piperidines and Ovarian-Cysts

The purpose of this study was to assess the feasibility of using the selective estrogen receptor modulator (SERM) acolbifene as a breast cancer prevention agent in premenopausal women. To do so, we assessed change in proliferation in benign breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) as a primary endpoint, along with changes in other risk biomarkers and objective and subjective side effects as secondary endpoints. Twenty-five women with cytologic hyperplasia ± atypia and ≥2% of breast epithelial cells staining positive for Ki-67, received 20 mg acolbifene daily for 6-8 months, and then had benign breast tissue and blood risk biomarkers reassessed. Ki-67 decreased from a median of 4.6% [interquartile range (IQR), 3.1%-8.5%] at baseline to 1.4% (IQR, 0.6%-3.5%) after acolbifene (P < 0.001; Wilcoxon signed-rank test), despite increases in bioavailable estradiol. There were also significant decreases in expression (RT-qPCR) of estrogen-inducible genes that code for pS2, ERα, and progesterone receptor (P ≤ 0.026). There was no significant change in serum IGF1, IGFBP3, IGF1:IGFBP3 ratio, or mammographic breast density. Subjective side effects were minimal with no significant increase in hot flashes, muscle cramps, arthralgias, or fatigue. Objective measures showed a clinically insignificant decrease in lumbar spine bone density (DEXA) and an increase in ovarian cysts but no change in endometrial thickness (sonography). In summary, acolbifene was associated with favorable changes in benign breast epithelial cell proliferation and estrogen-inducible gene expression but minimal side effects, suggesting a phase IIB placebo-controlled trial evaluating it further for breast cancer prevention.

Topics: Adult; Biopsy, Fine-Needle; Bone Density; Breast; Breast Neoplasms; Cell Proliferation; Epithelial Cells; Female; Humans; Ki-67 Antigen; Middle Aged; Ovarian Cysts; Pilot Projects; Piperidines; Premenopause; Real-Time Polymerase Chain Reaction; Risk Factors; Selective Estrogen Receptor Modulators; Transcriptome

Stress response to surgery is modulated by several factors, including magnitude of the injury, pain, type of procedure and choice of anaesthesia. Our purpose was to compare intra- and post-operative hormonal changes during total intravenous anaesthesia (TIVA) using propofol and remifentanil vs. sevoflurane anaesthesia in a low stress level surgical model (laparoscopy).. We randomly allocated 18 patients undergoing laparoscopic surgery for benign ovarian cysts in two groups to receive either TIVA (group A=9) or sevoflurane anaesthesia (group B=9). Perioperative plasma levels of norepinephrine (NE), epinephrine (E), adrenocorticotropic hormone (ACTH), cortisol and leptin were measured. Blood samples were collected pre-operatively (time 0), 30 min after the beginning of surgery (time 1), after extubation (time 2), and 2 h (time 3) and 4 h after surgery (time 4).. The comparative analysis between the groups shows significantly higher values of NE (P<0.001 at time 1 and P<0.01 at time 3), E (P<0.001 at times 1 and 2; P<0.01 at time 3 and P<0.05 at time 4), ACTH (P<0.001 at times 1 and 2; P<0.05 at time 3) and cortisol (P<0.001 at times 1 and 2; P<0.01 at time 3; P<0.05 at time 4) in group B. The serum values of leptin were not significantly different between the two groups.. The choice of anaesthesia does not seem to affect the leptin serum levels but influences the release of stress response markers: ACTH, cortisol, NE and E.

Topics: Adrenocorticotropic Hormone; Adult; Anesthesia; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Catecholamines; Epinephrine; Female; Humans; Hydrocortisone; Laparoscopy; Leptin; Methyl Ethers; Monitoring, Physiologic; Neurosecretory Systems; Norepinephrine; Ovarian Cysts; Perioperative Care; Piperidines; Propofol; Remifentanil; Sevoflurane; Time Factors

Monitoring of analgesia remains a challenge during general anaesthesia. Activation of Response Entropy (RE) to painful stimuli has been suggested to be a sign of inadequate analgesia. We evaluated the ability of RE to be more sensitive than State Entropy (SE) in measuring nociception in patients undergoing gynaecological laparoscopy. Our hypothesis was that while keeping SE at a predetermined level, RE would be higher in patients receiving a beta-blocking agent (esmolol) instead of an opioid (remifentanil) during a propofol/nitrous oxide anaesthesia.. Fifty-one women aged between 22-53 years were randomly assigned to receive esmolol (n=25) or remifentanil (n=26). SE was kept at 50+/-5. RE and SE were recorded at an interval of 30 s to 2 min and the areas under the RE and SE value-time curves (AUCRE and AUCSE) were calculated during the time of intubation and start of surgery as well as during the entire anaesthesia. The difference between RE and SE recordings in both groups was determined by subtracting the AUCSE from the corresponding AUCRE. Movements of the patients were recorded.. No significant differences were detected in any of the several AUC values between the groups. The difference between RE and SE recordings was similar in both groups. Every patient in the esmolol group moved some time during the procedure interfering with surgery while no one in the remifentanil group moved.. In patients undergoing gynaecological laparoscopic day-case surgery, RE seems not to be more sensitive than SE in guiding the use of opioids during general anaesthesia.

Topics: Adrenergic beta-Antagonists; Adult; Ambulatory Surgical Procedures; Anesthesia, General; Anesthetics, Intravenous; Area Under Curve; Electroencephalography; Electromyography; Endometriosis; Female; Gynecologic Surgical Procedures; Humans; Laparoscopy; Middle Aged; Monitoring, Intraoperative; Ovarian Cysts; Pain Measurement; Piperidines; Propanolamines; Propofol; Remifentanil

Topics: Anesthetics, Inhalation; Anesthetics, Intravenous; Epinephrine; Female; Human Growth Hormone; Humans; Hydrocortisone; Laparoscopy; Methyl Ethers; Neurosecretory Systems; Norepinephrine; Ovarian Cysts; Piperidines; Remifentanil; Sevoflurane; Stress, Physiological

Selective estrogen receptor modulators (SERMs) have the potential to treat estrogen sensitive diseases such as uterine leiomyoma and endometriosis, which are prevalent in reproductive age women. However, SERMs also increase the risk of developing ovarian cysts in this population, a phenomenon that is not seen in postmenopausal women. It is believed that current SERMs partially block estradiol's ability to downregulate gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus thereby interfering with estradiol's negative feedback, leading to increased ovarian stimulation by gonadotropins, and cyst formation. It has been postulated that a SERM with poor brain exposure would have less negative effect on the HPO axis, therefore reducing the risk of developing ovarian cysts. In order to test this hypothesis, we identified an early marker of SERM-dependent ovarian effects: upregulation of Cyp17a1 mRNA. SERMs known to cause ovarian cysts upregulate Cyp17a1 after only 4 days of dosing and suppression of the HPO axis prevented this regulation, indicating that ovarian expression of Cyp17a1 was secondary to SERM's effect on the brain. We then characterized three SERMs with similar binding affinity and antagonist effects on the uterus for their relative brain/plasma exposure and ovarian effects. We found that the degree of brain exposure correlated very well with Cyp17a1 expression.

Topics: Animals; Biomarkers; Brain; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Female; Naphthalenes; Ovarian Cysts; Ovary; Piperidines; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Selective Estrogen Receptor Modulators; Steroid 17-alpha-Hydroxylase; Up-Regulation