Teratogenic of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) on Eye Diameters and Body Weight in Chicken Embryo

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a chemical compound resulting from the burning effect that is very dangerous for humans, plants, or animals which can cause skin damage, immunotoxic, hepatotoxic, carcinogenic, teratogenic, effects on reproduction, growth processes, neurobehavioral, and endocrine effects that are specific In addition, this compound can also reduce embryo weight and increase embryo mortality. This study aimed to determine the teratogenic of TCDD administration on eye diameters and body weight of chicken embryo. In this study there were 2 treatment groups, i.e: 1) P1 as a normal group without the addition of TCDD, and 2) P2 as a group with the addition of TCDD of 5 ng / egg with dissolved in 5 µL corn oil. The treatment was carried out for 7 days. The measurement data of eye diameters and body weight of chicken embryo were analyzed by the unpaired sample T test. The analysis showed that the teratogenic of TCDD had a significant effect on eye diameters and body weight of chicken embryos, where the teratogenic of TCDD caused a decrease in eye diameters and body weight loss in chicken embryos.

Late Endocrine Effects After HSCT in Children With Nonmalignant Diseases; A Single Center Cohort Analysis

Endocrine complications are amongst the most frequent late effects after pediatric hematopoietic stem cell transplantation (HSCT) for malignant diseases. Little is known about the prevalence and risk factors of endocrine complications in children transplanted for nonmalignant diseases. This retrospective study included 134 males and 63 females transplanted for a non-malignant disease between 1997 and 2018 with at least 2 years of follow up. Endocrine late effects and growth were evaluated. Gonadal dysfunction was defined as transient or permanent elevation of gonadotropins or hypogonadotropic hypogonadism. Median age at HSCT was 5.7 years (IQR 2.8-11.3) and median follow-up was 6.2 years (IQR 3.0-10.4). Underlying diseases were inborn errors of immunity (n=74), hemoglobinopathies (n=66) and bone marrow failure (n=57). The majority of patients had received busulfan-based conditioning (46%) or treosulfan-based conditioning (34%). Gonadal dysfunction occurred in 24/44 (post)pubertal female patients (55%) and was permanent in 19/44 (43%). 22/44 received hormonal substitution, which could be discontinued in 7. In females who received busulfan-based conditioning 16/17 (94%) developed gonadal dysfunction compared to 5/15 (33%) patients with treosulfan-based conditioning; the odds ratio for permanent gonadal dysfunction was 18.7 (3.61-135, p=0.001). Gonadal dysfunction occurred in 28/66 (post)pubertal male patients (42%) and was permanent in 23/66 (35%). 6/66 received hormonal substitution, which could be discontinued in 1. Gonadal dysfunction was more common in males (post)pubertal at HSCT, 14/21 (67%), compared to those prepubertal at HSCT, 14/45 (31%), p=0.014. 3/15 treated with a treosulfan-based regimen (20%) developed gonadal dysfunction, all transient, versus 19/39 with a busulfan-based regimen (49%), with 2 transient. 29/187 patients developed hypothyroidism (16%), 7 patients received thyroxine treatment (4%). All patients with persistent primary hypothyroidism (n=6) had positive TPO-antibodies. 17 patients received growth hormone treatment and were excluded from analysis. In patients without growth hormone treatment near adult height (NAH) was -1.2 SDS (median, IQR -2.0- -0.3) below mean parental height (MPH) in males and -0.4 SDS (median, IQR -1.6-0.3) in females. NAH below -2 SDS was seen in 13/43 males (30%) and 2/36 females (6%). The majority of these patients already had a height below -2 SDS before HSCT (73%). In conclusion, this study on late endocrine effects after HSCT in children with nonmalignant diseases indicates frequent gonadal dysfunction, present in 55% of females and 42% of males. In this cohort, risk of gonadal dysfunction in females was higher after busulfan-based conditioning than treosulfan-based conditioning. Careful long-term endocrine follow-up is indicated.

Mitotane in the Treatment of Adrenocortical Carcinoma: Metabolic and Endocrine Disruption

Background: Mitotane is a well-known adrenocytolitic agent resulting in adrenal insufficiency. However, little is known about its multiple and complex metabolic and endocrine effects. Clinical Case: Patient is a 6 year 9 month old female who presented with acne, pubic hair and rapid weight gain. Initial evaluation showed elevated testosterone (64 ng/dL), 17-OH-progesterone (236 ng/dL), DHEA-S (922 mcg/dL), and random cortisol (30.9 mcg/dL) with suppressed ACTH (<2.0 pg/mL). She had an inappropriate lack of suppression after a 1 mg overnight dexamethasone suppression test (cortisol 49 mcg/dL, nl <2 mcg/dL). Abdominal CT showed large necrotic-appearing right adrenal mass (10.7x8.8x15 cm) with no metastasis. Surgical excision was complicated by intraoperative rupture. Pathology confirmed stage III right adrenal cortical carcinoma. Patient was started on etoposide, cisplatin, doxorubicin, and mitotane as adjuvant therapy. 6 days after surgery, her DHEA-S and cortisol levels were undetectable. She was started on glucocorticoid replacement therapy with hydrocortisone at 18 mg/m2/day. Due to severe nausea, she was switched to dexamethasone 5 mg/m2/day (245 mg/m2/day dose equivalent to hydrocortisone). However, the patient developed hypotension, increased nausea and emesis and was switched back to hydrocortisone. The patient’s clinical course was complicated by hyperlipidemia with total cholesterol 215 mg/dL, HDL 48 mg/dL and LDL 150 mg/dL, as well as central hypothyroidism with low FT4 (0.8 ng/dL) and an inappropriately low normal TSH (0.31 mcIU/mL). She was started on levothyroxine with a final dose of 2.6mcg/kg/day to achieve euthyroid state. Mineralocorticoid deficiency has been reported in a small number of case reports of mitotane use. Our patient continues to demonstrate adequate mineralocorticoid function based on her normal electrolytes, aldosterone and plasma renin activity level. Conclusion: Mitotane exerts multiple clinically relevant metabolic and endocrine effects. Patients treated with mitotane should be monitored for complications including mineralocorticoid deficiency, central hypothyroidism, and hyperlipidemia. Dexamethasone must be avoided because of the rapid inactivation by CYP4503A4 leading to adrenal crisis. Typical glucocorticoid replacement dose must be doubled due to induction of CYP3A4 activity that leads to glucocorticoid inactivation.

Insulin/IGF Axis in Breast Cancer: Clinical Evidence and Translational Insights

Background: Breast cancer (BC) is the most common neoplasm in women. Many clinical and preclinical studies investigated the possible relationship between host metabolism and BC. Significant differences among BC subtypes have been reported for glucose metabolism. Insulin can promote tumorigenesis through a direct effect on epithelial tissues or indirectly by affecting the levels of other modulators, such as the insulin-like growth factor (IGF) family of receptors, sex hormones, and adipokines. The potential anti-cancer activity of metformin is based on two principal effects: first, its capacity for lowering circulating insulin levels with indirect endocrine effects that may impact on tumor cell proliferation; second, its direct influence on many pro-cancer signaling pathways that are key drivers of BC aggressiveness. Methods: In the present review, the interaction between BC, host metabolism, and patients’ prognosis has been reviewed across available literature evidence. Conclusions: Obesity, metabolic syndrome, and insulin resistance are all involved in BC growth and could have a relevant impact on prognosis. All these factors act through a pro-inflammatory state, mediated by cytokines originated in fat tissue, and seem to be related to a higher risk of BC development and worse prognosis.