Changes in hair cortisol concentration in intrauterine device initiators: A prospective cohort study.

OBJECTIVES: Prior studies found increased hair cortisol concentration (a surrogate marker for hypothalamic-pituitary-adrenal axis activation) in users of the levonorgestrel intrauterine device (LNG 52 mg IUD). We evaluated change in hair cortisol and psychometric tests in women initiating a copper (CuT380 IUD) or LNG 52 mg IUD. STUDY DESIGN: We prospectively enrolled healthy women initiating an LNG 52 mg IUD or CuT380 IUD. Participants provided hair and blood samples and completed psychometric inventories (Patient Health Questionnaire-9, Positive and Negative Affect Schedule, and Psychological General Well-Being Index) after IUD insertion and at 6 and 12 months. We used liquid chromatography with tandem mass spectrometry to measure hair cortisol concentrations. We compared hair cortisol concentrations and psychometric test changes from baseline to 6 and 12 months using independent two-sample t tests. RESULTS: We enrolled 39 of our targeted 86 participants (LNG 52 mg IUD 26, CuT380 IUD 13). Thirty-eight subjects (LNG 52 mg IUD 25, CuT380 IUD 13) completed 6 months of follow-up. We found no difference between cohorts in the mean change in hair cortisol concentrations at 6 months (LNG 52 mg IUD n = 21 [-0.01 pg/mg (95% CI -1.26, 1.23); CuT380 IUD n = 13 [-1.31 pg/mg (-3.36, 0.73)]). While psychometric inventory results remained within normal ranges, LNG 52 mg IUD users reported a trend toward more favorable changes over time. CONCLUSIONS: We did not find clinically important differences in hair cortisol concentrations following initiation of a CuT380 IUD or LNG 52 mg IUD; psychometric inventories demonstrated no adverse effect of hormonal IUDs on mood. IMPLICATIONS: Our findings of similar hair cortisol concentrations following the initiation of either the LNG 52 mg IUD or CuT380 IUD suggest that hormonal IUDs do not increase cortisol concentrations or alter stress reactivity, and favorable effects on psychometric inventories provide further reassurance that the LNG 52 mg IUD has no adverse impact on mood. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03499379.

Manipulation of GABAergic steroids: Sex differences in the effects on alcohol drinking- and withdrawal-related behaviors.

Alcoholism is a complex disorder that represents an important contributor to health problems worldwide and that is difficult to encompass with a single preclinical model. Additionally, alcohol (ethanol) influences the function of many neurotransmitter systems, with the interaction at gamma-aminobutyric acid(A) (GABA(A)) receptors being integral for ethanol's reinforcing and several withdrawal-related effects. Given that some steroid derivatives exert rapid membrane actions as potent positive modulators of GABA(A) receptors and exhibit a similar pharmacological profile to that of ethanol, studies in the laboratory manipulated GABAergic steroid levels and determined the impact on ethanol's rewarding- and withdrawal-related effects. Manipulations focused on the progesterone metabolite allopregnanolone (ALLO), since it is the most potent endogenous GABAergic steroid identified. The underlying hypothesis is that fluctuations in GABAergic steroid levels (and the resultant change in GABAergic inhibitory tone) alter sensitivity to ethanol, leading to changes in the positive motivational or withdrawal-related effects of ethanol. This review describes results that emphasize sex differences in the effects of ALLO and the manipulation of its biosynthesis on alcohol reward-versus withdrawal-related behaviors, with females being less sensitive to the modulatory effects of ALLO on ethanol-drinking behaviors but more sensitive to some steroid manipulations on withdrawal-related behaviors. These findings imply the existence of sex differences in the sensitivity of GABA(A) receptors to GABAergic steroids within circuits relevant to alcohol reward versus withdrawal. Thus, sex differences in the modulation of GABAergic neurosteroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.

Multivariate analyses reveal common and drug-specific genetic influences on responses to four drugs of abuse.

Vulnerability to abused drugs is influenced by multiple genes unique to each drug and to risk genes for polydrug abuse. If several inbred mouse strains respond to different drugs similarly, this implies the action of a common group of genes. Simultaneous analysis of multiple responses to multiple drugs has been attempted infrequently. We performed multivariate analyses of published strain responses to four drugs. Genetic similarity in responses did not simply track pharmacological class. Withdrawal severity and preference for ethanol and diazepam were affected by many genes in common, although inversely. We focused on behavioral responses, but there is a growing archival database of physiological, pharmacological and biochemical strain traits. The genomics community is increasingly focusing on single-nucleotide polymorphism and haplotype-based gene mapping approaches, for which inbred strain data are also useful. Thus, similar analyses should be applicable to other laboratories, traits and genotypes.

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice.

The GABAergic neurosteroid allopregnanolone (ALLO) has been repeatedly shown to have an increased anticonvulsant effect during ethanol withdrawal in rats and in C57BL/6J mice. In contrast, the seizure prone DBA/2J inbred strain and the Withdrawal Seizure-Prone (WSP) selected line exhibited decreased sensitivity to ALLO's anticonvulsant effect during ethanol withdrawal, with no change in sensitivity in the Withdrawal Seizure-Resistant (WSR) line. To date, only male mice have been tested. Thus, the present study examined ALLO sensitivity during ethanol withdrawal in female WSP and WSR mice, since females display less severe physical symptoms of withdrawal and have higher circulating ALLO levels than males. Female WSP and WSR mice were exposed to ethanol vapor or air for 72h. During peak ethanol withdrawal, separate groups of mice were injected with vehicle or ALLO (0, 3.2, 10, or 17mg/kg, i.p.) prior to the timed tail vein infusion of pentylenetetrazol (PTZ). ALLO injection significantly increased the threshold dose for onset to PTZ-induced convulsions, indicating an anticonvulsant effect, in female WSP and WSR mice. During ethanol withdrawal, sensitivity to ALLO's anticonvulsant effect was slightly increased in female WSR mice but was significantly decreased in female WSP mice. This line difference in sensitivity to ALLO during ethanol withdrawal in female mice was similar to that in the male mice. Notably, all seizure prone genotypes tested to date displayed tolerance to the anticonvulsant effect of ALLO during ethanol withdrawal, suggesting that decreased sensitivity of GABA(A) receptors to ALLO may contribute to the increased ethanol withdrawal phenotype.

Ethanol intake patterns in female mice: influence of allopregnanolone and the inhibition of its synthesis.

The neurosteroid allopregnanolone (ALLO) is a positive modulator of GABA(A) receptors that exhibits a psychopharmacological profile similar to ethanol (i.e., anxiolytic, sedative-hypnotic). Based on research suggesting that manipulation of ALLO levels altered ethanol self-administration in male rodents, the current studies determined whether exogenous ALLO administration or the inhibition of its synthesis in vivo modulated ethanol intake patterns in female C57BL/6J mice. Lickometer circuits collected temporal lick records of ethanol (10%, v/v) and water consumption during daily 2h limited access sessions. Following the establishment of stable ethanol intake, studies examined the effect of an acute ALLO challenge (3.2-24.0 mg/kg) or a 7-day blockade of ALLO production with finasteride (FIN; 50 or 100 mg/kg) on ethanol intake in a within-subjects design. In contrast to results in male mice, ethanol dose (g/kg), ethanol preference and most of the bout parameters were unaltered by ALLO pretreatment in female mice. Ethanol intake in females also was recalcitrant to 7-day treatment with 50 mg/kg FIN, whereas 100 mg/kg FIN significantly reduced the ethanol dose consumed by 35%. The FIN-attenuated ethanol intake was attributable to a significant decrease in bout frequency (up to 45%), with lick patterns indicating reduced maintenance of consumption throughout the 2-h session. FIN also produced a dose-dependent decrease in brain ALLO levels. In conjunction with data in male mice, the present findings indicate that there are sex differences in the physiological regulation of ethanol intake patterns by GABAergic neurosteroids.

Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility.

Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5alpha-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p<.05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contribute to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression.

Aspiration Abortion With Immediate Intrauterine Device Insertion: Comparing Outcomes of Advanced Practice Clinicians and Physicians.

INTRODUCTION: Immediate postabortion intrauterine device (IUD) insertion is a safe, effective strategy to prevent subsequent unplanned pregnancy. Oregon is one of 5 US states where advanced practice clinicians perform aspiration abortions. This study compares outcomes of first-trimester aspiration abortion with immediate IUD insertion between advanced practice clinicians and physicians. METHODS: We conducted a historical cohort study of first-trimester aspiration abortions with immediate IUD insertion performed at our center from 2009 to 2011. We extracted demographic and clinical data from patient charts. Immediate complications including excessive blood loss, perforation, and reaspirations were recorded at the time of procedure. We used descriptive statistics and multivariable logistic regression to test for differences in outcomes by clinician type. RESULTS: Data were available on 669 of the 1134 combined procedures. Advanced practice clinicians performed 224 of these. There were no significant differences in immediate outcomes. The only immediate complications were reaspirations; 1.8% (4/224) in the advanced practice clinician group, and 2.0% (9/445) in the physician group (P = .83). DISCUSSION: We found no differences in outcomes between provider type for immediate IUD insertion after first-trimester aspiration abortion. This study helps reinforce that advanced practice clinicians can provide immediate postaspiration abortion IUD insertions with similar outcomes to those of physicians. Many countries do not allow advanced practice clinicians to perform this service, but a change in policy could help address family planning provider shortages.

Hydrocodone-acetaminophen for pain control in first-trimester surgical abortion: a randomized controlled trial.

OBJECTIVE: Although hydrocodone-acetaminophen is commonly used for pain control in first-trimester abortion, the efficacy of oral opioids for decreasing pain has not been established. Our objective was to estimate the effect of hydrocodone-acetaminophen on patient pain perception during first-trimester surgical abortion. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial. Patients (before 11 weeks of gestation) received standard premedication (ibuprofen and lorazepam) and a paracervical block with the addition of 10 mg hydrocodone and 650 mg acetaminophen or placebo 45-90 minutes before surgical abortion. A sample size of 120 was calculated to provide 80% power to show a 15-mm difference (α=0.05) in the primary outcome of pain with uterine aspiration (100-mm visual analog scale). Secondary outcomes were pain at additional time points, satisfaction, side effects, adverse events, and need for additional pain medications. RESULTS: There were no significant differences in demographics or baseline pain between groups. There were no differences in pain scores between patients receiving hydrocodone-acetaminophen compared with placebo during uterine aspiration (65.7 mm compared with 63.2 mm, P=.59) or other procedural time points. There were no differences in satisfaction or need for additional pain medications. Patients who received hydrocodone-acetaminophen had more postoperative nausea than those receiving placebo (P=.03) when controlling for baseline nausea. No medication-related adverse events were noted. CONCLUSION: Hydrocodone-acetaminophen does not decrease pain during first-trimester abortion and may increase postoperative nausea. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT01330459. LEVEL OF EVIDENCE: I.

Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability.

Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression.

A new look at the 5alpha-reductase inhibitor finasteride.

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.