Martin, Yvette N.

Background and objectives Buprenorphine is a partial µ-receptor agonist resistant to displacement from receptors by conventional opioids, which can block the effect of conventional opioids and may interfere with postoperative pain management. We aimed to quantify perioperative opioid use in patients receiving transdermal buprenorphine (TdBUP). Methods We identified patients receiving TdBUP who underwent surgery between 2004 and 2016. To compare opioid requirements (intravenous morphine equivalents (IV-MEq)), we constructed a matched study, matching each TdBUP patient with two opioid-naive patients by sex, age, and type of anesthesia and procedure. Results Nineteen unique patients underwent 22 procedures while receiving TdBUP. Total (IQR) amounts of IV-MEq (intraoperative, recovery room, and 24 hours after recovery-room discharge) were 98 (63, 145) and 46 (30, 65) mg IV-MEq for TdBUP and opioid-naive patients, respectively (p<0.001). Postoperative IV-MEq requirements were 54 (38, 90) and 15 (3, 35) mg for TdBUP and opioid-naive patients, respectively (p<0.001). Among TdBUP patients, higher preoperative doses of TdBUP were associated with greater postoperative opioid requirements (p=0.02). Specifically, patients with a 20 µg/hour TdBUP patch required 133.8 mg IV-MEq more postoperatively than patients with a 5 µg/hour patch (p=0.002). Following discharge from the recovery room, 17 (77%) TdBUP patients and 15 (34%) opioid-naive patients reported severe pain (OR 6.6 (95% CI 2.0 to 21.3); p<0.001; adjusting for baseline pain score, 5.0 (95% CI, 1.4 to 17.8); p=0.01). Conclusions Analgesic management for patients receiving TdBUP therapy must account for increased opioid needs, and greater preoperative doses of TdBUP were associated with greater postoperative opioid requirements.

Supplemental oxygen, used to treat hypoxia in preterm and term neonates, increases the risk of neonatal lung diseases, such as bronchopulmonary dysplasia (BPD) and asthma. There is a known sex predilection for BPD, but the underlying mechanisms are not clear. We tested the hypothesis that altered, local estradiol following hyperoxia contributes to pathophysiological changes observed in immature lung. In human fetal airway smooth muscle (fASM) cells exposed to normoxia or hyperoxia, we measured the expression of proteins involved in estrogen metabolism and cell proliferation responses to estradiol. In fASM cells, CYP1a1 expression was increased by hyperoxia, whereas hyperoxia-induced enhancement of cell proliferation was blunted by estradiol. Pharmacological studies indicated that these effects were attributable to upregulation of CYP1a1 and subsequent increased metabolism of estradiol to a downstream intermediate 2-methoxyestradiol. Microarray analysis of mouse lung exposed to 14 days of hyperoxia showed the most significant alteration in CYP1a1 expression, with minimal changes in expression of five other genes related to estrogen receptors, synthesis, and metabolism. Our novel results on estradiol metabolism in fetal and early postnatal lung in the context of hyperoxia indicate CYP1a1 as a potential mechanism for the protective effect of estradiol in hyperoxia-exposed immature lung, which may help explain the sex difference in neonatal lung diseases.

Pulmonary arterial hypertension (PAH), a form of pulmonary hypertension, is a complex disease of multifactorial origin. While new developments regarding pathophysiological features and therapeutic options in PAH are being reported, one important fact has emerged over the years: there is a sex difference in the incidence of this disease such that while there is a higher incidence in females, disease outcomes are much worse in males. Accordingly, recent attention has been focused on understanding the features of sex differences in the pulmonary circulation and the contributory mechanisms, particularly sex hormones and their role in the pathological and pathophysiological features of PAH. However, to date, there is no clear consensus whether sex hormones (particularly female sex steroids) are beneficial or detrimental in PAH. In this review, we highlight some of the most recent evidence regarding the influence of sex hormones (estrogen, testosterone, progesterone, dehydroepiandrosterone) and estrogen metabolites on key pathophysiological features of PAH such as proliferation, vascular remodeling, vasodilation/constriction, and inflammation, thus setting the stage for research avenues to identify novel therapeutic target for PAH as well as potentially other forms of pulmonary hypertension.

Abstract Aromatase (CYP19) is a critical enzyme in estrogen biosynthesis and aromatase inhibitors (AI) are employed widely for endocrine therapy in postmenopausal women with breast cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in the CYP19 gene may alter the effectiveness of AI therapy in the neoadjuvant setting. Genomic DNA was obtained for sequencing from 52 women pre-AI and post-AI treatment in this setting. Additionally, genomic DNA obtained from 82 samples of breast cancer and 19 samples of normal breast tissue was subjected to resequencing. No differences in CYP19 sequence were observed between tumor and germ-line DNA in the same patient. A total of 48 SNPs were identified including 4 novel SNPs when compared with previous resequencing data. For genotype-phenotype association studies, we determined the levels of aromatase activity, estrone, estradiol, and tumor size in patients pre-AI and post-AI treatment. We defined two tightly linked SNPs (rs6493497 and rs7176005 in the 5'-flanking region of CYP19 exon 1.1) that were significantly associated with a greater change in aromatase activity after AI treatment. In a follow-up study of 200 women with early-stage breast cancer who were treated with adjuvant anastrozole, these same two SNPs were also associated with higher plasma estradiol levels in patients pre-AI and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed likely functional effects of these two SNPs on transcription of CYP19. Our findings indicate that two common genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to aromatase inhibitors. Cancer Res; 70(1); 319–28