Nichole E. Carlson

Reexamination of Testosterone, Dihydrotestosterone, Estradiol and Estrone Levels across the Menstrual Cycle and in Postmenopausal Women Measured by Liquid Chromatography Tandem Mass Spectrometry

Measuring serum androgen levels in women has been challenging due to limitations in method accuracy, precision sensitivity and specificity at low hormone levels. The clinical significance of changes in sex steroids across the menstrual cycle and lifespan has remained controversial, in part due to these limitations. We used validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays to determine testosterone (T) and dihydrotestosterone (DHT) along with estradiol (E2) and estrone (E1) levels across the menstrual cycle of 31 healthy premenopausal females and in 19 postmenopausal females. Samples were obtained in ovulatory women in the early follicular phase (EFP), midcycle and mid luteal phase (MLP). Overall, the levels of T, DHT, E2 and E1 in premenopausal women measured by LC-MS/MS were lower overall than previously reported with immunoassays. In premenopausal women, serum T, free T, E2, E1 and SHBG levels peaked at midcycle and remained higher in the MLP, whereas DHT did not change. In postmenopausal women, T, free T, SHBG and DHT were significantly lower than in premenopausal women, concomitant with declines in E2 and E1. These data support the hypothesis that the changes in T and DHT that occur across the cycle may reflect changes in SHBG and estrogen, whereas in menopause, androgen levels decrease. LC-MS/MS may provide more accurate and precise measurement of sex steroid hormones than prior immunoassay methods and can be useful to assess the clinical significance of changes in T, DHT, E2 and E1 levels in females.

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity

BACKGROUNDnThis study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity.nnnSTUDY DESIGNnOvulatory reproductive-age women with normal weight (BMI <25 kg/m(2); n=10) and with obesity (BMI >30 kg/m(2); n=10) received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (follicle-stimulating hormone and luteinizing hormone) was measured during the second inpatient stay. Estradiol (E(2)) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2.nnnRESULTSnBMI was greater in the obese compared to the normal-BMI group [37.3 kg/m(2) (SD, 6.0) vs. 21.9 kg/m(2) (SD, 1.6); p<.05]. The LNG half-life was significantly longer in the obese group (52.1+/-29.4 vs. 25.6+/-9.3 h, p<.05), which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD, 0.5) vs. 2.5 ng/mL (SD, 0.7)] and a longer time to reach steady state (10 vs. 5 days) in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended toward greater HPO activity in the obese group. Additionally, more obese (6/10 vs. 3/10 normal BMI, p>.05) women exhibited E(2) levels consistent with development of a dominant follicle and P levels consistent with ovulation (2/10 vs. 1/10) during Cycle 2.nnnCONCLUSIONSnCompared to women with normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.

Return to driving within 5 years of moderate-severe traumatic brain injury

Primary objective: To examine return to driving and variables associated with that activity in a longitudinal database. Research design: Retrospective analysis of a large, national database. Methods and procedures: The sample was comprised of people with predominantly moderate–severe traumatic brain injury (TBI) enrolled in the TBI Model System national database at 16 centres and followed at 1 (n = 5942), 2 (n = 4628) and 5 (n = 2324) years after injury. Main outcomes and results: Respondents were classified as driving or not driving at each follow-up interval. Five years after injury, half the sample had returned to driving. Those with less severe injuries were quicker to return to driving, but, by 5 years, severity was not a factor. Those who were driving expressed a higher life satisfaction. Functional status at rehabilitation discharge, age at injury, race, pre-injury residence, pre-injury employment status and education level were associated with the odds of a person driving. Conclusions: Half of those with a moderate–severe TBI return to driving within 5 years and most of those within 1 year of injury. Driving is associated with increased life satisfaction. There are multiple factors that contribute to return to driving that do not relate to actual driving ability.

Correlations Between Endoscopy Score and Quality of Life Changes After Sinus Surgery

OBJECTIVEnTo assess whether change in endoscopy score correlates with change in health-related quality of life (HRQOL) following endoscopic sinus surgery for chronic rhinosinusitis.nnnDESIGNnProspective open cohort.nnnSETTINGnTertiary rhinology clinic.nnnPATIENTSnOne hundred two adult patients with and without nasal polyposis who elected to undergo endoscopic sinus surgery and were followed up for 12 +/- 2 months postoperatively.nnnINTERVENTIONnPatient characteristics and Lund-Mackay computed tomography scores were recorded preoperatively. Lund-Kennedy endoscopy scores and 2 HRQOL surveys, the Rhinosinusitis Disability Index and Chronic Sinusitis Survey, were examined before and after surgery.nnnMAIN OUTCOME MEASURESnPostoperative changes in endoscopy score and HRQOL were examined using bivariate and multivariate analyses.nnnRESULTSnStatistically significant improvements were found in endoscopy score (P < .001) and for all total and subscale HRQOL measures (P < .001). After controlling for baseline status and comorbid factors, improvement in endoscopy score significantly correlated with 12-month improvement on the total Rhinosinusitis Disability Index (P = .01), the physical (P = .01) and functional (P = .02) subscales of the Rhinosinusitis Disability Index, and the symptom subscale of the Chronic Sinusitis Survey (P = .003) but could explain only 25.5% to 36.6% of the linear variation for these HRQOL improvements.nnnCONCLUSIONSnFor most patients, endoscopy scores and disease-specific HRQOL significantly improve after endoscopic sinus surgery. Changes in endoscopy scores explain a portion of the improvement in HRQOL. For patients with chronic rhinosinusitis, improvements in disease-specific HRQOL outcomes are complex, multidimensional constructs that cannot be entirely explained by surgical changes measured by endoscopic examination. Trial Registration clinicaltrials.gov Identifier: NCT00799097.

Hypogonadism on admission to acute rehabilitation is correlated with lower functional status at admission and discharge

Primary objective: To investigate the association between hormone levels and functional status during acute TBI rehabilitation. Research design: Retrospective cohort study of 43 men with moderate-to-severe TBI admitted to an acute rehabilitation unit during a 1 year period. Methods and procedures: Labs were drawn on admission, including total and free testosterone (T), prolactin, adrenocorticotropin hormone (ACTH), cortisol, thyroid stimulating hormone (TSH), free thyroxine (fT4) and insulin-like growth factor (IGF-1). Functional Independence Measure (FIM) scores were obtained at admission and discharge. Main outcome and results: Associations between admission hormone levels and the main outcomes, admission and discharge FIM scores, were assessed using linear regression. Lower total and free T-levels at admission were associated with lower total FIM scores at admission (p < 0.038) and discharge (p < 0.046). Higher cortisol levels at admission were significantly associated with lower admission (p = 0.012) and discharge (p = 0.036) scores on the cognitive-FIM. Prolactin, TSH, fT4 and IGF-1 were not correlated with functional status. Conclusions: In men, lower total and free T-levels at admission to acute rehabilitation correlate with lower admission and discharge FIM scores. These data support the need for studies to investigate the impact of physiological testosterone therapy on outcomes during and post-rehabilitation.

Diurnal patterns of salivary cortisol and DHEA using a novel collection device: Electronic monitoring confirms accurate recording of collection time using this device

The accurate indication of saliva collection time is important for defining the diurnal decline in salivary cortisol as well as characterizing the cortisol awakening response. We tested a convenient and novel collection device for collecting saliva on strips of filter paper in a specially constructed booklet for determination of both cortisol and DHEA. In the present study, 31 healthy adults (mean age 43.5 years) collected saliva samples four times a day on three consecutive days using filter paper collection devices (Saliva Procurement and Integrated Testing (SPIT) booklet) which were maintained during the collection period in a large plastic bottle with an electronic monitoring cap. Subjects were asked to collect saliva samples at awakening, 30 min after awakening, before lunch and 600 min after awakening. The time of awakening and the time of collection before lunch were allowed to vary by each subjects schedule. A reliable relationship was observed between the time recorded by the subject directly on the booklet and the time recorded by electronic collection device (n=286 observations; r(2)=0.98). However, subjects did not consistently collect the saliva samples at the two specific times requested, 30 and 600 min after awakening. Both cortisol and DHEA revealed diurnal declines. In spite of variance in collection times at 30 min and 600 min after awakening, the slope of the diurnal decline in both salivary cortisol and DHEA was similar when we compared collection tolerances of ±7.5 and ±15 min for each steroid. These unique collection booklets proved to be a reliable method for recording collection times by subjects as well as for estimating diurnal salivary cortisol and DHEA patterns.

Residence following traumatic brain injury: a longitudinal study.

ObjectiveTo examine change in residence following traumatic brain injury (TBI) as a function of preinjury residential status, demographic factors, and injury-related characteristics. DesignProspective, observational study. SettingInpatient, comprehensive rehabilitation programs for persons with TBI. ParticipantsA total of 7925 patients with moderate or severe TBI receiving acute rehabilitation, and enrolled in the TBI Model Systems National Database. Main MeasuresPreinjury and discharge residential status determined during rehabilitation, and at 1, 2, and 5 years postinjury by telephone interview. Variables contributing to residential status included injury severity, demographic information, and functional status. ResultsThere was significant change in residence across 5 years characterized by discharge to a less independent residence following injury, with a return to a more independent residence over time. The most significant transition took place in the first year after injury. Residence prior to injury was the strongest predictor of residence after injury. Age and race were significantly associated with residence following TBI, with increasing age related to more independent residence, and whites more likely to live independently than are African Americans. Severity of injury had little impact, although functional status at rehabilitation discharge was associated with residence, with higher functional status associated with a more independent residence. ConclusionAmong persons who received acute rehabilitation for TBI, 35.4% were discharged from rehabilitation to a setting different from the one in which they resided before injury. The degree of change varied on the basis of preinjury residence. Overall, the results indicate that while many patients are discharged to a different residential setting than prior to their injury, some patients recover to the point where they are able to return to their premorbid residential setting. The most substantial change was for those living alone at the time of injury, and within the first year of injury.

Extended-use oral contraceptives and medically induced amenorrhea: attitudes, knowledge and prescribing habits of physicians.

BACKGROUNDnThe study was conducted to determine whether geographic location, primary specialty, attitudes and knowledge influence the prescribing habits of physicians regarding extended-use oral contraceptives (OC) and medically induced amenorrhea.nnnSTUDY DESIGNnPractice characteristics, contraceptive prescription habits, menstrual cycle physiology knowledge and attitudes about medically induced amenorrhea of Oregon obstetrics and gynecology (OBGYN) and family medicine physicians were assessed using either a cross-sectional postal or electronic mail survey. Attitudes were assessed using a series of Likert-style questions; multiple-choice responses were used to evaluate knowledge and prescribing habits.nnnRESULTSnOf the 713 physicians in the sample (email 575, paper 138), 233 returned the survey, for an overall response rate of 32.7%. Over 90% (211/233) of respondents prescribed OCs; of these, 73.9% (155/211) stated that they prescribed extended-use OCs either often (23.5%) or sometimes (50.5%). Without adjusting for other factors, physicians reporting an OBGYN specialty (odds ratio [OR] 8.02, 95% confidence interval [CI]: 3.40-18.91) or an urban practice location (OR 2.75, 95% CI: 1.42-5.30) were more likely to report prescribing extended-use OCs. However, after adjusting for other factors, attitude was the only factor which remained significantly associated with prescribing (OR 1.85, 95% CI 1.41-2.42).nnnCONCLUSIONnPhysicians attitudes regarding medically induced amenorrhea influence the use of extended-cycle OC more than any other characteristic.

A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use

BACKGROUNDnUnscheduled bleeding is the main side effect of continuous oral contraceptive pills (OCPs) and has been correlated with the up-regulation of matrix metalloprotineases (MMPs). The study objective was to determine if prophylactic administration of doxycycline (an MMP inhibitor at low subantimicrobial doses) would prevent unscheduled bleeding during the initiation of a continuous OCP.nnnSTUDY DESIGNnSubjects using cyclic hormonal contraceptives (combined OCPs, patch or ring) without unscheduled bleeding were switched to continuous OCPs (20 mcg ethinyl estradiol/100 mcg levonorgestrel). They were randomized to receive daily doxycycline [sustained-release subantimicrobial dose (40 mg daily)] or placebo for the first 84 days and then observed for an additional 28 days on the continuous OCP alone. The number of bleeding/spotting days and the time in days it took to achieve amenorrhea were compared using a t test.nnnRESULTSnSixty-five subjects were randomized. Although the use of doxycycline did not significantly decrease the number of mean bleeding/spotting days in the first 84 days of the study [doxycycline 14.75 (SE 2.30), placebo 17.78 (2.31), p=.36], women who received doxycycline had a significantly earlier onset of amenorrhea [mean last day of bleeding/spotting doxycycline 61.7 (7.7), placebo 85.2 (6.7), p=.03].nnnCONCLUSIONnThe coadministration of subantimicrobial-dose doxycycline during initiation of continuous OCPs results in a significant reduction in the length of time needed to achieve amenorrhea.

Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function

Background Reduced left ventricular (LV) ejection fraction increases the risk of ventricular arrhythmias; however, LV ejection fraction has a low sensitivity to predict ventricular arrhythmias. LV dilatation and mass may be useful to further risk-stratify for ventricular arrhythmias. Methods and Results Patients from the Genetic Risk of Assessment of Defibrillator Events (GRADE) study (N =930), a study of heart failure subjects with defibrillators, were assessed for appropriate implantable cardioverter-defibrillator shock and death, heart transplant, or ventricular assist device placement by LV diameter and mass. LV mass was divided into normal, mild, moderate, and severe classifications. Severe LV end-diastolic diameter had worse shock-free survival than normal and mild LV end-diastolic diameter (P =0.0002 and 0.0063, respectively; 2-year shock free, severe 74%, moderate 80%, mild 91%, normal 88%; 4-year shock free, severe 62%, moderate 69%, mild 72%, normal 81%) and freedom from death, transplant, or ventricular assist device compared with normal and moderate LV end-diastolic diameter (P<0.0001 and 0.0441, respectively; 2-year survival: severe 78%, moderate 85%, mild 82%, normal 89%; 4-year survival: severe 55%, moderate 64%, mild 63%, normal 74%). Severe LV mass had worse shock-free survival than normal and mild LV mass (P =0.0370 and 0.0280, respectively; 2-year shock free: severe 80%, moderate 81%, mild 91%, normal 87%; 4-year shock free: severe 68%, moderate 73%, mild 76%, normal 76%) but no association with death, transplant, or ventricular assist device (P =0.1319). In a multivariable Cox proportional hazards analysis adjusted for LV ejection fraction, LV end-diastolic diameter was associated with appropriate implantable cardioverter-defibrillator shocks (hazard ratio 1.22, P =0.020). LV end-diastolic diameter was associated with time to death, transplant, or ventricular assist device (hazard ratio 1.29, P =0.0009). Conclusions LV dilatation may complement ejection fraction to predict ventricular arrhythmias. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02045043.