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NEJM Evidence Jan 2024BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes...
BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: CYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes. RESULTS: Ninety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2. CONCLUSIONS: ODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)
Topics: Male; Humans; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Cholesterol Side-Chain Cleavage Enzyme; Prostate-Specific Antigen; Treatment Outcome; Androgen Receptor Antagonists
PubMed: 38320513
DOI: 10.1056/EVIDoa2300171 -
Gynecologic and Obstetric Investigation 2024Insulin resistance (IR) and compensatory hyperinsulinemia are considered contributing factors toward polycystic ovary syndrome (PCOS).
The Effects of Myo-Inositol and D-Chiro-Inositol in a Ratio 40:1 on Hormonal and Metabolic Profile in Women with Polycystic Ovary Syndrome Classified as Phenotype A by the Rotterdam Criteria and EMS-Type 1 by the EGOI Criteria.
SETTING
Insulin resistance (IR) and compensatory hyperinsulinemia are considered contributing factors toward polycystic ovary syndrome (PCOS).
OBJECTIVES
This study evaluates the frequency of metabolic abnormalities in PCOS patients and the effects of myo-inositol (MI) and D-chiro-inositol (DCI), in a 40:1 ratio on hormonal and metabolic parameters.
PARTICIPANTS
Thirty-four women with PCOS phenotype A (endocrine-metabolic syndrome [EMS-type 1]) between the ages of 20-40.
DESIGN
Open prospective study with phenotype A (EMS-type I, n = 34) supplemented with 2,255 mg/day of inositol (MI and DCI in a 40:1 ratio) for 3 months.
METHODS
The following were measured before and after treatment: serum levels of follicular stimulating hormone, luteinizing hormone (LH), estradiol, total and free testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), anti-Müllerian hormone, glucose, insulin, HOMA-IR, and body mass index (BMI).
RESULTS
55.9% of the enrolled patients were overweight or obese, 50% affected by IR, 17.6% with a history of gestational diabetes mellitus, and 61.8% had familial diabetes mellitus. At the conclusion of the study, BMI (p = 0.0029), HOMA-IR (p < 0.001) significantly decreased, along with decreased numbers of patients with elevated insulin levels. The supplementation resulted in decreased total testosterone (p < 0.001), free testosterone (p < 0.001), FAI (p < 0.001), and LH (p < 0.001); increased SHBG (p < 0.001) and estradiol (p < 0.001).
LIMITATIONS
The present analysis was limited to a 12-week follow-up, which precluded a long-term evaluation of the effects of MI and DCI combination. Also, this period was insufficient to achieve and analyze clinical changes such as restoration of the menstrual cycle, restoration of reproductive function, and clinical manifestations of hyperandrogenism.
CONCLUSIONS
Supplementation improved metabolic and hormonal profile in PCOS phenotype A (EMS-type I) patients. This builds upon previous work that demonstrated that combined inositol treatment may be effective in PCOS. The study presented herein, used a reduced concentration than in prior literature; however, a significant change in hormonal and metabolic parameters was still observed.
Topics: Female; Humans; Young Adult; Adult; Polycystic Ovary Syndrome; Inositol; Prospective Studies; Luteinizing Hormone; Insulin; Insulin Resistance; Estradiol; Testosterone; Phenotype; Metabolome
PubMed: 38295772
DOI: 10.1159/000536163 -
Frontiers in Endocrinology 2023There is insufficient attention to hypogonadism in Chinese males with type 2 diabetes mellitus (T2DM). We evaluated the relationship between Combined obesity- and...
BACKGROUND
There is insufficient attention to hypogonadism in Chinese males with type 2 diabetes mellitus (T2DM). We evaluated the relationship between Combined obesity- and lipid-related indices [Visceral Adiposity Index (VAI), Chinese Visceral Adiposity Index (CVAI), Triglyceride Glucose Index (TyG) and Lipid Accumulation Product (LAP)] with total testosterone (TT) and analyzed the predictive capability of the respective cut-off values.
METHODS
We recruited 958 hospitalized male patients with T2DM at the Affiliated Hospital of Qingdao University, collected baseline data and four calculated indices, and obtained their dominance ratio (OR) and corresponding 95% confidence intervals (CI) with TT by multivariate logistic regression. Receiver operating characteristic (ROC) curves were then used to determine cutoff values in predicting hypogonadism (TT< 12 nmol/L), and we also analyzed the combinations between the different indices.
RESULTS
VAI, CVAI, TyG, and LAP all have satisfactory predictive capabilities. The test capability (sensitivity and specificity) of all four indices was better or not worse than that of body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and waist circumference (WC). All four indices were effective predictors of hypogonadism at their respective cutoff values (VAI ≥ 2.284, CVAI ≥ 145.779, TyG ≥ 4.308, and LAP ≥ 59.850). Of these, LAP had the largest area under the curve (AUC, AUC = 0.852, Std. Error = 0.014, 95% CI = 0.818-0.873). However, the predictive capability of the combined indices was not significantly improved over the individual indices.
CONCLUSIONS
VAI, CVAI, TyG, and LAP are sensitive indices for predicting hypogonadism in Chinese male patients with T2DM. Considering the need for concise and accurate indices in clinical practice, we suggest LAP as a commonly used index.
Topics: Humans; Male; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Obesity; Testosterone; Glucose; Triglycerides; Hypogonadism; China
PubMed: 38260153
DOI: 10.3389/fendo.2023.1319582 -
Reviews in Endocrine & Metabolic... Jun 2024Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal... (Review)
Review
Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal insufficiency. The consequences of androgen deficiency and the effects of androgen replacement therapy have not been fully elucidated. While an impact of androgen deficiency on outcomes such as bone mineral density, quality of life, and sexual function is plausible, the available evidence is limited. There is currently no consensus on the definition of androgen deficiency in women and it is still controversial whether androgen substitution should be used in women with hypopituitarism and coexisting androgen deficiency. Some studies suggest beneficial clinical effects of androgen replacement but data on long-term benefits and risk are not available. Transdermal testosterone replacement therapy in hypopituitary women has shown some positive effects on bone metabolism and body composition. Studies of treatment with oral dehydroepiandrosterone have yielded mixed results, with some studies suggesting improvements in quality of life and sexual function. Further research is required to elucidate the impact of androgen deficiency and its replacement treatment on long-term outcomes in women with hypopituitarism. The lack of transdermal androgens for replacement in this patient population and limited outcome data limit its use. A cautious and personalized treatment approach in the clinical management of androgen deficiency in women with hypopituitarism is recommended while awaiting more efficacy and safety data.
Topics: Humans; Androgens; Female; Hypopituitarism; Hormone Replacement Therapy; Hypogonadism; Testosterone; Quality of Life
PubMed: 38240912
DOI: 10.1007/s11154-024-09873-1 -
Annals of Medicine and Surgery (2012) Jan 2024Edward syndrome is a severe chromosomal defect that occurs as a result of non-disjunction through meiosis. It presents with cardiac septal defects, horseshoe kidneys,...
INTRODUCTION AND IMPORTANCE
Edward syndrome is a severe chromosomal defect that occurs as a result of non-disjunction through meiosis. It presents with cardiac septal defects, horseshoe kidneys, patent ductus arteriosus, central nervous system dysgenesis, distinctive craniofacial deformities, and overriding or overlapping fingers. Klinefelter syndrome (47, XXY) is found in 1 in 660 newborn males. It is considered to be one of the most common genetic causes of infertility. It manifests with small firm testes, androgen insufficiency, and azoospermia.
CASE PRESENTATION
A 2-month-old male infant with a history of weakness in feeding, frequent convulsions, and an increase in cyanosis two days ago. There were multiple skeletal deformities and a tendency to spasm in the extremities, left ventricular atrophy, mitral atresia, atrial septal defect, ventricular septal defect with dilated right cavities, tricuspid valve regurgitation, pulmonary valve stenosis; and the aorta exits in the right ventricle. There is a widening of the subdural space, which was observed in the left frontal-parietal side with cortical atrophy in that area and a widening of the Sylvian fissure. A karyotype test confirmed the presence of Edward and Klinefelter syndromes.
CLINICAL DISCUSSION
Aneuploidy is a chromosomal issue characterized by an abnormal number of a chromosome copies. The coexistence of two aneuploidies is called "double aneuploidy" which is a rare occurrence. Herein, we report a case of a 2-month-old male with Edward syndrome and Klinefelter syndrome.
CONCLUSION
This publication aims to highlight the challenges in diagnosing and treating a complicated genetic disease.
PubMed: 38222680
DOI: 10.1097/MS9.0000000000001468 -
JCEM Case Reports Jan 2024Estrogen-secreting adrenocortical carcinoma (ACC) is exceedingly rare, representing 1% to 2% of all ACCs. We present a case of a 65-year-old man diagnosed with an...
Estrogen-secreting adrenocortical carcinoma (ACC) is exceedingly rare, representing 1% to 2% of all ACCs. We present a case of a 65-year-old man diagnosed with an estrogen-secreting, 4.3-cm right adrenal mass discovered during work-up for bilateral gynecomastia. Gynecomastia and hyperestrogenism resolved after laparoscopic adrenalectomy, and pathology was reported as adrenocortical adenoma. However, 5 years later, he again developed bilateral gynecomastia because of recurrent hyperestrogenism. Imaging revealed multiple metastases in the abdomen. Urine steroid profiling demonstrated increased androgen precursors, androgen metabolites, and glucocorticoid precursors. Ultrasound-guided biopsy of one of the metastases confirmed ACC. Initial therapy included debulking surgery with removal of metastatic lesions. Mitotane therapy was initiated 4 weeks later along with hydrocortisone for anticipated mitotane-induced adrenal insufficiency. Histopathology from the adrenalectomy specimen 5 years earlier was rereviewed and confirmed ACC. Estrogen-secreting adrenal tumors are exceedingly rare, and the majority are malignant. This case underlines the importance of making an initial accurate diagnosis of adrenal malignancy that allows better surgical planning and appropriate monitoring. Indeterminate imaging characteristics of the adrenal mass, as well as the presentation with estrogen excess, suggested an elevated risk for ACC. Initial pathology-based misdiagnosis illustrates the need for an expert adrenal pathologist to review these rare tumors.
PubMed: 38192879
DOI: 10.1210/jcemcr/luad143 -
Cureus Dec 2023Primary adrenal insufficiency (PAI), also known as Addison's disease (AD), is a condition resulting from adrenal gland diseases that lead to glucocorticoid and/or...
Primary adrenal insufficiency (PAI), also known as Addison's disease (AD), is a condition resulting from adrenal gland diseases that lead to glucocorticoid and/or mineralocorticoid deficiency, in addition to androgen deficiency in females. Here, we report a 40-year-old male indoor worker with an insignificant past medical history who presented to the dermatology clinic with a history of asymptomatic, slowly progressive skin hyperpigmentation for the past three years. It was associated with fatigue and weight loss. Skin examination revealed diffuse, non-scaly hyperpigmented patches on his face, dorsae of the hands, and palms. Early morning cortisol and adrenocorticotropic hormone (ACTH) serum levels were 1.00 µg/dl (5.0-19.4 µg/dl) and 2000 pg/mL (7.2-63.3 pg/mL), respectively. Based on the above clinical and laboratory findings, a diagnosis of AD was made. The patient was started on the following medications for 14 days: hydrocortisone 20 mg in divided doses (15 mg am/5 mg pm) and fludrocortisone 0.1 mg once daily (od). On the second visit, the patient's symptoms (both the cutaneous hyperpigmentation and fatigue) significantly improved, but he was complaining of edema in both upper and lower limbs, so the dose of fludrocortisone was reduced to 0.05 mg od.
PubMed: 38164302
DOI: 10.7759/cureus.49837 -
Frontiers in Endocrinology 2023Oxidative stress, resulting from dysregulation in the secretion of adrenal hormones, represents a major concern in human health. The present review comprehensively... (Review)
Review
Oxidative stress, resulting from dysregulation in the secretion of adrenal hormones, represents a major concern in human health. The present review comprehensively examines various categories of endocrine dysregulation within the adrenal glands, encompassing glucocorticoids, mineralocorticoids, and androgens. Additionally, a comprehensive account of adrenal hormone disorders, including adrenal insufficiency, Cushing's syndrome, and adrenal tumors, is presented, with particular emphasis on their intricate association with oxidative stress. The review also delves into an examination of various nutritional antioxidants, namely vitamin C, vitamin E, carotenoids, selenium, zinc, polyphenols, coenzyme Q10, and probiotics, and elucidates their role in mitigating the adverse effects of oxidative stress arising from imbalances in adrenal hormone levels. In conclusion, harnessing the power of nutritional antioxidants has the potential to help with oxidative stress caused by an imbalance in adrenal hormones. This could lead to new research and therapeutic interventions.
Topics: Humans; Antioxidants; Oxidative Stress; Adrenal Glands; Cushing Syndrome; Glucocorticoids
PubMed: 38098868
DOI: 10.3389/fendo.2023.1271521