Hormonal contraceptive use is associated with altered bone structural and metabolic responses to military training in women: An observational cohort study.

Military training increases tibial density and size. Female sex hormones may influence the adaption of bone to loading, but it is unknown if women using different hormonal contraceptives adapt similarly to military training. One hundred and sixteen women (57 women not using hormonal contraceptives [non-users], 38 combined oral contraceptive pill [COCP] users, 21 depot medroxyprogesterone acetate [DMPA] users) completed this study. Tibial volumetric bone mineral density (vBMD) and geometry were measured by peripheral quantitative computed tomography (4 %, 14 %, 38 %, and 66 % sites) at the start (week 1) and end (week 14) of British Army basic training. Circulating markers of bone and calcium metabolism were measured at weeks 1, 2, 4, 6, 10, and 14. Training increased trabecular vBMD at the 4 % site, periosteal perimeter at the 14 % and 66 % sites, and total area, cortical area, cortical thickness, and bone strength at all sites (0.1 to 1.6 %, p ≤ 0.009), with no differences between hormonal contraceptive groups (p ≥ 0.127). Trabecular vBMD increased at the 14 % site in non-users (0.8 %, p = 0.005), but not in COCP or DMPA users (p ≥ 0.205). Periosteal perimeter increased at the 38 % site in COCP (0.4 %, p < 0.001) and DMPA (0.5 %, p < 0.001) users, but not in non-users (p = 0.058). Training had no effect on periosteal perimeter at the 4 % site or cortical vBMD or endosteal perimeter at any site (p ≥ 0.168). ßCTX decreased and PINP increased during training with no difference between hormonal contraceptive groups. Training increased iPTH in non-users, but not COCP or DMPA users. Hormonal contraceptives may exert site-specific effects on the mechanobiology of bone, with higher endogenous oestradiol promoting trabecularisation and inhibiting periosteal expansion in non-users compared with hormonal contraceptive users.

Influence of gender and combined estrogen-progestin oral contraceptive on parotid saliva flow rate, pH, and electrolytes concentration.

OBJECTIVES: Endocrinal variations within an individual impact the electrolyte composition, pH, and flow-rate (FR) of saliva. The aim of this study was to evaluate the gender-specific differences and the effect of combined estrogen-progestin oral contraceptives (COCs) on FR, pH, and electrolyte concentrations in the parotid saliva (PS) of a group of healthy adults. MATERIAL AND METHODS: Stimulated PS was collected from 20 healthy adults using a Lashley cup; 11 males, 8 females, and 1 female undertaking combined contraceptive therapy (levonorgestrel/ethinyloestradiol 0.1 mg + 0.02 mg). FR and pH were recorded for each saliva sample. Electrolytes concentrations (Na+ , Ca2+ , K+ , Mg2+ ) were measured using inductively coupled plasma optical emission spectrometer (ICP-OES). Statistical analysis was performed, and the significance level was set at p < .05. RESULTS: PS FR varied from 0.13 to 0.42 mL/min in females not taking any medication and from 0.08 to 0.5 mL/min in males not taking any medication. PS pH of females and males not taking any medication ranged from 6.23 to 7.50 and from 6.15 to 7.55. PS pH and FR of the female taking COCs were 6.5 and 0.1 mL/min. PS pH, FR, and electrolytes concentrations (Ca2+ , Na+ , K+ , Mg2+ ) were not statistically significantly different between females and males not taking any medication. PS concentrations of Ca2+  and Na+ were significantly higher in the females taking COCs than in the females not taking any medication. Whereas, concentrations of K+ and Mg2+ did not differ significantly between the females taking COCs and the females not taking any medication. CONCLUSIONS: There are no significant gender-specific differences in PS flow rate, pH, and electrolyte concentrations of Na+ , Ca2+ , Mg2+ , and K+ . Combined hormonal oral contraceptive has a significant effect on PS flow rate, pH, Ca2+ , and Na+ concentrations. Whereas the PS concentration of K+ and Mg2+ are not influenced by COCs. These results warrant further investigation.

Behavioral characterization of co-exposure to cannabinoids and hormonal contraceptives in female rats.

Hormonal contraceptives are among the most widely used drugs by young healthy women to block ovulation and avoid pregnancy. They reduce the ovarian secretion of estradiol and progesterone, hormones that also modulate neuronal plasticity, cognitive functions, emotions and mood. Cannabis is the most commonly used illicit drug worldwide and its use is increasing among young women, many of which regularly take the "pill". Despite evidence of a bidirectional interaction between the endocannabinoid system and gonadal hormones, only very few studies have examined the consequences of cannabis consumption in young females under hormonal contraceptives treatment. To fill this gap, this study evaluated the behavioral effects of co-exposure to chronic 1) hormonal contraceptives, i.e., ethinyl estradiol (EE) plus levonorgestrel (LNG), one of the synthetic estrogen-progestin combinations of hormonal contraceptives, and 2) cannabinoid receptor agonist, i.e., WIN 55,212-2 (WIN), on motor activity, emotional state and cognitive functions in young adult female rats (8-11/experimental group). Hormonal and cannabinoid treatment started at post-natal day (PND) 52 and 56, respectively, while behavioral testing occurred between PND 84-95. The results show that chronic EE-LNG treatment, at doses (0.020 and 0.060 mg/rat, respectively) known to drastically reduce plasma progesterone levels, and the contextual exposure to WIN, at a dose (12.5 µg/kg/infusion) known to be rewarding in the rat, alters the hormonal milieu but does not cause further changes in locomotor activity compared to EE-LNG or WIN alone, and does not modify anxiety-like state (as measured by the elevated plus maze and the marble burying tests) and cognitive abilities (as measured by the novel object recognition and the prepulse inhibition tests) in young adult female rats. Although exposure to EE-LNG and WIN tends to increase the duration of immobility and to reduce the time spent swimming in the forced swimming test, there was not a significant additive effect suggestive of a depressive-like state. These findings allow deepening the current knowledge on the interaction between cannabinoid agonists and hormonal contraceptives and suggest that low, rewarding doses of cannabinoids do not significantly alter the motor and cognitive skills and do not induce anxiety or depressive-like states in females that use hormonal contraceptives.

Combined oral contraceptive with estetrol plus drospirenone: from pharmacokinetics to clinical applications.

INTRODUCTION: Drospirenone/estetrol (DRSP/E4) is a combined oral contraceptive (COC) recently approved in several countries. It is composed of 15 mg of E4, a natural estrogen produced by human fetal liver throughout pregnancy, and 3 mg of DRSP, the first synthetic progestin used in oral contraception derived from 17-α-spirolactone. E4 and DRSP synergistically prevent pregnancy by inhibiting ovulation. E4 differs from 17-ß-estradiol or ethinylestradiol because it represents a native estrogen with selective action in tissues (NEST), therefore it displays both agonist and antagonist estrogenic effects in different tissues. AREAS COVERED: In this paper, we reviewed the scientific literature published in English prior to April 2023 and gathered information on the pharmacodynamics and pharmacokinetics of DRSP, E4 and their combination for contraception. We also proposed possible clinical applications based on the characteristics of the components of this COC. EXPERT OPINION: E4/DRSP-based COC has shown high tolerability, safety and satisfaction and may represent a viable choice in young girls in need of oral contraception and pill users who suffer from high cholesterol, breast tenderness or water retention. Moreover, this new COC shows higher scheduled bleeding rate compared to other pills containing natural estrogens. All the data are reassuring, permitting long-term use.

Pharmacological investigation of vitamin E with combined oral contraceptives on INHBA gene against PCOS that intricate through melatonin PKC pathway.

The most prevalent endocrine and metabolic condition in women of reproductive age are polycystic ovary syndrome (PCOS) with significant risk factors such as circadian rhythm and melatonin disruption. The aim of this study is to assess the effect of vitamin E in combination with a combined oral contraceptive (COC) on continuous light-induced PCOS using hormonal measures, oxidative stress (OS) indicators, and the inhibin beta-A (INHBA) gene, which targets the melatonin protein kinase C (PKC) pathway. An in silico technique anticipated INHBA's binding affinity for vitamin E and COC. For the in vivo investigation (IAEC/240/2021), female SD rats were divided into six groups and subjected to a 16-week induction period, followed by a 2-month test drug treatment with drospirenone (DRSP) as a standard. Serum testosterone, FSH, melatonin, and OS were calculated as hormonal markers. The expression of the INHBA gene was studied to see if it could be linked to the circadian rhythm and OS via the melatonin PKC pathway. According to the in silico study, vitamin E and DRSP had higher binding energy for the INHBA (-8.6 kcal/mol and -8.4 kcal/mol, respectively). When compared to the control group, in vivo results showed a substantial decrease in testosterone levels (p = .05), as well as changes in FSH (p = .78) and melatonin (p = .13). IHNBA gene expression has also dramatically increased, stimulating FSH production in the pituitary gland. Vitamin E and COC concomitantly are beneficial against PCOS because it modulates OS, which in turn influences circadian rhythm and the melatonin PKC pathway.

Morphologic alterations of the fear circuitry: the role of sex hormones and oral contraceptives.

Background: Endogenous sex hormones and oral contraceptives (OCs) have been shown to influence key regions implicated in fear processing. While OC use has been found to impact brain morphology, methodological challenges remain to be addressed, such as avoiding selection bias between OC users and non-users, as well as examining potential lasting effects of OC intake. Objective: We investigated the current and lasting effects of OC use, as well as the interplay between the current hormonal milieu and history of hormonal contraception use on structural correlates of the fear circuitry. We also examined the role of endogenous and exogenous sex hormones within this network. Methods: We recruited healthy adults aged 23-35 who identified as women currently using (n = 62) or having used (n = 37) solely combined OCs, women who never used any hormonal contraceptives (n = 40), or men (n = 41). Salivary endogenous sex hormones and current users' salivary ethinyl estradiol (EE) were assessed using liquid chromatography - tandem mass spectrometry. Using structural magnetic resonance imaging, we extracted surface-based gray matter volumes (GMVs) and cortical thickness (CT) for regions of interest of the fear circuitry. Exploratory whole-brain analyses were conducted with surface-based and voxel-based morphometry methods. Results: Compared to men, all three groups of women exhibited a larger GMV of the dorsal anterior cingulate cortex, while only current users showed a thinner ventromedial prefrontal cortex. Irrespective of the menstrual cycle phase, never users exhibited a thicker right anterior insular cortex than past users. While associations with endogenous sex hormones remain unclear, we showed that EE dosage in current users had a greater influence on brain anatomy compared to salivary EE levels and progestin androgenicity, with lower doses being associated with smaller cortical GMVs. Discussion: Our results highlight a sex difference for the dorsal anterior cingulate cortex GMV (a fear-promoting region), as well as a reduced CT of the ventromedial prefrontal cortex (a fear-inhibiting region) specific to current OC use. Precisely, this finding was driven by lower EE doses. These findings may represent structural vulnerabilities to anxiety and stress-related disorders. We showed little evidence of durable anatomical effects, suggesting that OC intake can (reversibly) affect fear-related brain morphology.

Synthetic contraceptive hormones occlude the ability of nicotine to reduce ethanol consumption in ovary-intact female rats.

Rates of tobacco and alcohol use in women are rising, and women are more vulnerable than men to escalating tobacco and alcohol use. Many women use hormonal birth control, with the oral contraceptive pill being the most prevalent. Oral contraceptives contain both a progestin (synthetic progesterone) and a synthetic estrogen (ethinyl estradiol; EE) and are contraindicated for women over 35 years who smoke. Despite this, no studies have examined how synthetic contraceptive hormones impact this pattern of polysubstance use in females. To address this critical gap in the field, we treated ovary-intact female rats with either sesame oil (vehicle), the progestin levonorgestrel (LEVO; contained in formulations such as Alesse®), or the combination of EE+LEVO in addition to either undergoing single (nicotine or saline) or polydrug (nicotine and ethanol; EtOH) self-administration (SA) in a sequential use model. Rats preferred EtOH over water following extended EtOH drinking experience as well as after nicotine or saline SA experience, and rats undergoing only nicotine SA (water controls) consumed more nicotine as compared to rats co-using EtOH and nicotine. Importantly, this effect was occluded in groups treated with contraceptive hormones. In the sequential use group, both LEVO alone and the EE+LEVO combination occluded the ability of nicotine to decrease EtOH consumption. Interestingly, demand experiments suggest an economic substitute effect between nicotine and EtOH. Together, we show that chronic synthetic hormone exposure impacts nicotine and EtOH sequential use, demonstrating the crucial need to understand how chronic use of different contraceptive formulations alter patterns of polydrug use in women.

Mental rotation, episodic memory, and executive control: Possible effects of biological sex and oral contraceptive use.

Oral contraceptives (OCs) are one of the most common forms of hormonal birth control. A small literature suggests that OC use may affect visuospatial ability, episodic memory, and executive control. However, previous studies have been criticized for small sample sizes and the use of different, single cognitive tests. We investigated the degree to which biological sex and OC use might affect individual mental rotation, episodic memory, and executive control in a large sample of healthy, young adults (N = 155, including 52 OC users, 53 naturally cycling females, and 50 males) tested individually over videoconference. To measure cognition, we used a set of neuropsychological tasks inspired by Glisky and colleagues' two-factor episodic memory and executive control battery, from which two composite scores (based on principal component analysis) were derived for each participant. Our pre-registered analysis revealed a clear female advantage in episodic memory, independent of OC use. In an exploratory analysis, gist memory was elevated in OC users. Interestingly, we found no significant sex-related differences nor effects of OC use on mental rotation or executive control. Duration of OC use was also not related to any of our cognitive measures. These results suggest that the use of combined, monophasic OCs does not lead to many significant changes in cognition in young adults, although young females overall may have better episodic memory than young males. Additional studies, including longitudinal designs and looking in more detail at the menstrual cycle and OC use history, will further clarify the effects of different types of OCs and their duration of use on different aspects of cognition.

Evaluate the Changes of Body Mass Index and Blood Pressure in Combined Oral Contraceptive Pill Users.

The oral contraceptive pill, 'the pill', was introduced in the starting of the 1960s. Presently, worldwide about 100 million women are current users of combined hormonal contraceptives (COC) most frequently used in the western world. The most frequently used agents are a combination of drugs containing both the estrogen and progesterone. This combination is considered to be highly efficacious, generally considered 99.9% and a use effectiveness of 97.0% to 98.0%. This study was done to evaluate the changes of Body Mass Index (BMI) and Blood pressure ( BP) in combined oral contraceptive pill users in comparison to non- users. This cross sectional study was carried out in the Department of Physiology, Mymensingh Medical College, Mymensingh, Bangladesh from July 2021 to June 2022. Total number of 120 reproductive aged women, age ranged from 15-55 years was included in this study. Among them, sixty (60) combined oral contraceptive pill users subjects were taken as study group (Group II) and sixty (60) age matched oral pill non users subjects were taken as control group (Group I). Data were expressed as mean±SD and statistical significance of difference among the group was calculated by unpaired students' 't' test and Pearson's correlation coefficient test. The mean±SD of BMI of control group (Group I) and study group (Group II) were 22.50±1.50 kg/m² and 27.64±1.28 kg/m² respectively. In study group (Group II) BMI was increased. Result is statistically highly significant (p<0.001). The mean±SD of systolic blood pressure of control group (Group I) and study group (Group II) were 111.17±8.51 mm of Hg and 127.50±6.14 mm of Hg respectively. In this study the mean±SD of diastolic blood pressure of control group (Group I and study group (Group II) were 75.58±5.05mm of Hg and 87.00±4.89 mm of Hg respectively. In study group (Group II) diastolic blood pressure was increased. Result is statistically highly significant (p<0.001). So the assessment of this parameter is important for early detection and prevention of complication related to combined oral contraceptive pill use for leading a healthy life.

Oral contraceptives in the central nervous system: Basic pharmacology, methodological considerations, and current state of the field.

Millions of women around the world use combined oral contraceptives (OCs), yet surprisingly little is known about their central nervous system (CNS) effects. This article provides a short overview of the basic pharmacology of OCs, emphasizing features that may be relevant to understanding their effects in the CNS. Historical and recent findings from studies of cognitive function, mood, and negative affect (depressive changes under OC use) are then reviewed. We also present data from an archival dataset from our own laboratory in which we explore dysphoric changes in women using four generations of contraceptive progestins. Current data in the field are consistent with a modest effect of OC use on CNS variables, but conclusions based on current findings must be made very cautiously because of multiple methodological issues in many published studies to date, and inconsistencies in the findings. Directions for future research over the next 10 years are suggested. (150 words).

Combined oral contraceptives and mental health: Are adolescence and the gut-brain axis the missing links?

Combined oral contraceptives (containing synthetic forms of estradiol and progestins) are one of the most commonly used drugs among females. However, their effects on the gut-brain axis have not been investigated to a great extent despite clear evidence that suggest bi-directional interactions between the gut microbiome and endogenous sex hormones. Moreover, oral contraceptives are prescribed during adolescence, a critical period of development during which several brain structures and systems, such as hypothalamic-pituitary-gonadal axis, undergo maturation. Considering that oral contraceptives could impact the developing adolescent brain and that these effects may be mediated by the gut-brain axis, further research investigating the effects of oral contraceptives on the gut-brain axis is imperative. This article briefly reviews evidence from animal and human studies on the effects of combined oral contraceptives on the brain and the gut microbiota particularly during adolescence.

Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial.

STUDY QUESTION: Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only? SUMMARY ANSWER: The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation. WHAT IS KNOWN ALREADY: EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking. STUDY DESIGN, SIZE, DURATION: This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics. MAIN RESULTS AND THE ROLE OF CHANCE: Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay. LARGE SCALE DATA: Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction). LIMITATIONS, REASONS FOR CAUTION: The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results. WIDER IMPLICATIONS OF THE FINDINGS: The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens. STUDY FUNDING/COMPETING INTEREST(S): Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02352090. TRIAL REGISTRATION DATE: 27 January 2015. DATE OF FIRST PATIENT'S ENROLMENT: 1 April 2015.

Exposure to levonorgestrel-based birth control pill in early life and its persistent effects in zebrafish.

The consumption of progestins has increased considerably in recent decades, as has their disposal into the environment. These substances can negatively affect the reproduction, physiology, and behavior of non-target organisms, such as fish. We aimed to evaluate the effects of exposure to environmentally relevant concentrations of levonorgestrel-control birth based (1.3, 13.3, 133, and 1330 ng/L) on the development and behavior of zebrafish (Danio rerio) in terms of mortality, hatching, spontaneous movement, and larval and adult behavioral tests. Exposure caused anxiogenic-like behavior in larvae, which persisted in adults, as demonstrated by the light-dark test. In contrast, it caused anxiolytic-like behavior in the novel tank test. There was a high mortality rate at all tested concentrations and increases in the hormone cortisol at 13.3 ng/L that affected the sex ratio. These changes may lead to an ecological imbalance, emphasizing the risk of early exposure to progestins in the environment.

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial.

INTRODUCTION: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. MATERIAL AND METHODS: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). CLINICAL TRIAL REGISTRATION: NCT02352090. RESULTS: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. CONCLUSIONS: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

Effects of oral contraceptives plus orlistat in patients with polycystic ovary syndrome and overweight/obesity: A meta-analysis.

AIM: This meta-analysis was conducted to compare the effect and safety of oral contraceptive pills (OCP) plus orlistat with OCP alone in clinical, hormonal, and lipid metabolism outcomes in patients with polycystic ovary syndrome (PCOS) and overweight/obesity. METHODS: Pubmed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and SinoMed were systematically reviewed. A random-effects or fixed-effects model was used to pool the estimate. RESULTS: Eight studies were included in this meta-analysis. Significant reductions in BMI, WHR, and waist circumference were observed in combination group as compared with OCP alone group. Regarding the hormonal outcome, T, SHBG, FAI, LH, DHEAS, FSH, and E2 levels were significantly improved in combination group compared with OCP alone group. However, the TT and FT did not change significantly between the two groups. Regarding the lipid metabolism outcomes, TC, LDL-C, and TG levels were reduced and HDL-C level was increased in the combination group. Regarding the insulin metabolism outcomes, FINS and HOMA-IR levels were reduced in combination group than in OCP group. The ovulation rate, pregnancy rate, and overall effective rate were significantly higher in combination group than in OCP alone group. Fewer complications were observed in the combination group than in OCP group, and the difference between them was significant. CONCLUSION: This combination treatment of OCP and orlistat was more effective than OCP alone in reducing the weight, hormonal, lipid, and insulin metabolism profiles, as well as improving the ovulation rate, pregnancy rate, and overall effective rate, as compared with OCP alone.

Estradiol Valerate vs Ethinylestradiol in Combined Oral Contraceptives: Effects on the Pituitary-Ovarian Axis.

CONTEXT: Limited studies have compared the effects of combined oral contraceptives (COCs) containing natural estrogens and synthetic ethinylestradiol (EE) on reproductive hormones. OBJECTIVE: To compare estradiol valerate (EV) + dienogest (DNG), EE + DNG, and DNG alone (active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, anti-Müllerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the free androgen index (FAI). METHODS: This spin-off study from a randomized trial enrolled 59 healthy, 18 to 35-year-old ovulatory women, outpatients at Helsinki and Oulu University Hospitals, Finland, who were randomized to EV 2 mg + DNG 2-3 mg (n = 20); EE 0.03 mg + DNG 2 mg (n = 20); and DNG 2 mg (n = 19) for 9 weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Age and BMI were comparable between groups; 3 women discontinued. RESULTS: EV + DNG suppressed FSH by -27% (-51% to -3%) (median [95% CI]) vs EE + DNG, -64% (-78 to -51), P = 0.04, but AMH levels decreased similarly by -9% (-18 to -0.1) vs -13% (-28 to 0.2), P = 0.38, respectively. EV + DNG increased SHBG levels by 56% (30% to 82%) and EE + DNG by 385% (313% to 423%), P < 0.001. Total testosterone decreased by 16% (-27% to -5%) in the EV + DNG group but it did not decrease in the EE + DNG group, whereas the FAI decreased by -39% (-54% to -25%) vs -72% (-78% to -67%), P < 0.001. DNG alone did not induce changes in any of these parameters. CONCLUSION: Compared with EE + DNG, treatment with EV + DNG resulted in milder pituitary downregulation and reduced induction of hepatic SHBG synthesis-potentially carrying more beneficial health effects.

The Effect of Combined Oral Contraceptive Pills on Beclin-1 and LC3B Transcript Levels in Ovarian Endometrioma.

BACKGROUND: Autophagy is likely altered in patients with endometriosis. Ovarian steroid hormones seem to affect this changing of the autophagic process. OBJECTIVE: To study the effect of combined oral contraceptive (COC) pills on the expression of autophagic-related gene BECN1 and LC3B in the ectopic and eutopic endometria of patients with endometriosis. Material and Methods. The present quasiexperimental study recruited 36 women (18-45 years old) with endometrioma and nonendometrioma who were scheduled for surgery. Patients with endometrioma were randomly assigned to either a no-treatment group (n = 12) or a COC group (n = 12). The COC group was prescribed a daily oral pill composed of 3 mg drospirenone and 0.03 mg ethinyl estradiol for 6 weeks before surgery. The control group (n = 12) was composed of women without endometrioma. Ectopic endometriotic and endometrium tissues were collected from the no-treatment and COC groups, whereas the only endometrium was collected from the control group. These tissues were used for real-time PCR to measure the expression of the BECN1 and LC3B genes. RESULTS: The baseline demographic data were not different among the three groups. The BECN1 gene expression in endometrium tissue in the COC group was significantly less than that in the no-treatment and control groups (P = 0.011 and 0.029, respectively). No significant difference of endometriotic cyst BECN1 and LC3B gene expression was found between COC and no treatment. CONCLUSIONS: Oral COC pills for 6 weeks continuously before surgery decreased the eutopic endometrial expression (mRNA) of the BECN1 gene compared to those from healthy normal women and nontreated patients with an endometriotic cyst. The change in the expression of autophagy-related genes was more distinct in eutopic than ectopic endometria. This trial is registered with TCTR20170720002. Registered and enrolled the first patient on 20 July 2017.

Effects of Lemborexant on the Pharmacokinetics of Oral Contraceptives: Results From a Phase 1 Drug-Drug Interaction Study in Healthy Females.

Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug-drug interaction study was conducted. This single-center, open-label, fixed-sequence study examined potential drug-drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18-44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady-state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment.