Tammy L. Loucks

Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET study

BACKGROUND Preclinical studies demonstrate that 17beta-estradiol (E(2)) increases serotonin-2A receptor (5-HT(2A)R) density in rat frontal cortex. METHODS We investigated the impact of hormone replacement therapy on 5-HT(2A)R binding potential (BP) using positron emission tomography and [(18)F]altanserin in five postmenopausal women. Subjects were imaged at baseline, following 8 to 14 weeks of transdermal E(2), 0.1 mg/d, and following 2 to 6 weeks of E(2) plus micronized progesterone (P) 100 mg per os twice daily. Regional BPs in the anterior cingulate cortex, dorsolateral prefrontal cortex, and lateral orbitofrontal cortex were calculated by Logan analysis. RESULTS There was a main effect of time (p = .017) for 5-HT(2A)R BP, which increased 21.2%+/-2.6% following combined E(2) and P administration relative to baseline. This effect was evident in all cerebral cortex regions examined. CONCLUSIONS 5-HT(2A)R BP increased in widespread areas of the cerebral cortex following combined E(2) + P administration.

Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy

OBJECTIVE To determine whether cognitive behavior therapy (CBT) targeted to problematic attitudes common among women with functional hypothalamic amenorrhea would restore ovarian function. DESIGN Randomized, prospective, controlled intervention. SETTING Clinical research center in an academic medical institution. PATIENT(S) Sixteen women participated who had functional hypothalamic amenorrhea; were of normal body weight; and did not report psychiatric conditions, eating disorders, or excessive exercise. INTERVENTION(S) Subjects were randomized to CBT or observation for 20 weeks. MAIN OUTCOME MEASURE(S) Serum levels of E(2) and P and vaginal bleeding were monitored. RESULT(S) Of eight women treated with CBT, six resumed ovulating, one had partial recovery of ovarian function without evidence of ovulation, and one did not display return of ovarian function. Of those randomized to observation, one resumed ovulating, one had partial return of ovarian function, and six did not recover. Thus, CBT resulted in a higher rate of ovarian activity (87.5%) than did observation (25.0%), chi(2) = 7.14. CONCLUSION(S) A cognitive behavioral intervention designed to minimize problematic attitudes linked to hypothalamic allostasis was more likely to result in resumption of ovarian activity than observation. The prompt ovarian response to CBT suggests that a tailored behavioral intervention offers an efficacious treatment option that also avoids the pitfalls of pharmacological modalities.

Salivary cortisol reflects serum cortisol: analysis of circadian profiles

Background: Technical hurdles limit the characterization of key hormonal rhythms. Frequent sampling increases detection of changes in magnitude or circadian and ultradian patterns, but limits feasibility for clinical or research settings. These caveats are particularly pertinent for cortisol, a hormone that displays a prominent circadian rhythm and whose magnitude is tightly regulated in the absence of biobehavioural challenge. Ideally, one would like to obtain samples non-invasively from a matrix of interest at frequent intervals. While many investigations have reported a high correlation between serum and salivary cortisol assays, the degree to which salivary cortisol reflects the circadian patterns of circulating cortisol concentrations has not been established across a 24 h period. Methods: We obtained hourly serum and salivary samples over a 24 h period in nine adults in an inpatient setting. The circadian patterns for serum and salivary cortisol were analysed by harmonic regression. Results: For all but two subjects (both on oral contraceptives), the salivary cortisol concentration was synchronous with the serum concentration, indicating that the salivary assay could be substituted for the serum assay to assess circulating rhythmicity across the 24 h time frame. Conclusions: This statistical model has distinct improvement over the correlational approach of examining serum and saliva cortisol relationships. Saliva cortisol appears to represent serum cortisol across the 24 h period, except for those on oral contraceptives.

Acute Serum Hormone Levels: Characterization and Prognosis after Severe Traumatic Brain Injury

Experimental traumatic brain injury (TBI) studies report the neuroprotective effects of female sex steroids on multiple mechanisms of injury, with the clinical assumption that women have hormonally mediated neuroprotection because of the endogenous presence of these hormones. Other literature indicates that testosterone may exacerbate injury. Further, stress hormone abnormalities that accompany critical illness may both amplify or blunt sex steroid levels. To better understand the role of sex steroid exposure in mediating TBI, we 1) characterized temporal profiles of serum gonadal and stress hormones in a population with severe TBI during the acute phases of their injury; and 2) used a biological systems approach to evaluate these hormones as biomarkers predicting global outcome. The study population was 117 adults (28 women; 89 men) with severe TBI. Serum samples (n=536) were collected for 7 days post-TBI for cortisol, progesterone, testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Hormone data were linked with clinical data, including acute care mortality and Glasgow Outcome Scale (GOS) scores at 6 months. Hormone levels after TBI were compared to those in healthy controls (n=14). Group based trajectory analysis (TRAJ) was used to develop temporal hormone profiles that delineate distinct subpopulations in the cohort. Structural equations models were used to determine inter-relationships between hormones and outcomes within a multivariate model. Compared to controls, acute serum hormone levels were significantly altered after severe TBI. Changes in the post-TBI adrenal response and peripheral aromatization influenced hormone TRAJ profiles and contributed to the abnormalities, including increased estradiol in men and increased testosterone in women. In addition to older age and greater injury severity, increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women. These findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI.

Do polycystic-appearing ovaries affect the risk of cardiovascular disease among women with polycystic ovary syndrome? ☆

OBJECTIVE To determine if polycystic-appearing ovaries (PAO) are associated with differences in risk factors for cardiovascular disease among women with polycystic ovary syndrome (PCOS). DESIGN Case-control sub-study. SETTING Division of Reproductive Endocrinology, Magee-Womens Hospital. PATIENT(S) Women with PCOS (n = 63) and non-PCOS controls (n = 56). INTERVENTION Transvaginal ultrasonography and single sample venipuncture. MAIN OUTCOME MEASURE(S) Ultrasound ovarian appearance, fasting insulin, lipoproteins, androgens, LH/FSH ratio, anthropomorphic measurements, and blood pressure. RESULT(S) Women with PCOS had higher androgen and fasting insulin levels, a more adverse lipid profile, greater waist-hip and LH/FSH ratios, and a larger ovarian volume than controls. Thirty-three percent of the cases with PCOS, but only 5% of controls, showed PAO on ultrasound study (P<.01). PCOS cases with and without PAO had comparable levels of fasting insulin, lipids, and blood pressures. PCOS cases with PAO had a higher LH/FSH ratio (P=.028), increased levels of serum androstenedione (P=.029) and testosterone (P=.055), and greater ovarian volume (P=.024) compared to non-PAO patients. CONCLUSION Women with PCOS have greater cardiovascular risk than controls. Within PCOS cases, however, the ultrasound appearance of polycystic ovaries does not appear to further intensify the cardiovascular disease risk profile of these women.

Use of cognitive behavior therapy for functional hypothalamic amenorrhea.

Abstract:  Behaviors that chronically activate the hypothalamic‐pituitary‐adrenal (HPA) axis and/or suppress the hypothalamic‐pituitary‐thyroidal (HPT) axis disrupt the hypothalamic‐pituitary‐gonadal axis in women and men. Individuals with functional hypothalamic hypogonadism typically engage in a combination of behaviors that concomitantly heighten psychogenic stress and increase energy demand. Although it is not widely recognized clinically, functional forms of hypothalamic hypogonadism are more than an isolated disruption of gonadotropin‐releasing hormone (GnRH) drive and reproductive compromise. Indeed, women with functional hypothalamic amenorrhea display a constellation of neuroendocrine aberrations that reflect allostatic adjustments to chronic stress. Given these considerations, we have suggested that complete neuroendocrine recovery would involve more than reproductive recovery. Hormone replacement strategies have limited benefit because they do not ameliorate allostatic endocrine adjustments, particularly the activation of the adrenal and the suppression of the thyroidal axes. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of hypothalamic hypogonadism represent only or primarily an alteration in the hypothalamic‐pituitary‐gonadal axis. Potential health consequences of functional hypothalamic amenorrhea, often termed stress‐induced anovulation, may include an increased risk of cardiovascular disease, osteoporosis, depression, other psychiatric conditions, and dementia. Although fertility can be restored with exogenous administration of gonadotropins or pulsatile GnRH, fertility management alone will not permit recovery of the adrenal and thyroidal axes. Initiating pregnancy with exogenous means without reversing the hormonal milieu induced by chronic stress may increase the likelihood of poor obstetrical, fetal, or neonatal outcomes. In contrast, behavioral and psychological interventions that address problematic behaviors and attitudes, such as cognitive behavior therapy (CBT), have the potential to permit resumption of full ovarian function along with recovery of the adrenal, thyroidal, and other neuroendocrine aberrations. Full endocrine recovery potentially offers better individual, maternal, and child health.

Age, Sex, and Reproductive Hormone Effects on Brain Serotonin-1A and Serotonin-2A Receptor Binding in a Healthy Population

There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20–80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [11C]WAY100635 and [18F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (VT) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age2, sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004–0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05–0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03–0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults <50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex–hormone–serotonin receptor relationships.

Obesity and the hypothalamic-pituitary-adrenal axis in adolescent girls

Stress and stress-related concomitants, including hypothalamic-pituitary-adrenal (HPA) axis activation, are implicated in obesity and its attendant comorbidities. Little is known about this relationship in adolescents. To begin to address this important knowledge gap, we studied HPA axis activity in 262 healthy adolescent girls aged 11, 13, 15, and 17 years. We hypothesized that obesity would be correlated with increased HPA axis activity and reactivity. Measures of HPA axis activity included 3 blood samples obtained midday (between 1:00 and 2:00 pm) over the course of 40 minutes; overnight urine free cortisol; and cortisol levels 0, 20, and 40 minutes after venipuncture (cortisol reactivity). Measures of adiposity included body mass index (BMI), BMI z score (BMI-Z), percentage body fat, and fat distribution (central adiposity) assessed by dual-energy x-ray absorptiometry. Daytime levels of serum cortisol were inversely associated with BMI-Z and central adiposity (P < .05). The urine free cortisol excretion rate was positively correlated with BMI, BMI-Z, and central adiposity. There was blunting of cortisol response to venipuncture with increasing adiposity. Our results suggest that there may be reduced cortisol levels during the day and increased levels at night with increasing degree of adiposity. This study provides preliminary findings indicating an alteration of the circadian rhythm of cortisol with obesity. We conclude that obesity is associated with altered HPA activity in adolescent girls. The clinical implications of our findings require further investigation.

Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized controlled trial

OBJECTIVE To determine whether cognitive behavior therapy (CBT), which we had shown in a previous study to restore ovarian function in women with functional hypothalamic amenorrhea (FHA), could also ameliorate hypercortisolemia and improve other neuroendocrine and metabolic concomitants of in FHA. DESIGN Randomized controlled trial. SETTING Clinical research center at an academic medical university. PATIENT(S) Seventeen women with FHA were randomized either to CBT or observation. INTERVENTION(S) CBT versus observation. MAIN OUTCOME MEASURE(S) Circulatory concentrations of cortisol, leptin, thyroid-stimulating hormone (TSH), total and free thyronine (T(3)), and total and free thyroxine (T(4)) before and immediately after completion of CBT or observation. (Each woman served as her own control.) RESULT(S) Cognitive behavior therapy but not observation reduced cortisol levels in women with FHA. There were no changes in cortisol, leptin, TSH, T(3), or T(4) levels in women randomized to observation. Women treated with CBT showed increased levels of leptin and TSH, but their levels of T(3) and T(4) remained unchanged. CONCLUSION(S) In women with FHA, CBT ameliorated hypercortisolism and improved the neuroendocrine and metabolic concomitants of FHA while observation did not. We conclude that a cognitive, nonpharmacologic approach aimed at alleviating problematic attitudes not only can restore ovarian activity but also improve neuroendocrine and metabolic function in women with FHA. CLINICAL TRIAL REGISTRATION NUMBER NCT01674426.

Differences in Endocrine Parameters and Psychopathology in Girls with Premature Adrenarche versus On-time Adrenarche

Girls with premature adrenarche (PA) are at risk for multiple problems related to exaggerated androgen synthesis. Whether PA carries a risk of psychopathology remains unknown. This study examined group differences in: (a) anthropometric and endocrine parameters, and (b) mood and behavior problems, in 6-8 year-old girls with PA (n = 40) compared to on-time adrenarche girls (n = 36). PA girls were taller (p < or =0.05) and heavier (p < or =0.01) than the on-time adrenarche girls but body mass index showed no difference. PA girls had significantly (p <0.05) higher adrenal androgen and testosterone concentrations but not cortisol or leptin. PA girls also had significantly more oppositional defiant disorder, and higher symptom counts reflecting anxiety, mood or disruptive behavior disorders. PA girls may be more vulnerable to psychopathology than on-time adrenarche girls. The challenge of future studies is to determine which PA girls are at risk for psychopathology and which are more resilient.