Little evidence for sex or ovarian hormone influences on affective variability.

Women were historically excluded from research participation partly due to the assumption that ovarian hormone fluctuations lead to variation, especially in emotion, that could not be experimentally controlled. Although challenged in principle and practice, relevant empirical data are limited by single measurement occasions. The current paper fills this knowledge gap using data from a 75-day intensive longitudinal study. Three indices of daily affective variability-volatility, emotional inertia, and cyclicity-were evaluated using Bayesian inferential methods in 142 men, naturally cycling women, and women using three different oral contraceptive formulations (that "stabilize" hormone fluctuations). Results provided more evidence for similarities between men and women-and between naturally cycling women and oral contraceptive users-than for differences. Even if differences exist, effects are likely small. Thus, there is little indication that ovarian hormones influence affective variability in women to a greater extent than the biopsychosocial factors that influence daily emotion in men.

Plasma Homoarginine Concentrations According to Use of Hormonal Contraception.

Estrogen is a potent vasodilator through activation of endothelial nitric oxide synthase (eNOS). Arginine and its homologue homoarginine are substrates for NOS, while asymmetric dimethylarginine (ADMA) is a NOS inhibitor. Healthy, never-pregnant women aged 18 to 40 years (n = 158) were categorized according to use of hormonal contraception into non-users (n = 76), users of estrogen contraceptives (EC-users, n = 58) and users of progestins-only contraceptives (PC-users, n = 24). Plasma homoarginine, arginine, ADMA and SDMA concentrations were assayed using a LC-MS/MS method. Compared to non-users, EC users had higher plasma homoarginine (median (interquartile range) 1.63 (1.24, 2.04) vs. 2.39 (2.05, 2.85) µmol/L, p < 0.001), lower arginine (80.8 (72.4, 94.3) vs. 72.1 (62.9, 85.1) µmol/L, p = 0.008) and ADMA (0.52 (0.46, 0.59) vs. 0.48 (0.42, 0.54) µmol/L, p = 0.003) concentrations. The lowest median plasma homoarginine concentration (1.34 (0.92, 1.75) µmol) was seen in PC-users. No differences were seen in SDMA concentrations according to use of hormonal contraception. In healthy, never-pregnant women aged 18 to 40 years, use of estrogen containing contraception was associated with significantly higher plasma concentrations of homoarginine and lower plasma concentrations of arginine and ADMA as compared to non-users, while the lowest plasma homoarginine concentrations were seen in progestin-only users. Whether the observed changes in relation to use of hormonal contraception have an impact on cardiovascular status, should be evaluated in an intervention study.

Neural activity during traumatic film viewing is linked to endogenous estradiol and hormonal contraception.

Women are at higher risk for Posttraumatic Stress Disorder (PTSD) and recent research has highlighted a modulating role of female sex hormones for cognitive and emotional processes potentially underlying PTSD symptoms. However, studies combining fMRI recordings of brain activity during trauma film viewing with assessment of female sex hormones are missing. The trauma film paradigm - a widely used experimental analogue for trauma exposure - confronts healthy participants with traumatic film clips and thus allows studying peritraumatic processing under laboratory conditions. Following this paradigm, the current fMRI study examined the role of endogenous estradiol and synthetic sex hormones for the neural processing of traumatic (i.e., depicting interpersonal violence) vs. neutral films in 53 healthy women (mean age 22.3 years; 23 using hormonal contraception, HC). As predicted, traumatic films strongly activated areas of the fear processing network, such as amygdala, insula, and dorsal anterior cingulate cortex. Estradiol levels in women not using HC were positively correlated with ventromedial prefrontal activity. Furthermore, women using HC as compared to women without HC demonstrated heightened insula and dorsal anterior cingulate cortex activity during traumatic film viewing. These experimental results highlight the effects of both gonadal hormone status and HC intake on peritraumatic processing in neural regions relevant for emotion generation and regulation that have been found to be abnormal in PTSD.

Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy.

Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel. We show that the progestins bind to the androgen receptor (AR) with similar affinities to each other and progesterone, while none bind estrogen receptor (ER)-ß, and only norethisterone acetate, levonorgestrel and gestodene bind ERα. Comparative dose-response analysis revealed that progestins from the first three generations display similar androgenic activity to the natural androgen dihydrotestosterone for transactivation, while norethisterone acetate, levonorgestrel and gestodene are ERα agonists. We show for the first time that the anti-androgenic properties of progesterone and drospirenone are similar to the well-known AR antagonist hydroxyflutamide, while nomegestrol acetate is more potent and nestorone less potent than both hydroxyflutamide and progesterone. Moreover, we are the first to report that the older progestins, unlike progesterone and the fourth generation progestins, are efficacious ERα agonists for transrepression, while the selected progestins from the second and third generation are efficacious AR agonists for transrepression. Considering the progestin potencies and their reported free serum concentrations relative to dihydrotestosterone and estradiol, our results suggest that the progestins are likely to exert AR-, but not ERα- or ERß-mediated effects in vivo.

Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction.

BACKGROUND: Findings about sex differences in the field of fear conditioning and fear extinction have been mixed. At the psychophysiological level, sex differences emerge only when taking estradiol levels of women into consideration. This suggests that this hormone may also influence sex differences with regards to activations of brain regions involved in fear conditioning and its extinction. Importantly, the neurobiological correlates associated with the use of hormonal oral contraceptives in women have not been fully contrasted against men and against naturally cycling women with different levels of estradiol. In this study, we begin to fill these scientific gaps. METHODS: We recruited 37 healthy men and 48 healthy women. Of these women, 16 were using oral contraceptives (OC) and 32 were naturally cycling. For these naturally cycling women, a median split was performed on their serum estradiol levels to create a high estradiol (HE) group (n = 16) and a low estradiol (LE) group (n = 16). All participants underwent a 2-day fear conditioning and extinction paradigm in a 3 T MR scanner. Using the 4 groups (men, HE women, LE women, and OC users) and controlling for age and coil type, one-way ANCOVAs were performed to look at significant activations within the nodes of the fear circuit. Using post-hoc analyses, beta-weights were extracted in brain regions showing significant effects in order to unveil the differences based on hormonal status (men, HE, LE, OC). RESULTS: Significant main effect of hormonal status group was found across the different phases of the experiment and in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus. During conditioning, extinction and recall, most of the observed differences suggested higher activations among HE women relative to men. During the unconditioned response, however, a different pattern was observed with men showing significantly higher brain activations. CONCLUSIONS: Our data further support the important contribution of estradiol levels in the activation of brain regions underlying fear learning and extinction. The results highlight the need to document gonadal hormonal levels, menstrual cycle phase as well as oral contraceptive use in women in order to avoid overlooking sex differences when investigating the neurobiology of emotional regulation.

Efecto abortive de los anticonceptivos hormonales: una revisión / Abortifacient effect of hormonal contraceptives: a Review

En gran parte de la comunidad científica, así como del ámbito jurídico, al tratar del embrión no nacido, está vigente el criterio según el cual hay que definir el embarazo como el período que comprende sólo desde la implantación hasta el nacimiento natural. Esto lleva consigo otras novedades; por ejemplo, la redefinición de aborto como la eliminación del embrión sólo en ese período, o la extensión de la anticoncepción a cualquier medio que impida la unión entre los gametos como consecuencia de una relación íntima, o también que elimine el producto de la concepción antes de su implantación. De modo que la industria farmacéutica está lanzando al mercado, bajo el nombre de anticonceptivos, productos que actúan también mediante un mecanismo antiimplantatorio. Este hecho tiene grandes repercusiones éticas con relación al respeto del embrión, que obligan a reflexionar acerca de la valoración moral de la prescripción, dispensación y uso de estos medios. Ahora bien, ¿cuáles de los medios contraceptivos actualmente presentes en el mercado incluyen un efecto antiimplantatorio?, ¿qué mecanismos contribuyen a su acción farmacológica y en qué medida lo hacen? Esto es lo que hemos estudiado en este artículo, basándonos en la bibliografía científica disponible. Aunque no ha sido una tarea sencilla, puesto que los resultados aportados por la literatura varían mucho, se ha tratado de ofrecer una conclusión bastante precisa. Básicamente hemos cumplido un doble objetivo: actualizar y completar los estudios -pocos, parciales o lejanos en el tiempo- que tenían este mismo objeto; y ofrecer una valoración ética respecto al respeto de la vida naciente del uso de los anticonceptivos hormonales que pueden tener efecto antiimplantatorio

Most of the scientific community, as well as in a sector of international Law, when referring to the unborn embryo, pregnancy must be defined as the period extending from implantation to natural birth. This implies some novelty, such as the redefinition of abortion as the elimination of the embryo only within this period, and the extension of contraception to any means that impedes the union of the gametes as a consequence of a sexual intercourse, or also that which eliminates the product of conception prior to its implantation. Therefore, the pharmaceutical industry markets, under the name of contraceptives, products that act also by means of an anti-implantation mechanism. This fact has great ethical implications regarding the respect for the embryo which require a reflection on the moral valuation of the prescription, dispensation and use of these means. One may ask: which of the contraceptive means actually present in the market include an anti-implantation effect? What mechanisms contribute to their pharmacological action and in what measure do they do this? This is what we have studied in this article, based on the available scientific bibliography. We have basically fulfilled a double objective: updating and completing the studies -few, partial or distant in time- that had this same subject matter; and offering a moral valuation on the use of hormonal contraceptives that may have an anti-implantation effect, from the point of view of the respect due to the embryonic life

Effects of hormonal contraception on antiretroviral drug metabolism, pharmacokinetics and pharmacodynamics.

Among women, human immunodeficiency virus type 1 (HIV-1) infection is most prevalent in those of reproductive age. These women are also at risk of unintended or mistimed pregnancies. Hormonal contraceptives (HCs) are one of the most commonly used methods of family planning worldwide. Therefore, concurrent use of HC among women on antiretroviral medications (ARVs) is increasingly common. ARVs are being investigated and have been approved for pre-exposure prophylaxis (PrEP), and therefore, drug-drug interactions must also be considered in HIV-1-negative women who want to prevent both unintended pregnancy and HIV-1 infection. This article will review four main interactions: (i) the effect of HCs on ARV pharmacokinetics (PK) and pharmacodynamics (PD) during therapy, (ii) the effect of ARVs on HC PK and PD, (iii) the role of drug transporters on drug-drug interactions, and (iv) ongoing research into the effect of HCs on pre-exposure prophylaxis PK and PD.

Sex differences in urinary levels of several biological indicators of exposure: a simulation study using a compartmental-based toxicokinetic model.

Toxicokinetic modeling is a useful tool to describe or predict the behavior of a chemical agent in the human or animal organism. A general model based on four compartments was developed in a previous study to quantify the effect of human variability on a wide range of biological exposure indicators. The aim of this study was to adapt this existing general toxicokinetic model to three organic solvents--methyl ethyl ketone, 1-methoxy-2-propanol, and 1,1,1,-trichloroethane--and to take into account sex differences. In a previous human volunteer study we assessed the impact of sex on different biomarkers of exposure corresponding to the three organic solvents mentioned above. Results from that study suggested that not only physiological differences between men and women but also differences due to sex hormones levels could influence the toxicokinetics of the solvents. In fact the use of hormonal contraceptive had an effect on the urinary levels of several biomarkers, suggesting that exogenous sex hormones could influence CYP2E1 enzyme activity. These experimental data were used to calibrate the toxicokinetic models developed in this study. Our results showed that it was possible to use an existing general toxicokinetic model for other compounds. In fact, most of the simulation results showed good agreement with the experimental data obtained for the studied solvents, with a percentage of model predictions that lies within the 95% confidence interval varying from 44.4 to 90%. Results pointed out that for same exposure conditions, men and women can show important differences in urinary levels of biological indicators of exposure. Moreover, when running the models by simulating industrial working conditions, these differences could be even more pronounced. A general and simple toxicokinetic model, adapted for three well-known organic solvents, allowed us to show that metabolic parameters can have an important impact on the urinary levels of the corresponding biomarkers. These observations give evidence of an interindividual variability, an aspect that should have its place in the approaches for setting limits of occupational exposure.

Positive association between 25-hydroxyvitamin D and C-reactive protein is confounded by hormonal contraceptive use.

BACKGROUND: Studies of the relationship between vitamin D and inflammation are equivocal. This may be due to unaccounted confounding. Hormonal contraceptive (HC) use is associated with elevated circulating 25-hydroxyvitamin D [25(OH)D] in Caucasians and African-Americans, but its effects on 25(OH)D in other ethnicities are unclear. HC use is associated with elevated C-reactive protein (CRP), an inflammatory biomarker. Our objectives were to assess the effect of HC use on 25(OH)D across ethnic groups, and to examine the association between HC, 25(OH)D and CRP in an ethnically diverse population of young adults. METHODS: We recruited Caucasian, East Asian, and South Asian individuals (n=1,403) from Toronto, Canada. Fasting blood measures of 25(OH)D and CRP were obtained. RESULTS: Across ethnic groups, women HC users (n=280) had higher 25(OH)D and CRP than women HC non-users (n=695) and men (n=428) (p<0.008 and p<0.0001, respectively). Circulating 25(OH)D was positively associated with CRP in the entire population in models not accounting for HC use (ß=0.010±0.003; p<0.0001). There was no association when men and women HC non-users were examined separately. Among women HC users, there was no association after accounting for hormone dose. A positive association between 25(OH)D and CRP among individuals above the median 25(OH)D (≥51.9 nmol/L) was not significant after adjustment for HC use. No association was observed among individuals below the median. CONCLUSIONS: HC use and 25(OH)D were positively associated across ethnic groups. We found no association between 25(OH)D and CRP when HC use was accounted for. HC use confounds the association between 25(OH)D and CRP.

Comparison of serum and cervical mucus hormone levels during hormone-free interval of 24/4 vs. 21/7 combined oral contraceptives.

BACKGROUND: This study analyzes levels of progesterone, estradiol, norethindrone (NET) and ethinyl estradiol (EE) in serum and levels of NET in cervical mucus on the last day of the hormone-free interval (HFI) in users of 24/4 [norethindrone acetate (NETA)/EE-24] vs. 21/7 (NETA/EE-21) regimens. STUDY DESIGN: This was a randomized controlled, crossover, equivalency trial. Subjects were randomized to receive NETA/EE-24 or NETA/EE-21 for 2 months and then switched between study drugs. Blood and cervical mucus samples were obtained on Days 12-16 and on the last day of the HFI. RESULTS: From April 2010 to November 2011, 32 subjects were enrolled with 18 subjects completing all study visits. There were no statistically significant differences in either day 12-16 (p=.54) or last hormone-free day (p=.33) cervical mucus NET concentrations between the regimens. On the last day of the HFI, median serum progesterone levels did not differ significantly; however, users of NETA/EE-24 had higher levels of serum NET (p<.001) and users of NETA/EE-21 had higher levels of serum estradiol (p=.01). CONCLUSION: This data supports the fact that inhibition of the pituitary-ovarian axis occurs during oral contraceptive use and during the HFI. We demonstrated that a reduced HFI of 4 days resulted in better suppression of the ovarian hormone production, thereby reducing the risk of ovulation and potential contraceptive failure.

Oral contraceptives do not affect muscle strength and hop performance in active women.

OBJECTIVE: The primary aim of this study was to compare muscle strength in the upper and lower limb, as well as hop performance during oral contraceptive (OC) use with non-OC use in the same woman. A secondary aim was to compare muscle strength and hop performance within 3 specific phases of an OC cycle, as well as during a menstrual cycle of the corresponding cycle days (non-OC cycle). DESIGN: Crossover. SETTING: Research laboratory. PARTICIPANTS: Seventeen moderate to highly recreationally active women participated in the study. INTERVENTION: Observational study with no intervention. MAIN OUTCOME MEASURES: Maximal isokinetic muscle strength of knee extensors, isometric handgrip strength, and 1-leg hop test for distance were measured during 1 OC cycle and 1 non-OC cycle at 3 specific phases, respectively, using a crossover design. RESULTS: No significant differences were found in terms of muscle strength and hop performance between the OC cycle and the non-OC cycle. Furthermore, no significant difference in muscle strength and hop performance could be demonstrated within the OC cycle or within the phases of the menstrual cycle except from maximal isokinetic muscle strength in the knee extensors detected between the early follicular phase and the luteal phase. CONCLUSIONS: We found no support for any significant influence of OC use on muscle strength and hop performance in healthy moderately active women.

Sex differences in urinary levels of several biological indicators of exposure: a human volunteer study.

The aim of the study was to quantify the variability on biological indicators of exposure between men and women for three well known solvents: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile. Controlled human exposures were carried out in a 12 m³ exposure chamber for each solvent separately, during 6h and at half of the threshold limit value. The human volunteers groups were composed of ten young men and fifteen young women, including ten women using hormonal contraceptive. An analysis of variance mainly showed an effect on the urinary levels of several biomarkers of exposure among women due to the use of hormonal contraceptive, with an increase of more than 50% in metabolites concentrations and a decrease of up to 50% in unchanged substances concentrations, suggesting an increase in their metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele. Our study suggests that not only physiological differences between men and women but also differences due to sex hormones levels can have an impact on urinary concentrations of several biomarkers of exposure. The observed variability due to sex among biological exposure indices can lead to misinterpretation of biomonitoring results. This aspect should have its place in the approaches for setting limits of occupational exposure.

Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review.

The effect of obesity on drug metabolism and pharmacokinetics is poorly understood, and this is particularly true in regard to contraceptive steroids. This article will review the known and theoretical physiologic and pharmacologic interactions between obesity and contraceptive steroids.

Impact of oral contraception and neuroticism on cardiovascular stress reactivity across the menstrual cycle.

In order to avoid interpretation problems relating to the impact of reproductive hormones on cardiovascular variables, research on the psychosomatic etiology of cardiovascular disease frequently excludes women who use oral contraceptives (OCs), and sometimes women as a whole, from study samples. However, such conventions are based on a body of research that suffers from methodological limitations and, in any event, has produced inconclusive findings. Further, the relevant research fails to control for personality differences between users and non-users of OC that may, in turn, lead to differences in stress reactivity. In the present study, using a counterbalanced mixed-factorial design, 24 women (12 OC users and 12 non-users), drawn from a screening sample of 110, were tested across a 4-month timeframe. Cardiovascular reactivity (CVR) was measured during both the follicular and luteal phases of each woman's menstrual cycle. Menstrual phase and OC use were found to exert synergistic effects on CVR. A significant relationship between neuroticism and systolic blood pressure reactivity was observed, which was found to be contingent on menstrual phase. It is concluded that while menstrual phase and OC use are relevant, their contaminating influence on CVR research can be circumvented.

The relationship between 24-h urinary cortisol and bone in healthy young women.

BACKGROUND: Cortisol within the normal range has been associated with reduced bone density in the elderly, but little is known about this relationship in healthy young women. PURPOSE: The purpose of this study is to assess whether 24-h urinary free cortisol excretion (UFC) is related to bone density in 132 healthy, non-obese, regularly menstruating women, aged 19-35. METHOD: Participants completed questionnaires (food frequency, demographics, physical activity, dietary restraint, perceived stress, and daily stress) and a 24-h urine collection. UFC was determined by high-throughput liquid chromatography and tandem mass spectrometry. Anthropometrics were completed and a dual energy X-ray absorptiometry scan measured areal bone mineral density (aBMD, g/cm(2)) and bone mineral content (BMC, g) at the lumbar spine (L1-4), hip, and total body (TB) as well as total body lean (LBM) and fat mass. RESULTS: aBMD and BMC were significantly positively associated with height, LBM, physical activity, calcium intake, and duration of previous oral contraceptive use (except L1-4) and negatively with perceived stress. UFC was not correlated with any measured variables except urine volume (r = 0.17, p = 0.046). After adjusting for urine volume, height, LBM, ethnicity, and prior oral contraceptive use, UFC was significantly inversely associated with TB BMC (r = -0.30, p < 0.001) and aBMD (r = -0.27, p = 0.003), L1-4 aBMD (r = -0.19, p = 0.035) and BMC (r = -0.18, p = 0.049), and hip BMC (r = -0.23, p = 0.011). Further adjustment for sport activity, calcium intake and perceived stress did not change these relationships meaningfully except that L1-4 became nonsignificant (p < 0.07). CONCLUSION: Cortisol within the normal range appears to have a minor negative influence on bone density in healthy young women.

Oral contraception usage in relation to bone mineral density and bone turnover in adolescent girls.

OBJECTIVES: To compare the effect of a low-dose oral contraceptive (OC) containing 30 microg ethinyloestradiol (EE) with that of an ultra-low-dose OC containing 15 microg EE on bone turnover and BMD in healthy adolescent women and, in addition, to ascertain the influence of body mass index (BMI) and exercise on these indices of bone metabolism. METHODS: We recruited to the study 92 healthy girls aged between 16 and 19. They were divided into three groups. Participants in the first two groups used an OC with either 15 or 30 microg ethinyloestradiol (EE), whereas those in the third group used no hormonal contraception. Bone mineral density (BMD) and bone turnover markers were measured before and after 12 months of treatment. RESULTS: The BMD values of the total hip in females using the OC containing 30 microg EE was 0.912 g/cm(2) at baseline and 0.918 g/cm(2) after one year; in females using the OC containing 15 microg EE the corresponding values were 0.888 g/cm(2) and 0.895 g/cm(2) whereas in females who used no contraception BMD values were 0.942 g/cm(2) and 0.949 g/cm(2), respectively. The changes were statistically insignificant. Levels of osteocalcin and CTX had decreased after one year in all groups, but not statistically significantly so. CONCLUSION: Low dose and ultra-low dose oral contraceptives did not significantly differ in their effects on bone mineral density or bone turnover markers in adolescent girls aged 16-19.