in any subgroup.
No excess morbidity was observed in patients with raised prolactin due to pituitary tumours. Although the increased morbidity and mortality associated with defined patient subgroups are unlikely to be directly related to the elevation in serum prolactin, hyperprolactinaemia might act as a biomarker for the presence of some increased disease risk in these patients.
Metin Guclu, Sinem Kiyici, Zulfiye Gul, and Sinan Cavun
In the present study, we investigated the long-term effects of exenatide treatment on serum fasting ghrelin levels in patients with type 2 diabetes mellitus.
Type 2 diabetic patients, who were using metformin with and without the other antihyperglycemic drugs on a stable dose for at least 3 months, were enrolled in the study. BMI>35 kg/m2 and HbA1c>7.0% were the additional inclusion criteria. Oral antihyperglycemic drugs, other than metformin, were stopped, and metformin treatment was continued at 2000 mg per day. Exenatide treatment was initiated at 5 µg per dose subcutaneously (sc) twice daily, and after one month, the dose of exenatide was increased to 10 µg twice daily. Changes in anthropometric variables, glycemic control, lipid parameters and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment.
Thirty-eight patients (male/female = 7/31) entered the study. The mean age of patients was 50.5 ± 8.8 years with a mean diabetes duration of 8.5 ± 4.9 years. The mean BMI was 41.6 ± 6.3 kg/m2 and the mean HbA1c of patients was 8.9 ± 1.4%. The mean change in the weight of patients was −5.6 kg and the percentage change in weight was −5.2 ± 3.7% following 12 weeks of treatment. BMI, fasting plasma glucose and HbA1c levels of patients were decreased significantly (P < 0.001 and P < 0.001; respectively), while there was no change in lipid parameters. Serum fasting ghrelin levels were significantly suppressed following 12 weeks of exenatide treatment compared with baseline values (328.4 ± 166.8 vs 245.3 ± 164.8 pg/mL) (P = 0.024).
These results suggest that the effects of exenatide on weight loss may be related with the suppression of serum fasting ghrelin levels, which is an orexigenic peptide.
Eva Olga Melin, Jonatan Dereke, Maria Thunander, and Magnus Hillman
Neuroinflammatory responses are implicated in depression. The aim was to explore whether depression in patients with type 1 diabetes (T1D) was associated with high circulating galectin-3, controlling for metabolic variables, s-creatinine, life style factors, medication and cardiovascular complications.
Participants were T1D patients (n = 283, 56% men, age 18–59 years, diabetes duration ≥1 year). Depression was assessed by Hospital Anxiety and Depression Scale-depression subscale. Blood samples, anthropometrics and blood pressure were collected, and supplemented with data from medical records and the Swedish National Diabetes Registry. Galectin-3 ≥2.562 µg/l, corresponding to the 85th percentile, was defined as high galectin-3.
Median (quartile1, quartile3) galectin-3 (µg/l) was 1.3 (0.8, 2.9) for the 30 depressed patients, and 0.9 (0.5, 1.6) for the 253 non-depressed, P = 0.009. Depression was associated with high galectin-3 in all the 283 patients (adjusted odds ratio (AOR) 3.5), in the 161 men (AOR 3.4), and in the 122 women (AOR 3.9). HbA1c, s-lipids, s-creatinine, blood pressure, obesity, smoking, physical inactivity, cardiovascular complications and drugs (antihypertensive, lipid lowering, oral antidiabetic drugs and antidepressants) were not associated with high galectin-3.
This is the first study to show an association between depression and galectin-3. Depression was the only explored parameter associated with high circulating galectin-3 levels in 283 T1D patients. High galectin-3 levels might contribute to the increased risk for Alzheimer’s disease, cardiovascular and all-cause mortality observed in persons with depression. Potentially, in the future, treatment targeting galactin-3 might improve the prognosis for patients with high galectin-3 levels.
Maurício Martins da Silva, Lueni Lopes Felix Xavier, Carlos Frederico Lima Gonçalves, Ana Paula Santos-Silva, Francisca Diana Paiva-Melo, Mariana Lopes de Freitas, Rodrigo Soares Fortunato, Leandro Miranda-Alves, and Andrea Claudia Freitas Ferreira
Bisphenol A (BPA) is the most common monomer in polycarbonate plastics and an endocrine disruptor. Though some effects of BPA on thyroid hormone (TH) synthesis and action have been described, the impact of this compound on thyroid H2O2 generation remains elusive. H2O2 is a reactive oxygen species (ROS), which could have deleterious effect on thyrocytes if in excess. Therefore, herein we aimed at evaluating the effect of BPA exposition both in vivo and in vitro on H2O2 generation in thyrocytes, besides other essential steps for TH synthesis. Female Wistar rats were treated with vehicle (control) or BPA 40 mg/kg BW for 15 days, by gavage. We then evaluated thyroid iodide uptake, mediated by sodium-iodide symporter (NIS), thyroperoxidase (TPO) and dual oxidase (DOUX) activities (H2O2 generation). Hydrogen peroxide generation was increased, while iodide uptake and TPO activity were reduced by BPA exposition. We have also incubated the rat thyroid cell line PCCL3 with 10−9 M BPA and evaluated Nis and Duox mRNA levels, besides H2O2 generation. Similar to that found in vivo, BPA treatment also led to increased H2O2 generation in PCCL3. Nis mRNA levels were reduced and Duox2 mRNA levels were increased in BPA-exposed cells. To evaluate the importance of oxidative stress on BPA-induced Nis reduction, PCCL3 was treated with BPA in association to N-acetylcysteine, an antioxidant, which reversed the effect of BPA on Nis. Our data suggest that BPA increases ROS production in thyrocytes, what could lead to oxidative damage thus possibly predisposing to thyroid disease.
Maria Luisa Brandi, Stefania Bandinelli, Teresa Iantomasi, Francesca Giusti, Eleonora Talluri, Giovanna Sini, Fabrizio Nannipieri, Santina Battaglia, Riccardo Giusti, Colin Gerard Egan, and Luigi Ferrucci
This study aimed to evaluate the association between the endocrine-disrupting chemical, bisphenol A (BPA) on circulating levels of 25-hydroxy vitamin D (25(OD)D) and other vitamin D metabolites in an elderly population in Italy.
This was a retrospective analysis of the InCHIANTI Biobank in Italy. The association between vitamin D metabolites namely 1,25(OH)D, 25(OH)D, parathyroid hormone (PTH) and BPA levels were evaluated. Multiple regression models were used to examine the association between predictor variables with 1,25(OH)D or 25(OH)D levels.
Samples from 299 individuals aged 72.8 ± 15.7 years were examined. Mean levels of BPA, 1,25(OH)D and 25(OH)D were 351.2 ± 511.6 ng/dL, 43.7 ± 16.9 pg/mL and 20.2 ± 12.1 ng/mL, respectively. One hundred eighty individuals (60.2%) were deficient (<20 ng/mL) in 25(OH)D and this population also presented higher BPA levels (527.9 ± 1289.5 ng/dL vs 86.9 ± 116.8 ng/dL, P < 0.0001). Univariate analysis revealed that BPA levels were negatively correlated with both 1,25(OH)D (r= −0.67, P < 0.0001) and 25(OH)D (r= −0.69, P < 0.0001). Multivariate regression revealed that PTH (β: −0.23, 95% CI: −0.34, −0.13, P < 0.0001) and BPA (β: −0.25, 95% CI: −0.3, −0.19, P < 0.0001) remained significantly associated with 25(OH)D levels while BPA was also associated with 1,25(OH)D levels (β: −0.19, 95% CI: −0.22, −0.15, P < 0.0001). Receiver operating characteristic curve analysis showed that a BPA concentration of >113 ng/dL was the best cut-off to predict individuals deficient in 25(OH)D (area under the curve: 0.87, 95% CI: 0.82–0.90, P < 0.0001).
The strong negative association between BPA and vitamin D in this elderly population warrants further investigation, particularly since this population is already at greatest risk of hypovitaminosis and fracture.
Stine Linding Andersen and Stig Andersen
The management of hyperthyroidism in pregnant patients has been a topic of raised clinical awareness for decades. It is a strong recommendation that overt hyperthyroidism of Graves’ disease in pregnant women should be treated to prevent complications. The consequences of hyperthyroidism in pregnancy are less studied than hypothyroidism, and a literature review illustrates that the main burden of evidence to support current clinical guidance emerges from early observations of severe complications in Graves’ disease patients suffering from untreated hyperthyroidism in the pregnancy. On the other hand, the more long-term consequences in children born to mothers with hyperthyroidism are less clear. A hypothesis of fetal programming by maternal hyperthyroidism implies that excessive levels of maternal thyroid hormones impair fetal growth and development. Evidence from experimental studies provides clues on such mechanisms and report adverse developmental abnormalities in the fetal brain and other organs. Only few human studies addressed developmental outcomes in children born to mothers with hyperthyroidism and did not consistently support an association. In contrast, large observational human studies performed within the last decade substantiate a risk of teratogenic side effects to the use of antithyroid drugs in early pregnancy. Thus, scientific and clinical practice are challenged by the distinct role of the various exposures associated with Graves’ disease including the hyperthyroidism per se, the treatment, and thyroid autoimmunity. More basic and clinical studies are needed to extend knowledge on the effects of each exposure, on the potential interaction between exposures and with other determinants, and on the underlying mechanisms.
Anastasia K Armeni, Konstantinos Assimakopoulos, Dimitra Marioli, Vassiliki Koika, Euthychia Michaelidou, Niki Mourtzi, Gregoris Iconomou, and Neoklis A Georgopoulos
Over the past decades, research attention has increasingly been paid to the neurobiological component of sexual behavior. The aim of the present study was to investigate the correlation of estrogen receptor α (ERA) gene polymorphism (rs2234693-PvuII) (T→C substitution) and oxytocin receptor gene polymorphism (rs53576) (G→A substitution) with sexuality parameters of young, healthy women. One hundred thirty-three Greek heterosexual women, students in higher education institutions, 20–25 years of age, sexually active, with normal menstrual cycles (28–35 days), were recruited in the study. Exclusion criteria were chronic and/or major psychiatric diseases, use of oral contraceptive pills (OCs), polycystic ovary syndrome (PCOS), thyroid diseases as well as drugs that are implicated in hypothalamus–pituitary–gonadal axis. T allele (wildtype) of rs2234693 (PvuII) polymorphism of ERA gene was correlated with increased levels of arousal and lubrication, whereas A allele (polymorphic) of rs53576 (OXTR) polymorphism was correlated with increased arousal levels. The simultaneous presence of both T allele of rs2234693 (PvuII) and A allele of rs53576 (OXTR) polymorphisms (T + A group) was correlated with increased arousal, orgasm levels as well as female sexual function index full score. To our knowledge, this is the first study to investigate the interaction between ERA and OXTR with regard to sexual function in women. Female sexuality is a complex behavioral trait that encompasses both biological and psychological components. It seems that variability in female sexual response stems from genetic variability that characterizes endocrine, neurotransmitter and central nervous system influences.