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We assessed the effect of a progestin-based contraceptive treatment (chlormadinone acetate) on female heterosexual and homosexual behaviors in a free-ranging group of Japanese macaques (Macaca fuscata) living at Arashiyama-Kyoto, Central Japan. The data included estimated intensity of fertility cues, sexual solicitations and mounting behaviors collected daily during 17 consecutive mating seasons (1995-2012) from 159 females. Females that were on contraception: (1) exhibited less intense cues of putative fertility and for shorter periods; (2) were solicited by fewer males, and those males that did solicit them did so less often (i.e., lower heterosexual attractivity); (3) solicited fewer males and when they did perform sexual solicitations they did so less often (i.e., lower heterosexual proceptivity); (4) engaged in shorter heterosexual consortships with fewer male partners (i.e., lower heterosexual receptivity), compared with females that were not on contraception. In contrast, contraceptive treatment had no significant effect on the prevalence, occurrence, frequency, or duration of female homosexual behaviors. Even though heterosexual and homosexual behaviors can both be considered sexual in character and under hormonal control, our results suggested they are, to some extent, dissociable. Because females engaging in homosexual interactions showed less intense cues of putative fertility than those engaging in heterosexual interactions, regardless of contraceptive treatment, we argued that the hormonal threshold required for the expression of heterosexual behavior by females was associated with elevated sex hormones levels compared to homosexual behavior. We discussed the hormonal correlates of sexual behavior and partner preferences in Japanese macaques., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Arterial stiffness is associated with increased cardiovascular disease risk. Previous sex-based investigations of local and central stiffness report inconsistent findings and have not controlled for menstrual cycle phase in women. There is also evidence that sex hormones influence the vasculature, but their impact on arterial stiffness across a natural menstrual (NAT) or oral contraceptive pill (OCP) cycle has been understudied. This study sought to 1) examine potential sex differences in local and central stiffness, 2) compare stiffness profiles between NAT and OCP cycles, and 3) investigate the relationship between duration of OCP use and arterial stiffness. Sex hormone concentrations, β-stiffness index (local stiffness), and carotid-femoral pulse wave velocity [cfPWV (central stiffness)] were assessed in 53 healthy adults (22 ± 3 yr old, 20 men, 15 NAT women, and 18 OCP women). All participants were tested three times: men on the same day and time 1 wk apart, NAT women in menstrual, midfollicular and luteal phases of the menstrual cycle, and OCP women in placebo, early active and late active pill phases. β-Stiffness was higher in men than NAT and OCP women ( P < 0.001), whereas cfPWV was similar between groups ( P = 0.09). β-Stiffness and cfPWV did not differ across or between NAT and OCP cycles ( P > 0.05 for both) and were not associated with duration of OCP use (β-stiffness: r = 0.003, P = 0.99; cfPWV: r = -0.26, P = 0.30). The apparent sex differences in local, but not central, stiffness highlight the importance of assessing both indexes in comparisons between men and women. Furthermore, fluctuating sex hormone levels do not appear to influence β-stiffness or cfPWV. Therefore, these stiffness indexes may need to be assessed during only one cycle phase in women in future investigations. NEW & NOTEWORTHY We observed higher local, but not central, arterial stiffness in men than women. We also demonstrated that there are no differences in arterial stiffness between naturally cycling women and women who use monophasic oral contraceptive pills, and that the duration of oral contraceptive pill use does not influence arterial stiffness.

Sex hormone concentrations differ between men, premenopausal women with natural menstrual cycles (NAT), and premenopausal women using oral contraceptive pills (OCP), as well as across menstrual or OCP phases. This study sought to investigate how differences in sex hormones, particularly estradiol, between men and women and across cycle phases might influence brachial artery endothelial function. Fifty-three healthy adults (22 ± 3 yr, 20 men, 15 NAT women, and 18 second-, third-, or fourth-generation OCP women) underwent assessments of sex hormones and endothelial [flow-mediated dilation (FMD) test] and smooth muscle [nitroglycerin (NTG) test] function. Men were tested three times at 1-wk intervals, and women were tested three times throughout a single menstrual or OCP cycle (NAT: menstrual, midfollicular, and luteal phases and OCP: placebo/no pill, "early", and "late" active pill phases). Endogenous estradiol concentration was comparable between men and women in their NAT menstrual or OCP placebo phase ( P = 0.36) but increased throughout a NAT cycle ( P < 0.001). Allometrically scaled FMD did not change across a NAT or OCP cycle but was lower in both groups of women than in men ( P = 0.005), whereas scaled NTG was lower only in NAT women ( P = 0.001). Changes in estradiol across a NAT cycle were not associated with changes in relative FMD ( r 2  = 0.01, P = 0.62) or NTG ( r 2  = 0.09, P = 0.13). Duration of OCP use was negatively associated with the average relative FMD for second-generation OCP users only ( r = -0.65, P = 0.04). Our findings suggest that brachial endothelial function is unaffected by cyclic hormonal changes in premenopausal women but may be negatively impacted by longer-term use of second-generation OCPs. NEW & NOTEWORTHY We demonstrate that brachial artery flow-mediated dilation does not change across a menstrual or oral contraceptive pill cycle in premenopausal women but is lower in women than in men. Although unaffected by within-cycle changes in estradiol, brachial flow-mediated dilation is negatively correlated with duration of oral contraceptive pill use for second-generation pills.

HIV guidelines recommend assessment of conception issues for all people living with HIV. Studies have shown negligible risk of HIV transmission from well-treated patients with HIV, and therefore condoms are no longer recom-mended to reduce HIV transmission. Some antiretroviral agents are metabolised through the same enzyme systems in the liver as hormonal contraceptives, which can affect the plasma concentration of both drug classes and the effect of the drugs, including reduced contraceptive efficacy. This review discusses the interactions between antiretroviral agents and hormonal contraceptives.

Women who are receiving an oral anticoagulant appear to be at higher risk of developing bleeding-related adverse events than men. Physiological bleeding related to the ovulatory cycle poses an ongoing risk for bleeding complications during anticoagulant therapy. Abnormal uterine bleeding and hemorrhagic ovarian cysts are risks specific to women of reproductive age who are treated with anticoagulants. The use of combined oral contraceptives can help minimize such adverse events and would also mitigate the risks of obstetrical complications related to thrombosis and anticoagulation, in addition to avoiding fetal exposure to potentially teratogenic anticoagulants. Clinicians tend to interrupt oral contraceptives in women who are receiving oral anticoagulants despite the absence of evidence that they increase thrombotic risks when taken concurrently. This letter of opinion aims to support the use of oral contraceptives, when clinically indicated, in women of reproductive age who also are receiving an oral anticoagulant., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Oral contraceptive pill (OC) is one of the most popular form of contraception. Despite both behavioral and neuroimaging evidence of its significant impact on female brain and cognitive functions, much remains to be discovered regarding OCs targets in the brain and mechanisms of action. In the present study mental rotation performance was compared between women using anti-androgenic oral contraceptives (n = 35), naturally cycling (NC) women (n = 33) and men (n = 29). On average, OC users were less accurate than NC women and men. Men performed the task more accurately than NC women, but the difference reached significance only in the highest angular disparity condition (150 deg). The response time was positively related with progesterone level while accuracy was negatively related with 17ß-estradiol level, in NC, but not OC women. The comparison of slope and intercept values (parameters relating response time to angular disparity) revealed the main result of present study: OC users exhibited significantly lower slope compared to men and NC women, but there were no differences in intercept between groups. These results suggest that OC users instead of using rotation in mind strategy implemented some alternative method(s). We conclude that lower performance accuracy of OC users could be related to a less efficient performance strategy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We sought to determine whether oral contraception alters the gender-related differences observed in the exercise pressor reflex during isometric handgrip exercise. Fifteen men, fifteen normally menstruating women (WomenNM), and fifteen women taking monophasic oral contraceptives (WomenOC) completed two trials of a 3-min isometric handgrip exercise protocol performed at 30% of their maximal voluntary contraction: (1) where arterial occlusion was applied to the previously exercising arm during a 3-min recovery period (Occlusion trial); (2) where no arterial occlusion was applied during recovery (Control trial). Handgrip exercise elicited greater increases in mean arterial pressure (MAP) in MEN compared to both female groups (P < 0.05), and in WomenOC compared to WomenNM in both trials (P = 0.01, P = 0.03). After 3 min of recovery, sBP was 12% (P = 0.01) and 9% (P = 0.02) higher in the Occlusion trial when compared to the Control trial for MEN and WomenOC. Conversely, arterial occlusion in recovery from handgrip did not sustain elevated sBP in the Occlusion trial, and sBP returned to recovery levels not different to the Control trial, in WomenNM (P = 0.41). These data indicate that gender-related differences in the metaboreflex during isometric handgrip exercise exist between men and normally menstruating women, but are blunted when men are compared to women taking oral contraceptives. We conclude that the suppression of 17β-estradiol and/or progestogen in women via the administration of oral contraceptives attenuates sex-related differences in the metaboreflex during isometric handgrip exercise., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Obesity is a chronic, relapsing disease that necessitates a multidisciplinary approach to management. Behavioral changes are the foundation to management, but adjunctive therapy is often warranted, including pharmacologic therapies and/or bariatric surgery. Until recently, treatment options included only short-term therapy (≤12 weeks), and paths beyond that schedule were challenging, as knowledge of the biology of obesity was lacking. With increased recognition of obesity as a chronic, complex medical disease, newer agents have been approved as long-term therapy, and the cornerstone of treatment is chronic behavior and lifestyle change. In the last decade, the Food and Drug Administration (FDA) has approved several new weight loss medications for the chronic management of obesity. In this review paper, we provide the latest updates on obesity pharmacotherapy. The main areas we will cover include (1) pharmacological management of obesity, (2) a review of FDA-approved weight loss medications, (3) comanagement of obesity and its metabolic sequelae (type 2 diabetes mellitus, hypertension, and dyslipidemia), and (4) obesity-centric prescribing for mental illness, neurological disorders, and contraceptive planning., (© 2018 New York Academy of Sciences.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

HIV prevention research is focused on combining antiretrovirals (ARV) and progestin contraceptives to prevent HIV infection and pregnancy. The possibility that progestins compromise ARV anti-HIV activity prompted us to evaluate the effects of progestins on tenofovir (TFV) and TFV-alafenamide (TAF) on HIV infection and intracellular TFV-diphosphate (TFV-DP) concentrations in blood and genital CD4+ T cells. Following incubation of blood CD4+ T cells with TFV or TAF, Medroxyprogesterone acetate (MPA), but not Levonorgestrel, Norethisterone or progesterone, suppressed the anti-HIV effect of TFV by reducing intracellular TFV-DP, but had no effect on TAF inhibition of infection or TFV-DP. In contrast, with genital CD4+ T cells, MPA suppressed TAF inhibition of HIV infection and lowered of TFV-DP concentrations without affecting TFV protection. These findings demonstrate that MPA selectively compromises TFV and TAF protection in blood and genital CD4+ T cells and suggests that MPA may decrease ARV protection in individuals who use ARV intermittently for prevention.

This observational study was conducted in healthy premenopausal women, who presented themselves for contraceptive advice at the outpatient Family Planning Clinics of the Department of Obstetrics and Gynecology of the University of Cagliari, Hospital-University of Cagliari (Italy). After a screening period of three menstrual cycles, 48 women without contraindications to estroprogestin contraceptives (OCs) were included in the study. The primary purposes of the study were to evaluate whether a 12-month-treatment with the combined OC containing micronized estradiol (1.5 mg, E2) plus nomegestrol acetate (2.5 mg, NOMAC) (E2/NOMAC) interfere on anthropometric indices (AI), body composition (BC) and psychological status (PS). In subjects with dysmenorrhea (#36), its intensity was evaluated using the visuo analogic scale (VAS), both before and during the 12-month-treatment with E2/NOMAC. E2/NOMAC did not modify neither AI nor BC in the 40 subjects who concluded the study. The PS and the VAS of dysmenorrhea were significantly (p < 0.0001) improved from the first cycle of treatment and throughout the E2/NOMAC treatment in comparison with basal values. The study suggests that E2/NOMAC is devoid of negative effects on AI and BC, with additional benefits on PS and dysmenorrhea.

Objective: To evaluate the potential for a clinically relevant drug-drug interaction with concomitant use of a dapivirine vaginal ring, a novel antiretroviral-based HIV-1 prevention strategy, and hormonal contraception by examining contraceptive efficacies with and without dapivirine ring use., Design: A secondary analysis of women participating in MTN-020/ASPIRE, a randomized, double-blind, placebo-controlled trial of the dapivirine vaginal ring for HIV-1 prevention., Methods: Use of a highly effective method of contraception was an eligibility criterion for study participation. Urine pregnancy tests were performed monthly. Pregnancy incidence by arm was calculated separately for each hormonal contraceptive method and compared using an Andersen-Gill proportional hazards model stratified by site and censored at HIV-1 infection., Results: Of 2629 women enrolled, 2310 women returned for follow-up and reported using a hormonal contraceptive method at any point during study participation (1139 in the dapivirine arm and 1171 in the placebo arm). Pregnancy incidence in the dapivirine arm versus placebo among women using injectable depot medroxyprogesterone acetate was 0.43% vs. 0.54%, among women using injectable norethisterone enanthate was 1.15% vs. 0%, among women using hormonal implants was 0.22% vs. 0.69%, and among women using oral contraceptive pills was 32.26% vs. 28.01%. Pregnancy incidence did not differ by study arm for any of the hormonal contraceptive methods., Conclusions: Use of the dapivirine ring does not reduce the effectiveness of hormonal contraceptives for pregnancy prevention. Oral contraceptive pill use was associated with high pregnancy incidence, potentially because of poor pill adherence. Injectable and implantable methods were highly effective in preventing pregnancy.

Objective: To investigate the role of hormonal risk factors for amyotrophic lateral sclerosis (ALS) among women from 3 European countries., Methods: ALS cases and matched controls were recruited over 4 years in Ireland, Italy, and the Netherlands. Hormonal exposures, including reproductive history, breastfeeding, contraceptive use, hormonal replacement therapy, and gynecologic surgical history, were recorded with a validated questionnaire. Logistic regression models adjusted for age, education, study site, smoking, alcohol, and physical activity were used to determine the association between female hormones and ALS risk., Results: We included 653 patients and 1,217 controls. Oral contraceptive use was higher among controls (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51-0.84), and a dose-response effect was apparent. Hormone replacement therapy (HRT) was associated with a reduced risk of ALS only in the Netherlands (OR = 0.57, 95% CI 0.37-0.85). These findings were robust to sensitivity analysis, but there was some heterogeneity across study sites., Conclusions: This large case-control study across 3 different countries has demonstrated an association between exogenous estrogens and progestogens and reduced odds of ALS in women. These results are at variance with previous findings, which may be partly explained by differential regulatory, social, and cultural attitudes toward pregnancy, birth control, and HRT across the countries included. Our results indicate that hormonal factors may be important etiologic factors in ALS; however, a full understanding requires further investigation., (© 2017 American Academy of Neurology.)

Hormonal fluctuations during the natural cycle, as well as progestins used for hormonal contraception, can exert effects on mood especially in vulnerable women. Negative effects of levonorgestrel-releasing intrauterine contraception on mood are rare.

Objective: To summarize published evidence on drug interactions between hormonal contraceptives and antiretrovirals., Design: Systematic review of the published literature., Methods: We searched PubMed, POPLINE, and EMBASE for peer-reviewed publications of studies (in any language) from inception to 21 September 2015. We included studies of women using hormonal contraceptives and antiretrovirals concurrently. Outcomes of interest were effectiveness of either therapy, toxicity, or pharmacokinetics. We used standard abstraction forms to summarize and assess strengths and weaknesses., Results: Fifty reports from 46 studies were included. Most antiretrovirals whether used for therapy or prevention, have limited interactions with hormonal contraceptive methods, with the exception of efavirenz. Although depot medroxyprogesterone acetate is not affected, limited data on implants and combined oral contraceptive pills suggest that efavirenz-containing combination antiretroviral therapy may compromise contraceptive effectiveness of these methods. However, implants remain very effective despite such drug interactions. Antiretroviral plasma concentrations and effectiveness are generally not affected by hormonal contraceptives., Conclusion: Women taking antiretrovirals, for treatment or prevention, should not be denied access to the full range of hormonal contraceptive options, but should be counseled on the expected rates of unplanned pregnancy associated with all contraceptive methods, in order to make their own informed choices.

Objective: To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality., Outcomes: Overall efficacy of cited contraceptive methods, assessing reduction in pregnancy rate, safety, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the availability of cited contraceptive methods in Canada., Evidence: Medline and the Cochrane Database were searched for articles in English on subjects related to contraception, sexuality, and sexual health from January 1994 to December 2015 in order to update the Canadian Contraception Consensus published February-April 2004. Relevant Canadian government publications and position papers from appropriate health and family planning organizations were also reviewed., Values: The quality of the evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice are ranked according to the method described in this report., Summary Statements: RECOMMENDATIONS., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: In Australia, use and understanding of emergency contraception among women remains relatively low. This is despite the introduction of levonorgestrel emergency contraceptive pills (ECPs) more than a decade ago. In April 2016, a new ECP with the active ingredient ulipristal acetate became available in Australia., Objective: The aims of this article are to increase understanding of the recently introduced ulipristal acetate ECP, including its safety profile, effi-cacy and special considerations; dispel common myths and misconceptions about emergency contraception; and to provide guidance on emergency contraceptive management in general practice, considering the recent advances., Discussion: Women are more receptive to information about emergency contraception that has been provided by a general practitioner (GP). As such, the availability of the ulipristal acetate ECP in Australia provides an important opportunity for GPs to help women prevent unplanned pregnancies.

Purpose: To evaluate the dynamic and static retinal vascular functionality in young females using combined hormonal contraceptive (CHC)., Methods: Thirty-eight consecutive young female subjects were enrolled in this study between January 2015 and December 2015. Subjects were divided in two groups: CHC group, defined as CHC use for ≥6 months, and control group, defined as no current and prior CHC use. Participants underwent a dynamic and static retinal vessel analysis using the Dynamic Vessel Analyzer (DVA, Imedos, Jena, Germany)., Results: Seventeen subjects continuously took CHC for 54.6 ± 29.3 months, while 21 subjects belonged to control group. No difference was found between the CHC and control groups for age (p = 0.1), smoking status (p = 0.6), and systolic (p = 0.3) and diastolic (p = 0.1) blood pressure. With regard to dynamic analysis, women taking CHC exhibited a marked significant vasoconstriction following flicker stimulation in comparison with control group (-2.43 ± 2.5 vs 0.63 ± 2.1, respectively; p = 0.0002). No significant difference was observed between groups for mean arterial (p = 0.2) and venous dilatations (p = 0.3), arteriovenous ratio (p = 0.09), central retinal artery equivalent (p = 0.4), and central retinal venous equivalent (p = 0.5)., Conclusions: CHC may affect vessel reactivity to flicker light by increasing arteries constriction. This may reflect systemic changes in vascular functionality in subjects using CHC. Moreover, CHC should be considered as a confounding bias in studies involving DVA.

We tested the hypothesis that sympathetic responses to baroreceptor unloading may be affected by circulating sex hormones. During lower body negative pressure at -30, -60, and -80 mmHg, muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were recorded in women who were taking (n = 8) or not taking (n = 9) hormonal contraceptives. All women were tested twice, once during the low-hormone phase (i.e., the early follicular phase of the menstrual cycle and the placebo phase of hormonal contraceptive use), and again during the high-hormone phase (i.e., the midluteal phase of the menstrual cycle and active phase of contraceptive use). During baroreceptor unloading, the reductions in stroke volume and resultant increases in MSNA and total peripheral resistance were greater in high-hormone than low-hormone phases in both groups. When normalized to the fall in stroke volume, increases in MSNA were no longer different between hormone phases. While stroke volume and sympathetic responses were similar between women taking and not taking hormonal contraceptives, mean arterial pressure was maintained during baroreceptor unloading in women not taking hormonal contraceptives but not in women using hormonal contraceptives. These data suggest that differences in sympathetic activation between hormone phases, as elicited by lower body negative pressure, are the result of hormonally mediated changes in the hemodynamic consequences of negative pressure, rather than centrally driven alterations to sympathetic regulation., (Copyright © 2016 the American Physiological Society.)

Family planning options, including hormonal contraceptives, are essential for improving reproductive health among the more than 17 million women living with HIV worldwide. For these women, prevention of unintended pregnancy decreases maternal and child mortality, as well as reduces the risk of perinatal HIV transmission. Similarly, treatment of HIV with antiretroviral therapy (ART) is essential for reducing morbidity and mortality among HIV-positive individuals, as well as preventing HIV transmission between sexual partners or from mother to child. Importantly, despite the benefits of hormonal contraceptives, barriers to effective family planning methods exist for HIV-positive women. Specifically, drug-drug interactions can occur between some antiretroviral medications and some hormonal contraceptives, which may influence both contraceptive efficacy and tolerability. In addition, safety concerns have been raised about the impact of hormonal contraceptives on HIV disease progression, tolerability, and the risk of female-to-male HIV transmission. This review article summarizes the potential for drug-drug interactions, tolerability, and contraceptive effectiveness when hormonal contraceptives are combined with ART. In addition, the evidence surrounding the influence of hormonal contraceptives on HIV transmission and HIV disease progression in women living with HIV are summarized., Competing Interests: Kimberly Scarsi, Kristin Darin, Catherine Chappell, Stephanie Nitz, and Mohammed Lamorde have no conflicts of interest that are directly relevant to this content.

Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood., Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception., Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery., Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation., (© The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Anxiety disorders are more prevalent in women than men. One contributing factor may be the sex hormone estradiol, which is known to impact the long term recall of conditioned fear extinction, a laboratory procedure that forms the basis of exposure therapy for anxiety disorders. To date, the literature examining estradiol and fear extinction in humans has focused primarily on physiological measures of fear, such as skin conductance response (SCR) and fear potentiated startle. This is surprising, given that models of anxiety identify at least three important components: physiological symptoms, cognitive beliefs, and avoidance behavior. To help address this gap, we exposed women with naturally high (n=20) or low estradiol (n=19), women using hormonal contraceptives (n=16), and a male control group (n=18) to a fear extinction task, and measured SCR, US expectancy and CS valence ratings. During extinction recall, low estradiol was associated with greater recovery of SCR, but was not related to US expectancy or CS evaluation. Importantly, women using hormonal contraceptives showed a dissociation between SCR and cognitive beliefs: they exhibited a greater recovery of SCR during extinction recall, yet reported similar US expectancy and CS valence ratings to the other female groups. This divergence underscores the importance of assessing multiple measures of fear when examining the role of estradiol in human fear extinction, especially when considering the potential of estradiol as an enhancement for psychological treatments for anxiety disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Menstrual cycle-dependent changes have been reported for a variety of functions, including cognition, attention, emotion, inhibition, and perception. For several of these functions, an effect of hormonal contraceptives has also been discussed. Cognitive, attentional, emotional, inhibitory, and perceptual functions have been linked to distinct intrinsic connectivity networks during the resting state. However, changes in resting-state connectivity across the menstrual cycle phase and due to hormonal contraceptive use have only been investigated in two selected networks and without controlling for the type of hormonal contraceptives. In the present study, we demonstrate menstrual cycle and hormonal contraceptive-dependent changes in several intrinsic connectivity networks, including networks that have been related to emotion processing, olfaction, audition, vision, coordination, and two lateralized frontoparietal networks related to a variety of cognitive functions. These changes parallel behavioral changes in the functions associated with these networks. Changes in connectivity and changes in behavior occur during the same cycle phases. Furthermore, hormonal contraceptive-dependent effects were observed in the same networks and same target sites as menstrual cycle-related changes and were dependent on the androgenicity of the progestin component contained in the hormonal contraceptive.

Irregular uterine bleeding is a major side effect of long-acting progestogen-only contraceptives in women, and is the primary reason women discontinue their use. In this study, a mouse model of endometrial breakdown was established using a subcutaneous progesterone implant to understand how irregular bleeding begins. Although progestogens sustained decidualization, endometrial breakdown was still observed in this model. We, therefore, hypothesized that endometrial breakdown might involve functional progesterone withdrawal. Using co-immunoprecipitation assays, we observed the constitutive activation of nuclear factor kappa-b (NF-κB) p65 and its interaction with the progesterone receptor (PGR); moreover, transcriptional activity of the PGR was also repressed by NF-κB activity in primary mouse and human decidual stromal cells that mimic progesterone maintenance. Yet the ratio of PGR-B to PGR-A was not increased in the mouse model. In vivo comparison of endometrial breakdown induced by progesterone withdrawal to that seen during sustained progesterone exposure, in the presence of NF-κB inhibitors, revealed that NF-κB-mediated functional progesterone withdrawal is involved in endometrial breakdown in this implant model. These data prompt further studies to determine the homology of this functional progesterone withdrawal mechanism in human endometrium. Mol. Reprod. Dev. 83: 780-791, 2016 © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: In recent years, several new oral contraceptives have become available. In some ways, they represent an evolution in terms of individualization and compliance on the part of women. The new formulations make it increasingly possible to prescribe a specific hormonal contraceptive on an individual basis., Methods: A systematic literature search of PubMed was performed using the following combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptive'. Only English-language papers published between January 2000 and July 2014 were included in our analysis. The present review analyzes all aspects of the choice of oral contraceptives in the different phases of a woman's life in detail., Results: Regarding the estrogen component, lowering the dose of ethinylestradiol (EE) helped reduce associated side effects. Natural estradiol is now available and represents a valid alternative to EE. And regarding progestins, the dose has changed over time, as well as the endocrine and metabolic characteristics. These are the fruit of much research into improvement of old products (19-nor-progesterone-derived progestins) with androgenic effects and testing of new molecules with improved metabolic neutrality in terms of insulin sensitivity and lipid parameters. New progestins were a genuine turning point because they greatly reduced major side effects, such as water retention, and their anti-androgenic properties made them indicated for all forms of hyperandrogenism associated with acne and mild hirsutism. The associations of estradiol/dienogest and estradiol/nomegestrol acetate are the most suitable contraceptives for women with abundant menstrual bleeding and can increase the number of potential users of hormonal contraception., Conclusion: Progress in the provision of new oral contraceptives has improved the risk/benefit ratio, by increasing benefits and reducing risks. The present challenge is to tailor contraceptives to individual needs in terms of efficacy and protection of reproductive health., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. POCs include injectables, intrauterine contraception, implants, and oral contraceptives. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users., Objectives: The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight., Search Methods: Until 4 August 2016, we searched MEDLINE, CENTRAL, POPLINE, LILACS, ClinicalTrials.gov, and ICTRP. For the initial review, we contacted investigators to identify other trials., Selection Criteria: We considered comparative studies that examined a POC versus another contraceptive method or no contraceptive. The primary outcome was mean change in body weight or mean change in body composition. We also considered the dichotomous outcome of loss or gain of a specified amount of weight., Data Collection and Analysis: Two authors extracted the data. Non-randomized studies (NRS) need to control for confounding factors. We used adjusted measures for the primary effects in NRS or the results of matched analysis from paired samples. If the report did not provide adjusted measures for the primary analysis, we used unadjusted outcomes. For RCTs and NRS without adjusted measures, we computed the mean difference (MD) with 95% confidence interval (CI) for continuous variables. For dichotomous outcomes, we calculated the Mantel-Haenszel odds ratio (OR) with 95% CI., Main Results: We found 22 eligible studies that included a total of 11,450 women. With 6 NRS added to this update, the review includes 17 NRS and 5 RCTs. By contraceptive method, the review has 16 studies of depot medroxyprogesterone acetate (DMPA), 4 of levonorgestrel-releasing intrauterine contraception (LNG-IUC), 5 for implants, and 2 for progestin-only pills.Comparison groups did not differ significantly for weight change or other body composition measure in 15 studies. Five studies with moderate or low quality evidence showed differences between study arms. Two studies of a six-rod implant also indicated some differences, but the evidence was low quality.Three studies showed differences for DMPA users compared with women not using a hormonal method. In a retrospective study, weight gain (kg) was greater for DMPA versus copper (Cu) IUC in years one (MD 2.28, 95% CI 1.79 to 2.77), two (MD 2.71, 95% CI 2.12 to 3.30), and three (MD 3.17, 95% CI 2.51 to 3.83). A prospective study showed adolescents using DMPA had a greater increase in body fat (%) compared with a group not using a hormonal method (MD 11.00, 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (MD -4.00, 95% CI -6.93 to -1.07). A more recent retrospective study reported greater mean increases with use of DMPA versus Cu IUC for weight (kg) at years 1 (1.3 vs 0.2), 4 (3.5 vs 1.9), and 10 (6.6 vs 4.9).Two studies reported a greater mean increase in body fat mass (%) for POC users versus women not using a hormonal method. The method was LNG-IUC in two studies (reported means 2.5 versus -1.3; P = 0.029); (MD 1.60, 95% CI 0.45 to 2.75). One also studied a desogestrel-containing pill (MD 3.30, 95% CI 2.08 to 4.52). Both studies showed a greater decrease in lean body mass among POC users., Authors' Conclusions: We considered the overall quality of evidence to be low; more than half of the studies had low quality evidence. The main reasons for downgrading were lack of randomizations (NRS) and high loss to follow-up or early discontinuation.These 22 studies showed limited evidence of change in weight or body composition with use of POCs. Mean weight gain at 6 or 12 months was less than 2 kg (4.4 lb) for most studies. Those with multiyear data showed mean weight change was approximately twice as much at two to four years than at one year, but generally the study groups did not differ significantly. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain., Competing Interests: DECLARATIONS OF INTEREST The authors, Lopez LM, Ramesh S, Chen M, Edelman A, Otterness C, Trussell J, and Helmerhorst FM, have no conflicts of interest to declare regarding this review.

Previous neuroimaging research has demonstrated that female gonadal hormones can alter the structure and function of adult women's brains. So far, we do not know how hormonal contraceptives affect female brain structure, in part because within-person longitudinal observations are lacking. Here, we compared 28 young women before and after three months of regular contraceptive intake with 28 naturally cycling women of comparable age. The goal was to explore within-person neural change in women using contraceptives. Neuroimaging, hormonal, cognitive, and affect data were collected at two time points for each participant. A voxel-wise whole-brain comparison of both groups revealed decreased gray matter volume in the left amygdala/anterior parahippocampal gyrus in women using contraceptives as compared to the control group. Resting-state functional connectivity of this region with the dorsolateral prefrontal cortex changed from positive to negative connectivity following contraceptive intake whereas the opposite held for the control group. An exploratory analysis revealed that gray matter volume in the left amygdala/anterior parahippocampal gyrus was associated with positive affect at the second time point. There were no systematic differences in cognitive performance change between the groups. These findings provide initial insights into effects of hormonal contraceptives on the human brain and expand previous findings on hormone-related amygdala/hippocampal complex plasticity. The affected brain regions may be related to psychological wellbeing, underlining the importance of future studies on contraceptive-induced brain changes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Data on combined hormonal oral contraceptives' (OCs) effects on metabolic changes in women with polycystic ovary syndrome (PCOS) have been conflicting and were predominantly based on OCs with cyproterone acetate (unavailable in the United States) Most studies did not include normal women as controls. We compared metabolic changes before and after an OC commonly used in the United States between women with and without PCOS., Methods: Ten PCOS and 20 control women took ethinyl estradiol 35 μg and norgestimate 0.18/0.215/0.25 mg. Fasting glucose and insulin, area-under-the-curve (AUC) glucose and insulin, insulin sensitivity (homeostatic model assessment of insulin sensitivity index [HOMA-ISI] and Matsuda index), insulinogenic index (Δinsulin0-30 minutes/Δglucose0-30 minutes), blood pressure, and lipids were evaluated at baseline and after three cycles of OC., Results: At baseline, PCOS women had lower insulin sensitivity (Matsuda index p = 0.0093, HOMA-ISI p = 0.0397), higher fasting insulin (p = 0.0495), fasting glucose (p = 0.0393), AUC insulin (p = 0.0023), and triglycerides (p = 0.0044) versus controls. Baseline AUC glucose did not differ between PCOS women and controls. After 3 months of OC use, glucose tolerance worsened in PCOS women versus controls (p = 0.0468). Higher baseline androgens were predictive of worsened glucose tolerance, and a reduction of AUC insulin during OC use. The insulinogenic index significantly decreased in PCOS women (p < 0.01), while fasting insulin and insulin resistance significantly worsened in control women., Conclusion: Women with PCOS exhibited worsened glucose tolerance (demonstrated by AUC glucose) after 3 months of a commonly used OC compared with control women. Larger studies with longer follow-up should confirm these findings.

Despite the widespread use of oral contraceptive pills (OCs), little is known about their impact on psychological processes and emotional competencies. Recent data indicate impaired emotion recognition in OC users compared to naturally cycling females. Building upon these findings, the current study investigated the influence of OC use on three components of empathy, i.e., emotion recognition, perspective-taking, and affective responsiveness. We compared naturally cycling women to two groups of OC users, one being tested in their pill-free week and one in the phase of active intake. Whereas groups did not differ in emotion recognition and perspective-taking, an effect of pill phase was evident for affective responsiveness: Females currently taking the pill showed better performance than those in their pill-free week. These processing advantages complement previous findings on menstrual cycle effects and thereby suggest an association with changes in endogenous and exogenous reproductive hormones. The current study highlights the need for future research to shed more light on the neuroendocrine alterations accompanying OC intake., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Measurement of heart rate variability (HRV) is an established method to assess the activity of the autonomic nervous system. The aim of this review was to examine the link between HRV, reproductive life stages and menopausal hormone therapy. A literature review was performed using the Medline database. Based on title and abstract, 45 studies were extracted out of 261 citations screened. Due to different study designs and evaluation methods, HRV indices were not directly comparable. Qualitative comparisons in between the vast majority of studies, however, demonstrated a decrease of the vagal dominance on the heart from the follicular to the luteal cycle phase, although some studies asserted no change. The intake of oral contraceptives appeared not to alter the vagal modulation of the heart. All investigations agreed on a decline of HRV towards higher sympathetic control after menopause. Different menopausal hormone therapy approaches showed a supporting impact of estrogen on HRV in most studies. A combined therapy of estrogen and progestogens revoked this benefit. Further research is needed to demonstrate how this process might be attenuated by different menopausal hormone therapies.

The hypothalamic peptide oxytocin (OXT) has been identified as a key modulator of pair-bonding in men, but its effects in women are still elusive. Moreover, there is substantial evidence that hormonal contraception (HC) influences partner preferences and sexual satisfaction, which constitute core domains of OXT function. We thus hypothesized that OXT effects on partner-related behavioral and neural responses could be significantly altered in women using HC. In this functional magnetic resonance imaging study involving 40 pair-bonded women, 21 of whom were using HC, we investigated whether a 24-IU nasal dose of OXT would modulate brain reward responses evoked by the romantic partner's face relative to the faces of familiar and unfamiliar people. Treatment with OXT increased the perceived attractiveness of the partner relative to other men, which was paralleled by elevated responses in reward-associated regions, including the nucleus accumbens. These effects of OXT were absent in women using HC. Our results confirm and extend previous findings in men that OXT interacts with the brain reward system to reinforce partner value representations, indicating a common OXT-dependent mechanism underlying partner attraction in both sexes. This mechanism may be disturbed in women using HC, suggesting that gonadal steroids could alter partner-specific OXT effects., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Background: Chronic application of third generation progestagens as contraceptives or hormone replacement therapy (HRT) could influence the serum lipid profile, and consequently the bile and gallstone composition. The aim of this study was to determine components of serum, bile and gallstones in women of reproductive age or postmenopausal women using hormonal third generation for at least two years., Methods: We enrolled 101 Caucasian women with cholelithiasis. The study included 45 women of reproductive age and 56 postmenopausal women who were divided into subgroups receiving or not exogenous female hormones. In patients we determined serum levels of 17β-estradiol, triglycerides, HDL and LDL cholesterol as well as composition of gallstones and bile., Results: The postmenopausal women showed a significant reduction in the concentration of bile acids in serum while the application of HRT caused an increase in their contents. Serum total and LDL cholesterol in postmenopausal women was higher than in women without hormonal contraception and postmenopausal patients with HRT. Moreover, women taking the exogenous hormones showed a reduced content of calcium ions in both serum, bile and gallstones., Conclusions: Our observations confirm that the chronic use of oral contraceptives and hormone replacement therapy cause an increase in bile lithogenity.

Context: Besides their role in intestinal resorption of lipids, bile acids are regarded as endocrine and metabolic signaling molecules. The detailed profile of bile acid species in peripheral blood after an oral lipid tolerance test (OLTT) is unknown., Objective: We quantified the regulation of 18 bile acids after OLTT in healthy individuals., Material and Methods: 100 volunteers were characterized by anthropometric and laboratory parameters and underwent OLTT. Venous blood was drawn in the fasted state (0 h) and at 2h, 4h, and 6 h after OLTT. Serum concentrations of 18 bile acids were measured by LC-MS/MS., Results: All of the 6 taurine-conjugated bile acids (TUDCA, THDCA, TCA, TCDCA, TDCA, TLCA) and all of the 6 glycine-conjugated bile acids (GUDCA, GHDCA, GCA, GCDCA, GDCA, GLCA) rose significantly at 2h and remained elevated during OLTT. Of the primary bile acids, CA remained unchanged, whereas CDCA significantly decreased at 4h. Of the secondary bile acids, DCA, UDCA and HDCA were not altered, whereas LCA decreased. There was a significant positive correlation between the intestinal feed-back regulator of bile acid synthesis FGF-19 and bile acids. This correlation seems to depend on all of the six taurine-conjugated bile acids and on GCA, GDCA, and GCDCA. Females and users of hormonal contraception displayed higher levels of taurine-conjugated bile acids., Conclusions: The novelty of the study is based on the identification of single bile acids during OLTT. LC-MS/MS-based quantification of bile acids in serum provides a reliable tool for future investigation of endocrine and metabolic effects of bile acids.

Anti-Müllerian hormone (AMH) is an important factor associated with female fertility and the ovarian reserve. There are several past studies available concerning the influence of hormonal contraception (HC) on serum AMH levels. Recent studies have reported that AMH levels in women using HC can be about 30% lower compared to those not using HC. However, earlier studies showed no reduction in AMH levels in HC users. We decided to evaluate the effects of long-term HC use (mean duration of HC use: 11.4 years) on AMH levels in women. To exclude potential shorter and reversible decreasing effects of HC on fertility function, we decided to include women in the study who had stopped using HC 1 year before the AMH sample collection. We examined 105 women who used HC and 44 women who had never used HC. The median concentration of AMH in the group of long-term users of HC was 2.89 and 3.37 ng/ml in the group of women who had never used HC. We found no statistically significant difference (p = 0.3261). In conclusion, we observed no negative impact of HC on the AMH serum levels. AMH can be used as an ovarian reserve marker for these women.

Objectives: Cognitive control, which can be described as the ability to moderate impulses, has not previously been investigated in users of combined hormonal contraception (CHC). Given the suggested modulatory role of ovarian steroids in prefrontal dopaminergic function, which in turn taps into cognitive control, this randomised, double-blinded, placebo-controlled oral contraceptive trial set out to investigate the brain activity pattern during response inhibition in CHC users., Methods: Thirty-four women were randomised to one treatment cycle with a levonorgestrel-containing CHC or placebo. The women performed a Go/NoGo task to measure brain activity during response inhibition by use of event-related functional magnetic resonance imaging (fMRI) prior to and during the CHC/placebo treatment cycle., Results: No differences between CHC and placebo users in number of correct inhibitions were found during treatment, but only women on CHC significantly improved their performance between the baseline and treatment assessments. During the treatment cycle CHC users displayed decreased activity in the right middle frontal gyrus in comparison with placebo users. No other significant activations were evident between treatment groups or within groups., Conclusion: Overall, CHC use had marginal effects on brain activity during response inhibition. If anything, the findings of the study may suggest reduced effort or increased efficiency in maintaining orbitofrontal cortex inhibitory cognitive control when using a combined oral contraceptive.

Objectives: Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150mcg Nestorone® (NES) and 15mcg ethinyl estradiol (EE)., Study Design: A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers)., Results: Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen., Conclusion: NES/EE CVR for up to 13cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure., Implications: Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This pilot study investigates whether an educational handout could increase short-term information retention about drug interactions between antiepileptic drugs (AEDs) and hormonal contraceptives among female epilepsy patients of reproductive age., Study Design: This is a pilot randomized controlled trial of an educational intervention among reproductive-age women with epilepsy in an academic neurology clinic. Investigators measured knowledge before and after participants received either usual care or the educational handout. The 10-question test assessed increased knowledge of which AEDs affected efficacy of certain hormonal contraceptives and was assessed by calculating the improvement in score between the pretest and posttest. The educational handout included the names of AEDs that have drug interactions with certain contraceptives and the efficacy of the contraceptives., Results: A total of 42 epilepsy patients participated in this study. Fourteen participants were taking AEDs that are enzyme p450 inducers and 13 participants were taking Lamotrigine. Twenty women were randomized to receive the educational handout and 22 women were randomized to usual care. We found no statistical difference in the groups with regard to age, ethnicity or level of education. We found a significantly higher improvement in quiz scores in the educational handout group (3.65 point increase) compared to the usual care group (0.68 point increase) as calculated by the Student's two-sample t test (p<.001)., Conclusions: An educational handout on drug interactions and contraceptives resulted in increased short-term information retention on this topic among reproductive-age female epilepsy patients., Implications: This pilot study highlights the need for further larger studies to evaluate the impact of educational interventions on improving patient knowledge about the drug interaction of AEDs and hormonal contraceptives., (Copyright © 2016. Published by Elsevier Inc.)

Previous studies have shown that resting heart rate variability (HRV) is modified by different phases of the menstrual cycle in nonusers of oral contraceptive pills (OCP); however, the effect of OCP on autonomic control of the heart remains unclear. The purpose of this study was to investigate HRV during the low hormone (LH-not taking OCP) and during the high hormone (HH-active OCP use) phases of the menstrual cycle in young women. Seventeen healthy women (19-31 years) taking OCP for at least 6 consecutive months were enrolled in this study. Plasma estradiol and progesterone were verified at each visit. HRV was assessed by using one-lead electrocardiography in time and frequency domains, in which participants rested in the supine position for a 20-min period with a breathing rate of 15 cycles/min. In addition, resting heart rate, and systolic and diastolic blood pressure were obtained. Both plasma estradiol (LH: 19.8 ± 4.2 pg/mL vs. HH: 12.4 ± 1.5 pg/mL; p > .05) and progesterone (LH: 0.247 ± 0.58 ng/mL vs. HH: 0.371 ± 0.08 ng/mL; p > .05) (mean ± SE) levels were similar in both phases. No significant difference was obtained for any component of HRV, heart rate, or blood pressure between the LH and HH phases (p > .05). These results provide preliminary evidence that use of OCP does not affect HRV during the menstrual cycle in healthy women., (© 2015 Society for Psychophysiological Research.)

Oral steroid contraception is a popular method of family planning worldwide. Over the past several decades, this method of contraception has changed significantly by decreasing the estrogen dose, changing the progestin component, and reducing the hormone free interval. Despite the popularity of oral steroid contraception, there has been much criticism regarding the associated risks of venous thromboembolism and stroke. Despite these established, yet uncommon risks, oral steroid contraception has many important health benefits. This review highlights the available formulations of oral contraceptives along with their evidence-based associated risks and benefits. Highlights regarding future directions for development of novel oral contraceptives are also addressed.

Resting-state fMRI is a promising imaging technique to evaluate functions in the human brain in health and disease. Different hormonal stages of the female menstrual cycle and hormonal contraceptives use affect results in task-based fMRI; it is however not yet clarified whether resting state networks are also altered. A population of 18 women with a natural cycle, and 19 women using hormonal contraceptives was examined in a longitudinal study-design. The natural cycle group was scanned at 3 time-points (follicular phase, ovulation, luteal phase), and the contraceptives group was scanned twice (inactive pill-phase, active pill-phase). Blood samples were acquired to evaluate hormonal concentrations, and premenstrual symptoms were assessed through daily record of severity of problems questionnaires. Results show no major alterations in the default mode network and the executive control network between different hormonal phases, across or within groups. A positive correlation of functional connectivity in the posterior part of the default mode network (DMN) was found with premenstrual-like symptoms in the hormonal contraceptives group. Using the current methodology, the studied resting state networks seem to show a decent stability throughout menstrual cycle phases. Also, no effect of hormonal contraceptive use is found. Interestingly, we show for the first time an association of DMN alterations with premenstrual-like symptoms, experienced during the inactive pill-phase by a sub-population of women., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Despite a high prevalence of macroprolactinemia in the population, the only drugs found to change macroprolactin (big-big prolactin) levels were dopamine receptor agonists., Methods: The aim of this study was to investigate the effect of oral contraceptive pills containing ethinyl estradiol and levonorgestrel on serum macroprolactin levels in patients with macroprolactinemia. The study population included 21 premenopausal women with isolated macroprolactinemia, 11 of whom were treated with oral contraceptive pills. Serum prolactin and macroprolactin levels were assessed at baseline and after 16 weeks of treatment., Results: Oral contraceptive pills administered for 16 weeks slightly increased pre-polyethylene glycol serum prolactin levels and macroprolactin levels and the effect of this treatment correlated with their baseline values., Conclusions: Our results suggest that oral contraceptive pills containing ethinyl estradiol and levonorgestrel exhibit a stimulatory effect on macroprolactin production in women with basically high macroprolactin levels., (Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Objective: The incidence and disease course of multiple sclerosis (MS) is influenced by sex steroids, and several studies have shown less disease activity during high estrogen states. We have previously shown variation in symptom experience related to the estrogen/progestogen phase in women using combined hormonal contraceptives (CHC) in a small sample. The aim of this study was to confirm these results in a larger sample., Study Design: Self-assessment of symptoms of MS in relation to CHC cycle by 22 female MS patients. A symptom diary based on a validated instrument for cyclical symptoms was used. Mean symptom scores for high and low estrogen/progestogen phases were compared., Results: The women scored four out of ten symptoms significantly higher during the pill-free week than during the CHC phase (p<.05)., Conclusion: Women with MS report more pronounced symptoms during the pill-free, low-estrogen/progestogen phase of CHC use. Future studies should investigate, with a prospective, controlled design, the effects that continuous-use regimens of CHC have in women with MS., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Sex steroid hormones may explain known gender-related variations in asthma prevalence and clinical manifestation. We investigated the relationship between use of hormonal contraceptives and asthma in women, and assessed evidence of biological interaction between use of hormonal contraceptives and body mass index in this relationship., Design: Population-based analysis using data from serial (i.e. 2003, 2008 and 2010) Scottish Health Surveys., Setting: Random samples of the Scottish general population., Participants: A total of 3257 non-pregnant, 16-45-year-old women., Exposure: Current use of hormonal contraceptives., Main Outcome Measures: Self-reported current physician-diagnosed asthma, current wheezing symptoms, wheezing attacks and treatment for asthma or wheeze., Results: Women comprising 30.9% (95% confidence interval 29.3-32.5) were currently using any hormonal contraceptive and current physician-diagnosed asthma was present in 6.5% (95% confidence interval 5.7-7.4). Use of any hormonal contraceptive was associated with reduced risk of current physician-diagnosed asthma (odds ratio 0.68; 95% confidence interval 0.47-0.98) and receiving ≥3 asthma care episodes (odds ratio 0.45; 95% confidence interval 0.25-0.82), but the evidence was equivocal for wheezing attacks. Use of hormonal contraceptives among overweight or obese women was non-statistically significantly associated with asthma, but there was 42-135% increased risk in overweight and obese non-contraceptive using women., Conclusions: Use of hormonal contraceptives may reduce asthma exacerbations and number of care episodes. Overweight and obese non-contraceptive-using women may be at increased risk of asthma. Prospective studies are now needed to confirm these findings. Both oestrogen and progesterone may stimulate smooth airway muscle function and inhibit the activities of TH2 responses. Future studies should investigate these underlying mechanisms., (© The Royal Society of Medicine.)

Purpose: To investigate the influence of the use of oral hormonal contraceptive agents (OCA) on the biochemical indices related to metabolic zinc utilization and distribution, and to bone turnover in young adult women., Methods: Cross-sectional study. Blood and urine samples from non-users (-OCA; control; n=69) and users of hormonal contraceptives for at least 3 months (+OCA; n=62) were collected under controlled conditions. Indices of zinc homeostasis and of bone turnover were analyzed in serum or plasma (total, albumin-bound and α2-macroglobulin-bound zinc, albumin and total and bone alkaline phosphatase activity), in erythrocytes (zinc and metallothionein) and in urine (zinc, calcium and hydroxyproline). The habitual zinc and calcium intakes were evaluated by a food frequency questionnaire., Results: Dietary zinc intake was similar in both groups and on average above recommended values, whereas calcium intake was similarly sub-adequate in +OCA and -OCA. Compared to controls, +OCA had lower concentrations of total and α2-macroglobulin-bound zinc (11 and 28.5%, respectively, p<0.001), serum albumin (13%, p<0.01), total and bone-specific alkaline phosphatase activity (13 and 18%, respectively, p<0.05), erythrocyte metallothionein (13%, p<0.01), and, urinary zinc (34%, p<0.05)., Conclusions: OCA use decreases serum zinc, alters zinc distribution in major serum fractions with possible effects on tissue uptake, enhances zinc retention in the body and decreases bone turnover. Prolonged OCA use may lead to lower peak bone mass and/or to impaired bone mass maintenance in young women, particularly in those with marginal calcium intake. The observed OCA effects were more evident in women younger than 25 years and in nulliparous women, deserving special attention in future studies.

Endogenous female sex hormones influence muscle sympathetic nerve activity (MSNA), a regulator of arterial blood pressure and important factor in hypertension development. Although ≈80% of American women report using hormonal contraceptives sometime during their life, the influence of combined oral contraceptives (OCs) on MSNA and systemic hemodynamics remains equivocal. The goal of this study was to determine whether women taking OCs have altered MSNA and hemodynamics (cardiac output and total peripheral resistance) at rest during the placebo phase of OC use compared with women with natural menstrual cycles during the early follicular phase. We retrospectively analyzed data from studies in which healthy, premenopausal women (aged 18-35 years) participated. We collected MSNA values at rest and hemodynamic measurements in women taking OCs (n=53; 25±4 years) and women with natural menstrual cycles (n=74; 25±4 years). Blood pressure was higher in women taking OCs versus those with natural menstrual cycles (mean arterial pressure, 89±1 versus 85±1 mm Hg, respectively; P=0.01), although MSNA was similar in both groups (MSNA burst incidence, 16±1 versus 18±1 bursts/100 heartbeats, respectively; P=0.19). In a subset of women in which detailed hemodynamic data were available, those taking OCs (n=33) had similar cardiac output (4.9±0.2 versus 4.7±0.2 L/min, respectively; P=0.47) and total peripheral resistance (19.2±0.8 versus 20.0±0.9 U, respectively; P=0.51) as women with natural menstrual cycles (n=22). In conclusion, women taking OCs have higher resting blood pressure and similar MSNA and hemodynamics during the placebo phase of OC use when compared with naturally menstruating women in the early follicular phase., (© 2015 American Heart Association, Inc.)

Importance: Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair gene mutation (Lynch syndrome)., Objective: To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome., Design, Setting, and Participants: A retrospective cohort study included 1128 women with a mismatch repair gene mutation identified from the Colon Cancer Family Registry. Data were analyzed with a weighted cohort approach. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand., Exposures: Age at menarche, first and last live birth, and menopause; number of live births; hormonal contraceptive use; and postmenopausal hormone use., Main Outcomes and Measures: Self-reported diagnosis of endometrial cancer., Results: Endometrial cancer was diagnosed in 133 women (incidence rate per 100 person-years, 0.29; 95% CI, 0.24 to 0.34). Endometrial cancer was diagnosed in 11% (n = 70) of women with age at menarche greater than or equal to 13 years compared with 12.6% (n = 57) of women with age at menarche less than 13 years (incidence rate per 100 person-years, 0.27 vs 0.31; rate difference, -0.04 [95% CI, -0.15 to 0.05]; hazard ratio per year, 0.85 [95% CI, 0.73 to 0.99]; P = .04). Endometrial cancer was diagnosed in 10.8% (n = 88) of parous women compared with 14.4% (n = 40) of nulliparous women (incidence rate per 100 person-years, 0.25 vs 0.43; rate difference, -0.18 [95% CI, -0.32 to -0.04]; hazard ratio, 0.21 [95% CI, 0.10 to 0.42]; P < .001). Endometrial cancer was diagnosed in 8.7% (n = 70) of women who used hormonal contraceptives greater than or equal to 1 year compared with 19.2% (n = 57) of women who used contraceptives less than 1 year (incidence rate per 100 person-years, 0.22 vs 0.45; rate difference, -0.23 [95% CI, -0.36 to -0.11]; hazard ratio, 0.39 [95% CI, 0.23 to 0.64]; P < .001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use., Conclusions and Relevance: For women with a mismatch repair gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a mismatch repair gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.

Background: Accumulating evidence is indicating that hormonal factors play a role in new-onset allergic rhinitis and asthma after puberty., Objective: To determine whether age at menarche and use of hormonal contraceptives predict new-onset allergic rhinitis and asthma after puberty in young German women., Methods: A prospective community-based cohort study followed 1,191 girls 9 to 11 years old to early adulthood (19-24 years old). Self-administrated questionnaires concerning age at menarche, use of hormonal contraceptives, and status and age at onset of physician-diagnosed allergic rhinitis and asthma were collected at 16 to 18 and 19 to 24 years of age. Logistic regression models were used to analyze the incidence of asthma and allergic rhinitis after puberty and pooled estimates were obtained from the final model., Results: Eleven percent of girls developed allergic rhinitis after menarche and 3% reported new-onset asthma. Late menarche (>13 years of age) was statistically significantly inversely related to allergic rhinitis (adjusted odds ratio [OR] 0.32, 95% confidence interval [CI] 0.14-0.74) but did not reach the level of statistical significance for asthma (OR 0.32, 95% CI 0.07-1.42). Use of hormonal contraceptives was inversely associated with new-onset allergic rhinitis (OR 0.14, 95% CI 0.08-0.23) and asthma (OR 0.27, 95% CI 0.12-0.58) after puberty., Conclusion: This study shows that girls with late onset of menarche are less likely to develop allergic rhinitis after puberty compared with those who have menarche at an average age. These findings also suggest that, in addition to endogenous hormones, hormonal contraceptives play a role and might protect young women from allergies and asthma., (Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)