A population-based approach to analyzing pulses in time series of hormone data.

Studies of reproductive physiology involve rapid sampling protocols that result in time series of hormone concentrations. The signature pattern in these times series is pulses of hormone release. Various statistical models for quantifying the pulsatile release features exist. Currently these models are fitted separately to each individual and the resulting estimates averaged to arrive at post hoc population-level estimates. When the signal-to-noise ratio is small or the time of observation is short (e.g., 6 h), this two-stage estimation approach can fail. This work extends the single-subject modelling framework to a population framework similar to what exists for complex pharamacokinetics data. The goal is to leverage information across subjects to more clearly identify pulse locations and improve estimation of other model parameters. This modelling extension has proven difficult because the pulse number and locations are unknown. Here, we show that simultaneously modelling a group of subjects is computationally feasible in a Bayesian framework using a birth-death Markov chain Monte Carlo estimation algorithm. Via simulation, we show that this population-based approach reduces the false positive and negative pulse detection rates and results in less biased estimates of population-level parameters of frequency, pulse size, and hormone elimination. We then apply the approach to a reproductive study in healthy women where approximately one-third of the 21 subjects in the study did not have appropriate fits using the single-subject fitting approach. Using the population model produced more precise, biologically plausible estimates of all model parameters. Copyright © 2017 John Wiley & Sons, Ltd.

A comparison of methods for analyzing time series of pulsatile hormone data.

Many endocrine systems are regulated by pulsatile hormones - hormones that are secreted intermittently in boluses rather than continuously over time. To study pulsatile secretion, blood is drawn every few minutes for an extended period. The result is a time series of hormone concentrations for each individual. The goal is to estimate pulsatile hormone secretion features such as frequency, location, duration, and amount of pulsatile and non-pulsatile secretion and compare these features between groups. Various statistical approaches to analyzing these data have been proposed, but validation has generally focused on one hormone. Thus, we lack a broad understanding of each method's performance. By using simulated data with features seen in reproductive and stress hormones, we investigated the performance of three recently developed statistical approaches for analyzing pulsatile hormone data and compared them to a frequently used deconvolution approach. We found that methods incorporating a changing baseline modeled both constant and changing baseline shapes well; however, the added model flexibility resulted in a slight increase in bias in other model parameters. When pulses were well defined and baseline constant, Bayesian approaches performed similar to the existing deconvolution method. The increase in computation time of Bayesian approaches offered improved estimation and more accurate quantification of estimation variation in situations where pulse locations were not clearly identifiable. Within the class of deconvolution models for fitting pulsatile hormone data, the Bayesian approach with a changing baseline offered adequate results over the widest range of data.

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.

Health status, mood, and cognition in experimentally induced subclinical thyrotoxicosis.

OBJECTIVE: Our objective was to determine whether subclinical thyrotoxicosis alters health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, cross-over study of usual dose l-T(4) (euthyroid arm) vs. higher dose l-T(4) (subclinical thyrotoxicosis arm) in hypothyroid subjects. PATIENTS: A total of 33 hypothyroid subjects receiving l-T(4) were included in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition: Short Form 36 (SF-36); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, and Digit Span Backwards), and motor learning (Pursuit Rotor). These were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels decreased from 2.15 to 0.17 mU/liter on the subclinical thyrotoxicosis arm (P < 0.0001), with normal mean free T(4) and free T(3) levels. The SF-36 physical component summary and general health subscale were slightly worse during the subclinical thyrotoxicosis arm, whereas the mental health subscale was marginally improved. The POMS confusion, depression, and tension subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did not change. This improvement was related to changes in the SF-36 physical component summary and POMS tension subscales and free T(3) levels. CONCLUSIONS: We found slightly impaired physical health status but improvements in measures of mental health and mood in l-T(4) treated hypothyroid subjects when subclinical thyrotoxicosis was induced in a blinded, randomized fashion. Motor learning was also improved. These findings suggest that thyroid hormone directly affects brain areas responsible for affect and motor function.

Trajectories of brain loss in aging and the development of cognitive impairment.

BACKGROUND: The use of volumetric MRI as a biomarker for assessing transitions to dementia presumes that more rapid brain loss marks the clinical transition from benign aging to mild cognitive impairment (MCI). The trajectory of this volume loss relative to the timing of the clinical transition to dementia has not been established. METHODS: The authors annually evaluated 79 healthy elderly subjects for up to 15 consecutive years with standardized clinical examinations and volumetric brain MRI assessments of ventricular volume. During the study period, 37 subjects developed MCI. A mixed effects model with a change point modeled the pattern of brain volume loss in healthy aging compared with subjects diagnosed with MCI. RESULTS: The brain loss trajectory of subjects developing MCI during follow-up differed from healthy aging in a two-phase process. First, the annual rate of expansion of ventricular volume decreased with age; however, the annual rates of expansion were greater in those who developed cognitive impairment during follow-up compared with those who did not. Further, subjects who developed MCI had an acceleration of ventricular volume expansion approximately 2.3 years prior to clinical diagnosis of MCI. CONCLUSIONS: Ventricular expansion is faster in those developing mild cognitive impairment years prior to clinical symptoms, and eventually a more rapid expansion occurs approximately 24 months prior to the emergence of clinical symptoms. These differential rates of preclinical atrophy suggest that there are specific windows for optimal timing of introduction of dementia prevention therapies in the future.

Blood-brain barrier impairment in Alzheimer disease: stability and functional significance.

OBJECTIVE: To determine the stability and functional significance of blood-brain barrier (BBB) integrity in patients with mild to moderate Alzheimer disease (AD). METHODS: Thirty-six patients (mean age 71 +/- 7 years) with mild to moderate AD (Mini-Mental State Examination [MMSE] 19 +/- 5) participated in a biomarker study involving clinical assessments, brain imaging, and CSF and plasma collection over 1 year. BBB integrity was assessed with the CSF-albumin index (CSF-AI). RESULTS: BBB disruption was present in an important subgroup of patients (n = 8/36, 22%) at all time points measured. CSF-AI was highly reproducible over 1 year with an intraclass correlation of 0.96. Age, sex, and APOE status did not correlate with CSF-AI. Vascular factors (blood pressure, Hachinski ischemia score, MR-derived white matter hyperintensity, body mass index) were not strongly associated with CSF-AI levels (p = 0.066). CSF/plasma IgG ratio correlated with CSF-AI in a manner indicating that peripheral IgG has greater access to the CNS in patients with an impaired BBB. Further evidence for the physiologic significance of the CSF-AI was noted in the form of correlations with rates of disease progression, including annual change on MMSE (r(2) = 0.11, p = 0.023), annual Clinical Dementia Rating sum-of-boxes change (r(2) = 0.29, p = 0.001), and annual ventricular volume change (r(2) = 0.17, p = 0.007). CONCLUSIONS: Blood-brain barrier (BBB) impairment is a stable characteristic over 1 year and present in an important subgroup of patients with Alzheimer disease. Age, gender, APOE status, vascular risk factors, and baseline Mini-Mental State Examination score did not explain the variability in BBB integrity. A role for BBB impairment as a modifier of disease progression is suggested by correlations between CSF-albumin index and measures of disease progression over 1 year.

Health status, mood, and cognition in experimentally induced subclinical hypothyroidism.

OBJECTIVE: The objective of the study was to determine whether subclinical hypothyroidism causes decrements in health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, crossover study of usual dose l-thyroxine (L-T4) (euthyroid arm) vs. lower dose L-T4 (subclinical hypothyroid arm) in hypothyroid subjects. PATIENTS: Nineteen subjects on L-T4 therapy for primary hypothyroidism participated in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition using validated instruments: Short Form 36, Profile of Mood States, and tests of declarative memory (paragraph recall, complex figure), working memory (N-back, subject ordered pointing, digit span backward), and motor learning (pursuit rotor). The same measures were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels increased to 17 mU/liter on the subclinical hypothyroid arm (P < 0.0001). Mean free T4 and free T3 levels remained within the normal range. The Profile of Mood States fatigue subscale and Short Form 36 general health subscale were slightly worse during the subclinical hypothyroid arm. Measures of working memory (N-back, subject ordered pointing) were worse during the subclinical hypothyroid arm. These differences did not depend on mood or health status but were related to changes in free T4 or free T3 levels. There were no decrements in declarative memory or motor learning. CONCLUSIONS: We found mild decrements in health status and mood in L-T4-treated hypothyroid subjects when subclinical hypothyroidism was induced in a blinded, randomized fashion. More importantly, there were independent decrements in working memory, which suggests that subclinical hypothyroidism specifically impacts brain areas responsible for working memory.

Basal circadian cortisol secretion in women with temporomandibular disorders.

Muscular temporomandibular disorder (TMD) is a common stress-related condition showing marked comorbidity with depression and fibromyalgia (FM), both of which are associated with dysregulation of cortisol secretion. We measured cortisol levels in 15 women with well-defined TMD and 15 matched controls by sampling blood at 10-minute intervals over 24 hours in a controlled environment. TMD patients showed markedly increased daytime cortisol levels 30% to 50% higher than those of controls (p = 0.0032) and a one-hour phase delay in the timing of maximum cortisol levels (p = 0.048). Increased activation of the stress hormone axis by conscious pain perception is a likely explanation, but the magnitude of the increase could indicate that pain in the facial region acts as a greater stimulus than pain elsewhere in the body.

Twenty-four-hour ACTH and cortisol pulsatility in depressed women.

Increased plasma cortisol in patients with major depression is a well documented finding, although it is present in only 25-30% of subjects with major depression. However, ACTH and cortisol are secreted in a pulsatile manner, so it is unclear if increased ACTH secretion occurs in depression and if there are changes in the pulsatile components of ACTH secretion. Ten-minute sampling for ACTH and cortisol was performed for 24 hr in 25 premenopausal depressed women, whose age and menstrual cycle day matched control women. As a group, the depressed women demonstrated a trend to increase cortisol secretion (p = 0.089). There was no difference in mean cortisol between the patient group as a whole (8.36 +/- 2.9 microg/dl) and those patients meeting criteria for atypical depression (8.38 +/- 1.9 microg/dl), but patients meeting criteria for endogenous showed increased cortisol (12.17 +/- 4 microg/dl) Mean ACTH was not significantly different between patients and controls. Pulse analyses revealed similar number of secretory events and similar amplitudes for cortisol secretory bursts in patients and controls. The baseline component area under the curve of cortisol secretion was increased at a trend level (p =.064) in depressed patients, and the baseline AUC for ACTH was significantly increased in depressed patients (p =.045). No differences were found in pulsatile components of ACTH secretion between patients and matched controls. Harmonic analyses indicated no significant differences between patients and controls on any detected rhythm for ACTH or cortisol. These data suggest that the pulsatile and circadian components of the HPA axis are normal in premenopausal depressed women and that only 24% of depressed women demonstrate hypercortisolemia.

Alteration in the hypothalamic-pituitary-ovarian axis in depressed women.

BACKGROUND: Stress and corticotropin-releasing hormone inhibit the reproductive axis. We hypothesized that reproductive axis hormone secretion, particularly luteinizing hormone secretion, is inhibited in women with depression, similar to what has been observed to be caused by stress in numerous species. METHODS: Blood samples were collected every 10 minutes for 12 hours in 25 untreated premenopausal women with depression and 25 nondepressed women who were matched by age and menstrual cycle day. Samples were assayed for luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone. RESULTS: The mean plasma estradiol level was 30% lower in the follicular phase in women with depression than in their matched controls: 191 + 136 vs 261 + 169 pmol/L (52 + 37 vs 71 + 46 pg/mL). The half-life of luteinizing hormone was significantly shorter in women with depression than in their matched controls during both the follicular (22% shorter) and luteal (15% shorter) phases. CONCLUSIONS: The blood levels of reproductive hormones were mostly normal in women with depression, but the blood level of estradiol was significantly lower. Estradiol is known to affect a number of neurotransmitter systems in the brain. Arch Gen Psychiatry. 2000;57:1157-1162.

Prostaglandins mediate the endotoxin-induced suppression of pulsatile gonadotropin-releasing hormone and luteinizing hormone secretion in the ewe.

Five experiments were conducted to test the hypothesis that PGs mediate the endotoxin-induced inhibition of pulsatile GnRH and LH secretion in the ewe. Our approach was to test whether the PG synthesis inhibitor, flurbiprofen, could reverse the inhibitory effects of endotoxin on pulsatile LH and GnRH secretion in ovariectomized ewes. Exp 1-4 were cross-over experiments in which ewes received either flurbiprofen or vehicle 2 weeks apart. Jugular blood samples were taken for LH analysis throughout a 9-h experimental period. Depending on the specific purpose of the experiment, flurbiprofen or vehicle was administered after 3.5 h, followed by endotoxin, vehicle, or ovarian steroids (estradiol plus progesterone) at 4 h. In Exp 1, flurbiprofen reversed the endotoxin-induced suppression of mean serum LH concentrations and the elevation of body temperature. In Exp 2, flurbiprofen prevented the endotoxin-induced inhibition of pulsatile LH secretion and stimulation of fever, reduced the stimulation of plasma cortisol and progesterone, but did not affect the rise in circulating tumor necrosis factor-alpha. In Exp 3, flurbiprofen in the absence of endotoxin had no effect on pulsatile LH secretion. In Exp 4, flurbiprofen failed to prevent suppression of pulsatile LH secretion induced by luteal phase levels of the ovarian steroids progesterone and estradiol, which produce a nonimmune suppression of gonadotropin secretion. In Exp 5, flurbiprofen prevented the endotoxin-induced inhibition of pulsatile GnRH release into pituitary portal blood. Our finding that this PG synthesis inhibitor reverses the inhibitory effect of endotoxin leads to the conclusion that PGs mediate the suppressive effects of this immune/inflammatory challenge on pulsatile GnRH and LH secretion.