Serum and hair steroid profiles in patients with nonfunctioning pituitary adenoma undergoing surgery: A prospective observational study.

Patients who undergo transsphenoidal surgery (TSS) experience perioperative hormonal changes, but there are few studies on the perioperative changes of serum and hair steroid profiles. This study investigated the perioperative changes in steroid metabolic signatures in patients with nonfunctioning pituitary adenoma (NFPA) who underwent transsphenoidal surgery (TSS). A total of 55 participants who underwent TSS for NFPA at a single center between July 2017 and October 2018 were enrolled. Fifteen serum steroids and their metabolic ratios were profiled using gas chromatography-mass spectrometry (GC-MS) before and 1 day, 1 week, and 3 months after TSS. Five steroids from hair samples collected 1 day and 3 months after TSS were also quantitatively compared. Serum cortisol and its A-ring reductive metabolites, as well as 6ß-hydroxycortisol, increased dramatically 1 day after TSS and then gradually decreased. Seven serum steroids, including adrenal androgens and mineralocorticoids, and hair cortisone levels were significantly lower in patients with preoperative adrenocorticotropic hormone (ACTH) deficiency (N = 7) than in those without ACTH deficiency (N = 48). Serum levels of dehydroepiandrosterone (DHEA) levels 1 week after TSS predicted ACTH deficiency 3 months after TSS, with 100 % sensitivity and 86 % specificity. A significant positive correlation between the preoperative serum and hair DHEA levels (r = 0.356, P = 0.008) was observed. These findings suggest that the levels of DHEA in both the serum and hair could be an early marker of ACTH deficiency after TSS. In addition, hair cortisone may be a useful preoperative indicator of chronic ACTH deficiency.

Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2.

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.