Μg Ethinyl Estradiol Research Articles

L-glutamine supplementation exerts cardio-renal protection in estrogen-progestin oral contraceptive-treated female rats

Glycogen and lipid disruptions represent a spectrum of metabolic disorders that are crucial risk factors for cardiovascular disease in estrogen-progestin oral contraceptive (COC) users. l-glutamine (GLN) has been shown to exert a modulatory effect in metabolic disorders-related syndromes. We therefore hypothesized that GLN supplementation would protect against myocardial and renal glycogen-lipid mishandling in COC-treated animals by modulation of Glucose-6-phosphate dehydrogenase (G6PD) and xanthine oxidase (XO) activities. Adult female Wistar rats were randomly allotted into control, GLN, COC and COC + GLN groups (six rats per group). The groups received vehicle (distilled water, p.o.), GLN (1 g/kg), COC containing 1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel and COC plus GLN respectively, daily for 8 weeks. Data showed that treatment with COC led to metabolically-induced obesity with correspondent increased visceral and epicardial fat mass. It also led to increased plasma, myocardial and renal triglyceride, free fatty acid, malondialdehyde (MDA), XO activity, uric acid content and decreased glutathione content and G6PD activity. In addition, COC increased myocardial but not renal glycogen content, and increased myocardial and renal glycogen synthase activity, increased plasma and renal lactate production and plasma aspartate transaminase/alanine aminotransferase (AST/ALT) ratio. However, these alterations were attenuated when supplemented with GLN except plasma AST/ALT ratio. Collectively, the present results indicate that estrogen-progestin oral contraceptive causes metabolically-induced obesity that is accompanied by differential myocardial and renal metabolic disturbances. The findings also suggest that irrespective of varying metabolic phenotypes, GLN exerts protection against cardio-renal dysmetabolism by modulation of XO and G6PD activities.

The use of Dimia for the treatment of premenstrual syndrome in adolescent girls

Today, premenstrual syndrome (PMS) remains one of the relevant issues of adolescent gynecology. The difficulty in treatment of PMS in adolescent girls is associated with a large number of factors. The combination of hormonal, neuro-vegetative, metabolic, mental and emotional deviations requires a comprehensive and more differentiated approach to the treatment of this disease. Aim. Assessment of clinical efficacy and safety of using drospirenone 3 mg and ethinylestradiol 20 µg combination for the treatment of PMS in adolescent girls aged 14-18. Outcomes and methods. The study included female 50 patients who met the criteria: age of 14 to 18 years, no severe extragenital pathology, the menstrual cycle duration within 6 months - 25-32±2 days. Based on examination data, all patients were prescribed a drug containing 3 mg of drospirenone and 20 μg of ethinylestradiol. The duration of therapy was 6 months. Results. Under the drug therapy, a significant decrease in the intensity of PMS manifestations occurred. Conclusions. The use of drospirenone 3 mg and ethinylestradiol 20 µg combination for 3 months in patients with PMS has a beneficial effect on the autonomic nervous system, significantly reduces the rate of pain before and during menstruation, helps to decrease the number and intensity of menstrual flow and ultimately significantly improves the quality of patient life.

Effects of Estrogen Replacement on Bone Geometry and Microarchitecture in Adolescent and Young Adult Oligoamenorrheic Athletes: A Randomized Trial.

Oligoamenorrheic athletes (OAs) have lower bone mineral density (BMD) and greater impairment of bone microarchitecture, and therefore higher fracture rates compared to eumenorrheic athletes. Although improvements in areal BMD (aBMD; measured by dual-energy X-ray absorptiometry) in OAs have been demonstrated with transdermal estrogen treatment, effects of such treatment on bone microarchitecture are unknown. Here we explore effects of transdermal versus oral estrogen versus no estrogen on bone microarchitecture in OA. Seventy-five OAs (ages 14 to 25 years) were randomized to (i) a 100-μg 17β-estradiol transdermal patch (PATCH) administered continuously with 200 mg cyclic oral micronized progesterone; (ii) a combined 30 μg ethinyl estradiol and 0.15 mg desogestrel pill (PILL); or (iii) no estrogen/progesterone (NONE) and were followed for 12 months. Calcium (≥1200 mg) and vitamin D (800 IU) supplements were provided to all. Bone microarchitecture was assessed using high-resolution peripheral quantitative CT at the distal tibia and radius at baseline and 1 year. At baseline, randomization groups did not differ by age, body mass index, percent body fat, duration of amenorrhea, vitamin D levels, BMD, or bone microarchitecture measurements. After 1 year of treatment, at the distal tibia there were significantly greater increases in total and trabecular volumetric BMD (vBMD), cortical area and thickness, and trabecular number in the PATCH versus PILL groups. Trabecular area decreased significantly in the PATCH group versus the PILL and NONE groups. Less robust differences between groups were seen at the distal radius, where percent change in cortical area and thickness was significantly greater in the PATCH versus PILL and NONE groups, and changes in cortical vBMD were significantly greater in the PATCH versus PILL groups. In conclusion, in young OAs, bone structural parameters show greater improvement after 1 year of treatment with transdermal 17β-estradiol versus ethinyl estradiol-containing pills, particularly at the tibia. © 2019 American Society for Bone and Mineral Research.

Combined but not single treatment with ethinylestradiol/levonorgestrel and spironolactone reduces plasminogen activator inhibitor-1 in insulin-resistant ovariectomised rats.

Objective:Increased circulating level of plasminogen activator inhibitor-1 (PAI-1) is associated with menopausal oestrogen deficiency. We therefore hypothesised that the combined oral contraceptive (COC) with spironolactone (SPL) improves insulin resistance (IR) in ovariectomised (OVX) rats by reducing circulating PAI-1.Methods:Twelve-week-old female Wistar rats were divided into sham-operated (SHM), OVX, OVX+SPL (0.25 mg/kg), COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) and OVX+COC+SPL rats treated with COC and SPL daily for eight weeks. IR was assessed by homeostatic model assessment of IR (HOMA-IR).Results:Data showed that OVX rats had a higher HOMA-IR value that is associated with increased visceral adiposity, triglycerides (TG), total cholesterol/high-density lipoprotein cholesterol (HDL-C), TG/HDL-C, plasma insulin, GSK-3, corticosterone and decreased 17β-oestradiol. However, these effects were attenuated in OVX+COC, OVX+SPL and OVX+COC+SPL rats compared to OVX rats. OVX rats had lower PAI-1 than SHM rats, whereas the beneficial effect on IR and other parameters by COC or SPL was accompanied with increased PAI-1. Improvement of IR and other parameters with combined COC and SPL in OVX rats was accompanied with reduced PAI-1.Conclusion:Taken together, COC or SPL improves IR independent of PAI-1, whereas a combination of COC and SPL in OVX rats ameliorates IR in a PAI-1-dependent manner.

Oral ethinylestradiol-levonorgestrel normalizes fructose-induced hepatic lipid accumulation and glycogen depletion in female rats.

The present study investigated the effects of oral ethinylestradiol-levonorgestrel (EEL) on hepatic lipid and glycogen contents during high fructose (HF) intake, and determined whether pyruvate dehydrogenase kinase-4 (PDK-4) and glucose-6-phosphate dehydrogenase (G6PD) activity were involved in HF and (or) EEL-induced hepatic dysmetabolism. Female Wistar rats weighing 140-160 g were divided into groups. The control, EEL, HF, and EEL+HF groups received water (vehicle, p.o.), 1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel (p.o.), fructose (10% w/v), and EEL plus HF, respectively, on a daily basis for 8 weeks. Results revealed that treatment with EEL or HF led to insulin resistance, hyperinsulinemia, increased hepatic uric acid production and triglyceride content, reduced glycogen content, and reduced production of plasma or hepatic glutathione- and G6PD-dependent antioxidants. HF but not EEL also increased fasting glucose and hepatic PDK-4. Nonetheless, these alterations were attenuated by EEL in HF-treated rats. Our results demonstrate that hepatic lipid accumulation and glycogen depletion induced by HF is accompanied by increased PDK-4 and defective G6PD activity. The findings also suggest that EEL would attenuate hepatic lipid accumulation and glycogen depletion by suppression of PDK-4 and enhancement of a G6PD-dependent antioxidant barrier.

Influence of Oral Contraceptive Use on Adaptations to Resistance Training.

Introduction: The majority of young women use oral contraceptives (OCs). Use of OCs has been associated with lower myofibrillar protein and tendon collagen synthesis rates, but it is unknown whether OCs will limit the adaptive response of myotendinous tissue to resistance training.Design and Methods: Fourteen healthy untrained young regular OC users (24 ± 1 years, fat% 32 ± 1, 35 ± 2 ml⋅min-1⋅kg-1) and 14 NOC users (non-OC, controls) (24 ± 1 years, fat% 32 ± 2, 34 ± 2 ml⋅min-1⋅kg-1) performed a 10-week supervised lower extremity progressive resistance training program. Before and after the intervention biopsies from the vastus lateralis muscle and the patellar tendon were obtained. Muscle (quadriceps) and tendon cross-sectional area (CSA) was determined by magnetic resonance imaging (MRI) scans, and muscle fiber CSA was determined by histochemistry. Maximal isometric knee extension strength was assessed by dynamometry while 1 repetition maximum (RM) was determined during knee extension.Results: Training enhanced CSA in both muscle (p < 0.001) and tendon (p < 0.01). A trend toward a greater increase in muscle CSA was observed for OC (11%) compared to NOC (8%) (interaction p = 0.06). Analysis of mean muscle fiber type CSA showed a trend toward an increase in type II muscle fiber area in both groups (p = 0.11, interaction p = 0.98), whereas type I muscle fiber CSA increased in the OC group (n = 9, 3821 ± 197 to 4490 ± 313 mm2, p < 0.05), but not in NOC (n = 7, 4020 ± 348 to 3777 ± 354 mm2, p = 0.40) (interaction p < 0.05). Post hoc analyses indicated that the effect of OCs on muscle mass increase was induced by the OC-users (n = 7), who used OCs containing 30 μg ethinyl estradiol (EE), whereas the response in users taking OCs with 20 μg EE (n = 7) did not differ from NOC. Both the OC and NOC group experienced an increase in maximal knee strength (p < 0.001) and 1RM leg extension (p < 0.001) after the training period with no difference between groups.Conclusion: Use of OCs during a 10-week supervised progressive resistance training program was associated with a trend toward a greater increase in muscle mass and a significantly greater increase in type I muscle fiber area compared to controls. Yet, use of OCs did not influence the overall increase in muscle strength related to training.

Hormonal contraception as a method of social adaptation of women in modern society

Relevance. Currently, women make up more than 40% of the global workforce and more than half of students studying at universities around the world. Women's education, especially at a high level, tends to increase female employment. The mismatch of the style and rhythm of modern life with a genetically determined and working millennium reproductive program requires the choice of a specific approach to social adaptation. Aim. Analysis of literary sources on the use of hormonal contraception as a method of social adaptation. Materials and methods. To write this review, domestic and foreign publications were searched in Russian and international search systems (PubMed, eLibrary, etc.) for the last 2-10 years. The review included articles from peer-reviewed literature. Results. The review describes the features of modern hormonal contraceptives. Their non-contraceptive effects are presented. The individual non-contraceptive effects of a combined oral contraceptive containing 30 mg of ethinyl estradiol and 2 mg of chlormadinone acetate were determined. It has been established that the use of this contraceptive helps to improve the well-being and mood of patients, which allows you to actively use this contraceptive in routine clinical practice with premenstrual syndrome, dysmenorrhea, without the use of analgesics. Conclusions. The numerous positive effects of ethinyl estradiol and chlormadinone acetate allow the use of the drug as a means to increase social adaptation, and, consequently, improve the quality of life.

Combined oral contraceptive in female mice causes hyperinsulinemia due to β-cell hypersecretion and reduction in insulin clearance

Oral contraception is the most commonly used interventional method in the world. However, several women employ the continuous use of these hormones to avoid pre- and menstruation discomforts. Some studies indicate that oral contraceptives are associated with disturbances in glycemia and the effects of the use of a continuous regime are poorly elucidated. Herein, we evaluated the effects of the continuous administration of a combined oral contraceptive (COC) composed by ethinyl estradiol (EE) and drospirenone (DRSP) on glucose homeostasis in female mice. Adult Swiss mice received 0.6 μg EE and 60 μg DRSP (COC group) or vehicle [control (CTL)] daily by gavage for 35 days. COC treatment had no effect on body weight or adiposity, but increased uterus weight and induced hepatomegaly. Importantly, COC females displayed normal glycemia and glucose tolerance, but hyperinsulinemia and lower plasma C-peptide/insulin ratio, indicating reduced insulin clearance. Furthermore, COC mice displayed reduced protein content of the β subunit of the insulin receptor (IRβ) in the liver. Additionally, pancreatic islets isolated from COC mice secreted more insulin in response to increasing glucose concentrations. This effect was associated with the activity of steroid hormones, since INS-1E cells incubated with EE plus DRSP also secreted more insulin. Therefore, we provide the first evidence that the continuous administration of EE and DRSP lead to hyperinsulinemia, due to enhancement of insulin secretion and the reduction of insulin degradation, which possibly lead to the down-regulation of hepatic IRβ. These findings suggest that the continuous administration of COC could cause insulin resistance with the prolongation of treatment.

Involvement of glucocorticoid and mineralocorticoid receptors in lipid accumulation and depressed G6PD activity in the livers of rats treated with postpartum oral estrogen-progestin.

Postpartum contraception is an important step for preventing closely spaced pregnancy. Combined oral contraceptive (COC) has been linked to cardiometabolic disturbances. We therefore hypothesized that postpartum oral estrogen-progestin use induces hepatic lipid accumulation that is associated with glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation via adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA)-dependent pathway. Female Wistar rats weighing 130-150g were mated to achieve timed pregnancy and delivery. Twenty-four (24) dams were randomly assigned to receive vehicle (po), COC (1.0μg ethinylestradiol and 5.0μg levonorgestrel; po), COC with GR blockade (mifepristone; 80.0mg/kg; po) and COC with MR blockade (spironolactone; 0.25mg/kg; po) daily between 3rd and 11th week postpartum. Data showed that postpartum COC resulted in glucose dysregulation, increased visceral adiposity, liver weight, plasma corticosterone, aldosterone, circulating and hepatic free fatty acid (FFA), triglyceride (TG), adenosine deaminase (ADA), uric acid production, lactate production, and oxidative marker injury. On the other hand, G6PD-dependent antioxidant defenses were depressed by postpartum COC. However, these effects were attenuated by GR or MR blockade. Our data demonstrate that enhanced G6PD-dependent antioxidant defenses and suppressed ADA/XO/UA pathway in the liver by GR or MR blockade improves glucose dysregulation and hepatic TG accumulation induced by postpartum COC. This study implies a plausible involvement of GR and MR via defective G6PD-dependent antioxidant barrier and increased activity of ADA/XO/UA pathway in postpartum COC-induced hepatic lipid accumulation.

Dipeptidyl peptidase-4 inhibition protects the liver of insulin-resistant female rats against triglyceride accumulation by suppressing uric acid

Dipeptidyl peptidase-4 (DPP-4) inhibition has been shown to exert beneficial effects against insulin resistance (IR) and type 2 diabetes. Combined oral contraceptive (COC) treatment is associated with impaired glucose and lipid metabolism but the mechanisms are elusive. We therefore, hypothesized that DPP-4 inhibition ameliorates COC-induced glucose dysregulation and hepatic triglyceride (TG) accumulation through adenosine deaminase (ADA) /xanthine oxidase (XO) /uric acid-dependent pathway. Female Wistar rats received (po) vehicle and COC (1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel; po) with or without DPP-4 inhibitor (sitagliptin; 100 mg/kg; po) for 8 weeks (n = 6/group). Glucose dysmetabolism was assessed by elevated fasting blood glucose, impaired oral glucose tolerance test and homeostatic model assessment of IR. Treatment with COC led to increased plasma fasting glucose, triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, IR and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic TG, TG/HDL-cholesterol ratio, malondialdehyde, uric acid (plasma; 25.2 ± 0.6 mg/dl; hepatic 128.9 ± 8.0 mg/100 mg tissue), lactate dehydrogenase, DPP-4, ADA and XO (plasma;10.5 ± 1.1 U/L; hepatic 21.2 ± 1.4 U/g protein) activities. Likewise, COC led to reduction in nitric oxide level. However, DPP-4 inhibition significantly ameliorated these alterations induced by COC treatment through suppression of uric acid (plasma; 15.1 ± 1.0 mg/dl, hepatic; 75.6 ± 5.0 mg/100 mg tissue), XO (plasma; 4.1 ± 0.9 U/L, hepatic; 8.7 ± 0.4 U/g protein), ADA and DPP-4 activities suggesting their involvement in glucose dysregulation and hepatic TG accumulation induced by COC treatment. Therefore, DPP-4 inhibition would impact positively on cardiometabolic disorders, at least in part, through XO, ADA and uric acid suppression.

The Impact of Two Combined Oral Contraceptives Containing Ethinyl Estradiol and Drospirenone on Whole Blood Clot Viscoelasticity and the Biophysical and Biochemical Characteristics of Erythrocytes.

Venous thrombosis is associated with combined oral contraceptive (COC) use. We investigated the impact of two ethinyl estradiol (EE) and drospirenone (DRSP) containing COCs (3 mg DRSP/20 µg EE and 3 µg DRSP/30 µg EE) on the viscoelasticity of whole blood clots along with the biophysical and biochemical characteristics of erythrocytes. Thromboelastography (TEG) analysis showed a tendency toward a hypercoagulable state in the COCs groups that was more pronounced with higher EE concentrations. Light microscopy and scanning electron microscopy (SEM) showed rouleaux formation of erythrocytes and alterations to the erythrocyte shape for both COC groups, which was attributed to membrane damage. SEM analysis showed spontaneous activation of fibrin and platelets in the COC groups, along with interactions between erythrocytes and platelets and/or fibrin. Confocal microscopy confirmed compromised membrane integrity in the COC groups compared to controls. Global thrombosis test analysis showed increased platelet activation and low thrombolysis in both COC groups when compared to controls. In conclusion, DRSP/EE formulations impact erythrocytes' biophysical and biochemical properties to cause a shift in hemostasis to a prothrombotic state. Although these effects are mostly subclinical the long-term effects and risks involved with the use of these hormones should be considered carefully for each individual.

The effect of hormone therapy on bone mineral density and cardiovascular factors among Iranian female athletes with amenorrhea/oligomenorrhea: A randomized clinical trial.

Background: Functional hypothalamic menstrual disorder (FHMD) has a destructive effect on the athlete’s bone mineral density and cardiovascular system. Utilizing hormone replacement therapy to treat FHMD in athletes is controversial. This study was conducted to examine the effect of hormone therapy on bone density and the cardiovascular system of professional female athletes with FHMD. Methods: In this study, 18 female athletes with at least a 2- year history of FHMD were recruited in a 9-month single blind randomized clinical intervention (RCT) and randomly classified into 2 groups: the oral contraceptive pills (OCP) group, who received a lowdose combined oral contraceptive (OC) containing 30 µg ethinyl estradiol and 150 µg levonorgestrel (n= 10), and the control group (n= 8). Bone mineral densitometry (BMD) and certain cardiovascular risk factors were measured before and after the 9-month trial. The Chi square test was used to compare the quantitative and qualitative results. Results: Bone mineral density did not change significantly in either group. Very low density lipoprotein (VLDL) (p= 0.035) and Apolipoprotein B (Apo B) (p= 0.04) reduced significantly in the OCP group. An increase was observed in the serum levels of Apolipoprotein A (Apo A) (p= 0.01) in the control group. Changes in the Apo B to Apo A ratio was significant in both groups (OCP group: p= 0.018, control group: p= 0.040). No significant changes were observed in the other measured factors. Conclusion: Although the administration of estrogen did not significantly increase bone mineral density, it had positive effects on the cardiovascular system and lipid profile.

Blockade of mineralocorticoid receptor ameliorates oral contraceptive-induced insulin resistance by suppressing elevated uric acid and glycogen synthase kinase-3 instead of circulating mineralocorticoid

Context: Estrogen–progestin combined oral contraceptive (COC) has been connected to mineralocorticoid receptor (MR) activation and adverse cardiometabolic events. We consequently hypothesised that insulin resistance (IR), hyperuricemia, and elevated circulating GSK-3 induced by COC is through activation of MR via mineralocorticoid and glucocorticoid pathways.Methods: Female Wistar rats aged 12 weeks received (po) vehicle and COC (1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel) with or without MR blocker (0.25 mg/kg spironolactone; Spl), daily for eight weeks.Results: Data showed that COC treatment led to increased IR, 1-hour postload glucose level, insulinemia, triglyceride/HDL-cholesterol ratio, total cholesterol/HDL-cholesterol ratio, uric acid, GSK-3, aldosterone, corticosterone values, impaired glucose tolerance and pancreatic β-cell function. However, MR blockade by Spl ameliorated all these alterations except that of aldosterone.Conclusion: The results demonstrate that COC induces IR, hyperuricemia and high GSK-3 levels through activation of MR via glucocorticoid dependent pathway.

The impact of oral contraception with ethinyl estradiol and chlormadinone acetate on sexual function of women

Hormonal contraception influences various areas of female health and behavior. The study group included 41 women aged 18-25 (mean age 22.2 ± 3.4) years who used oral contraception with 3 mg of ethinyl estradiol and 2 mg of chlormadinone acetate for six months. The mean body mass index (BMI) of women from the study group was 23. 5 ± 2.3 kg/m2 . The exclusion criteria from the study group where contraindications for hormonal contraception (liver disease, porphyria, thrombosis, hormonally dependent cancer, and migraine). The control group included 31 women aged 18-25 (mean age 21.6 ± 2.4) years who did not use hormonal contraception. The mean BMI of controls was 22.4 ± 1.7 kg/m2. Both the age and the BMI of controls were no statistically different from the study group. The sexual function of the studied women was assessed with the use of Female Sexual Function Index (FSFI). FSFI is a multidimensional self-reporting tool for the assessment of female sexual function. It consists of six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain (with 19 items). There were no statistically relevant differences between the study group and the controls in relations to the FSFI parameters. There is no impact of oral contraception with 3 mg of ethinyl estradiol and 2 mg of chlormadinone acetate on sexual function of users.

Sodium acetate improves disrupted glucoregulation and hepatic triglyceride content in insulin-resistant female rats: involvement of adenosine deaminase and dipeptidyl peptidase-4 activities.

Combined oral contraceptive (COC) treatment has been shown to be associated with glucose deregulation and increased triglyceride levels, but the mechanisms are elusive. Soluble dipeptidyl peptidase-4 (sDPP-4) and adenosine deaminase (ADA) are involved in the initiation and/or progression of cardiometabolic disorders. We therefore, hypothesized that increased DPP-4 and ADA activities are involved in glucose deregulation and hepatic triglyceride accumulation induced by COC treatment. This study also investigated whether short-chain fatty acid, acetate, would protect against COC-induced dysmetabolic effects. Female Wistar rats received (p.o.) vehicle and COC (1.0μg ethinylestradiol plus 5.0μg levonorgestrel) with or without sodium acetate (ACE; 200mg) for 8weeks. Treatment with COC led to increased plasma triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, insulin resistance, and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic triglycerides (TG), TG/HDL-cholesterol ratio, malondialdehyde, uric acid, lactate dehydrogenase, DPP-4, ADA, and xanthine oxidase (XO) activities. On the other hand, COC led to reduction in nitric oxide level. However, ACE significantly ameliorated the alterations induced by COC treatment, but XO activity remains elevated during COC treatment. This result also demonstrates that increased DPP-4 and ADA activities are at least in part involved in glucose deregulation and hepatic TG accumulation induced by COC treatment. Therefore, sodium acetate would impact positively on cardiometabolic disorders, at least in part, by inhibition of DPP-4 and ADA activities.

Oral ethinylestradiol-levonorgestrel attenuates cardiac glycogen and triglyceride accumulation in high fructose female rats by suppressing pyruvate dehydrogenase kinase-4.

Fructose (FRU) intake has increased dramatically in recent decades with a corresponding increased incidence of insulin resistance (IR), particularly in young adults. The use of oral ethinylestradiol-levonorgestrel (EEL) formulation is also common among young women worldwide. The present study aimed at determining the effect of EEL on high fructose-induced cardiac triglyceride (TG) and glycogen accumulation. The study also investigated the possible involvement of pyruvate dehydrogenase kinase-4 (PDK-4) in EEL and/or high fructose metabolic effects on the heart. Ten-week-old female Wistar rats were allotted into four groups. The control, EEL, FRU, and EEL + FRU rats received distilled water (vehicle, p.o.), 1.0μg ethinylestradiol plus 5.0μg levonorgestrel (p.o.), 10% fructose (w/v), and 1.0μg ethinylestradiol plus 5.0μg levonorgestrel and 10% fructose, respectively, daily for 8weeks. Data showed that EEL or high fructose caused IR' impaired glucose tolerance' hyperlipidemia' increased plasma lactate, lactate dehydrogenase, PDK-4, uric acid, xanthine oxidase (XO), adenosine deaminase (ADA), malondialdehyde (MDA), cardiac uric acid, TG, TG/HDL- cholesterol, glycogen synthesis, MDA, and visceral fat content and reduced glutathione. High fructose also resulted in impaired pancreatic β-cell function, hyperglycemia, and increased cardiac PDK-4, lactate synthesis, and mass. Nonetheless, these alterations were ameliorated in EEL plus high fructose rats. This study demonstrates that high fructose-induced myocardial TG and glycogen accumulation is attributable to increased PDK-4. Besides, EEL could be a useful pharmacological utility for protection against cardiac dysmetabolism by inhibiting PDK-4.

A4800 Dipeptidyl peptidase-4 inhibition prevents increased hepatic triglyceride content in insulin-resistant female rats

Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibition has been show to exert beneficial effects against insulin resistance (IR) and fatty liver disease. Combined oral contraceptive (COC) treatment has been shown to be associated with glucose deregulation and increased hepatic triglyceride (TG) levels, but the mechanisms are elusive. We therefore, hypothesized that DPP-4 inhibition (DPP-4i) will ameliorate COC-induced glucose dysregulation and hepatic TG accumulation through adenosine deaminase (ADA) /xanthine oxidase (XO) /uric acid-dependent pathway. Methods: Female Wistar rats received (po) vehicle and COC (1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel; po) with or without DPP-4 inhibitor (sitagliptin; 100 mg/kg; po) for 8 weeks (n = 6/group). Glucose dysmetabolism was accessed by elevated fasting blood glucose, impaired oral glucose tolerance test and homeostatic model assessment of insulin resistance. Results: Treatment with COC led to increased plasma fasting glucose, triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, IR and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic triglycerides (TG), TG/HDL-cholesterol ratio, malondialdehyde, uric acid, lactate dehydrogenase, DPP-4, ADA and XO activities. On the other hand, COC led to reduction in nitric oxide level. However, DPP-4i significantly ameliorated these alterations induced by COC treatment except plasma and hepatic XO activity. Conclusion: This demonstrates that increased uric acid, DPP-4 and ADA activities are involved in glucose dysregulation and hepatic TG accumulation induced by COC treatment. Therefore, DPP-4i would impact positively on cardiometabolic disorders, at least in part, through ADA and uric acid suppression.

Combined oral contraceptive interference with the ability of ulipristal acetate to delay ovulation: A prospective cohort study

ObjectiveTo determine if a combined oral contraceptive (COC) initiated shortly after ulipristal acetate (UPA) administration interferes with its mechanism of action. Study designHealthy, reproductive-age women of normal BMI with proven ovulation (serum progesterone >3 ng/ml) were enrolled for three cycles (Cycle 1, UPA only; Cycle 2 washout; Cycle 3 UPA plus COC). During Cycles 1 and 3, subjects were monitored with transvaginal ultrasound and blood sampling for progesterone and LH every other day until a dominant follicle measuring >15 mm was visualized. In both treatment cycles, subjects received UPA (30mg) and were followed daily with similar monitoring for up to 7 days. In Cycle 3 only, subjects initiated a daily COC (0.15 mg levonorgestrel/30 μg ethinyl estradiol) 2 days after UPA. The study had 80% power to detect a 15% difference in the proportion of cycles with at least a 5-day delay in follicle rupture. We assessed follicle rupture as >50% decrease in mean size and adjudicated unclear outcomes with serum hormones. ResultsA total of 36 women enrolled and 33 completed all study procedures [age 28.4 years (SD 3.9); BMI 23.4 (SD 2.4)]. Compared to Cycle 1, more subjects demonstrated evidence of follicle rupture in <5 days in Cycle 3 [1/33 (3%) vs. 9/33 (27%), p = .008]. We also included data from 2 subjects who experienced rupture prior to COC dosing in the analysis. ConclusionUPA’s effectiveness is significantly reduced by administering COCs 2 days later. ImplicationsThis study demonstrates that UPA’s efficacy as an emergency contraceptive is reduced with early exposure to COCs.

Inhibition of adenosine deaminase and xanthine oxidase by valproic acid abates hepatic triglyceride accumulation independent of corticosteroids in female rats treated with estrogen-progestin.

Elevated circulating uric acid has been postulated to play an important pathophysiological role in estrogen-progestin combined oral contraceptive (COC)-induced hypertension and endothelial dysfunction. We hypothesized that disruption of glucoregulation and liver triglyceride (TG) accumulation induced by COC use would be abated by valproic acid (VPA) treatment through suppression of adenosine deaminase (ADA) and xanthine oxidase (XO) activities. Female Wistar rats aged 9-10 weeks were treated with a combination of estrogen-progestin COC steroids (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel; p.o.) with or without VPA (100.0 mg/kg; p.o.) daily for 6 weeks. The result shows that the disrupted glucoregulation and associated elevated hepatic ADA activity, plasma and hepatic XO activity, uric acid (UA), TG/HDL-cholesterol, total cholesterol, and malondialdehyde induced by COC treatment were attenuated by VPA treatment. However, VPA did not have any effect on plasma aldosterone, corticosterone, ADA, circulating and hepatic free fatty acid. Our results demonstrate that suppression of plasma and hepatic XO activities, along with hepatic ADA activity and UA by VPA treatment, protects against disrupted glucoregulation and increased liver TG by COC independent of elevated corticosteroids. The findings imply that VPA would provide protection against the development of cardiometabolic disorder via inhibition of the ADA/XO/UA-mediated pathway.

Oral contraceptive use and cutaneous melanoma risk: A French prospective cohort study

Introduction Evidence suggests that cutaneous melanoma, the most lethal form of skin cancer, may be influenced by sex hormones. Oral hormones are the leading contraception method in industrialized countries and represent a significant source of exogenous hormone use. Several studies reported a positive association between oral contraceptive (OC) use and melanoma risk. However, findings were conflicting and data from large prospective studies are lacking. Our aim was to explore the associations between OC use and melanoma risk in women. Methods E3 N is a prospective cohort of 98,995 French women aged 40–65 years at inclusion in 1990. Use of oral hormones for contraception was collected through a self-administered questionnaire at baseline, and detailed information on lifetime use of OCs was then recorded every 2–3 years from 1992. We computed hazard ratios (HRs) and 95% Confidence Intervals (CIs) using Cox regression models adjusted for age, birth cohort, pigmentary traits, residential UV exposure in county of birth and at inclusion, and family history of skin cancer. We stratified the results according to melanoma site and histological type using competing-risk models. To examine potential confounding by sun exposure, we used data from E3N-SunExp, a nested case-control study in which a specific questionnaire on lifetime residential and recreational UV exposures was sent to all incident skin cancer cases and 3 controls per case (matched on age, county of birth, education, and length of follow-up in the cohort) in 2008. Analyses in the sub-cohort were performed through logistic regression modelling. Results Between 1992 and 2008, 539 melanoma cases were ascertained among 79,365 women. In age-adjusted models, there was a modest association between ever use of OCs and melanoma risk (HR = 1.18, 95% CI = 0.98–1.42), which was reduced after full adjustment (HR = 1.14, 95% CI = 0.95–1.38). The association was stronger in long-term users (HR = 1.33, 95% CI = 1.00–1.75 for a duration of use of at least 10 years, compared with never use of OCs). Among ever users, there was an inverse association with age at first use (Ptrend = 0.01), consistent with longer durations of OC use in women with a younger age at first use. However, we found no evidence of an association with age at last use or time since last use. When exploring different formulations, the association between ever use of OCs and melanoma risk was restricted to OCs containing high doses of estrogen (≥ 50 μg of ethinyl estradiol) (HR = 1.26, CI = 1.03–1.53). In subtype- and site-specific analyses, ever use of OCs appeared positively associated with all types and sites of melanoma, except the trunk, although no heterogeneity was detected across subtypes (Phomogeneity = 0.54) or sites (Phomogeneity = 0.23). In the E3N-SunExp population, associations between OC use and melanoma risk were not substantially modified after adjustment for residential or recreational UV exposure. However, while we found no association between OC use and sun exposure, we observed that OC use was positively associated with sunscreen use (Ptrend = 0.04 from no protection to increasing SPF) and tanning bed use (odds ratio = 1.14, 95% CI = 1.01–1.29 for ever vs. never use), even after adjusting for age and year of birth. Conclusions Overall, our findings do not support a strong association between OC use and melanoma risk. OC users were more likely to use sunscreen and tanning beds, suggesting a specific profile of OC users regarding their attitude towards tanning. Therefore, we cannot exclude that the observed relation between OC use and melanoma risk, which has been debated in the literature for almost 40 years, could relate to particular sun exposure behaviors in users. Further research, including social and behavioral description of OC users, is thus critical to increase our understanding of the risk profile of women diagnosed with melanoma, and to question the hypothesis of a hormonal influence on melanoma risk.