An exploratory study on the association of lifestyle factors with serum etonogestrel concentrations among contraceptive implant users.

PURPOSE: To explore how diet and exercise habits associate with serum etonogestrel concentrations among contraceptive implant users. MATERIALS AND METHODS: We conducted a secondary analysis of healthy, reproductive-age women using etonogestrel implants. This study was registered on ClinicalTrials.gov, NCT03092037. We assessed diet and exercise habits with two validated surveys: Healthy Eating Vital Signs and the Stanford Brief Activity Survey. Participants previously had their serum etonogestrel concentrations measured using a validated liquid-chromatography mass-spectrometry assay. We then used linear modelling to test for associations between survey responses and serum etonogestrel concentrations. RESULTS: Among 129 participants, diet and exercise habits had no significant associations with serum etonogestrel concentrations (p = 0.22-0.72), with inconsistent effects found for increased caloric intake and sedentary lifestyle. CONCLUSION: This exploratory study found no significant effect of diet or exercise habits on steady-state pharmacokinetics among contraceptive implant users. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT03092037.

Comparison of plasma etonogestrel concentrations sampled from the contralateral-to-implant and ipsilateral-to-implant arms of contraceptive implant users.

OBJECTIVE: To compare plasma etonogestrel concentrations sampled from the contralateral- versus ipsilateral-to-implant arm. STUDY DESIGN: Sub-analysis of a cross-sectional study in Botswana in 33 participants who provided contralateral and ipsilateral blood samples. RESULTS: Plasma etonogestrel concentrations in contralateral and ipsilateral specimens were highly correlated (correlation coefficient = 0.99; p < 0.0001). Bland-Altman analysis of agreement showed that etonogestrel levels were on average 5.9 pg/mL higher (2.1%) in ipsilateral compared to contralateral specimens (95% confidence interval: -4.1, 15.9 pg/mL). CONCLUSIONS: We found no meaningful differences in plasma etonogestrel concentrations between samples taken from the contralateral- versus ipsilateral-to-implant arm. IMPLICATIONS: Our data suggest that etonogestrel plasma concentrations are unlikely to be meaningfully different between samples drawn from the ipsilateral- versus the contralateral-to-implant arms in etonogestrel contraceptive implant users.

Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives.

OBJECTIVE: In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. METHODS: In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 µg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed. RESULTS: The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers. CONCLUSION: CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

Relationship Between Etonogestrel Concentrations and Bleeding Patterns in Contraceptive Implant Users.

OBJECTIVE: To estimate whether serum etonogestrel concentrations influence bleeding patterns and related side effects in contraceptive implant users. METHODS: We conducted a prospective cross-sectional study with healthy, reproductive-aged women using etonogestrel implants for 12-36 months. Participants completed a brief questionnaire to assess their current bleeding pattern and any experience of abnormal bleeding with the implant. We then measured serum etonogestrel concentrations. We also reviewed the charts of participants to determine whether a prescription for oral contraceptive pills was ever given for treatment of implant-related bothersome bleeding. We performed multivariable logistic regression to test for associations between serum etonogestrel concentrations and both bleeding patterns and related side effects. RESULTS: We enrolled 350 women, and 59.4% reported having experienced abnormal bleeding with the contraceptive implant. Only 14.9% of participants reported amenorrhea and 37.7% reported monthly periods. Among participants with reviewable medical records (n=253), roughly 20% had received a prescription for oral contraceptive pills during implant use. Increasing serum etonogestrel concentrations were significantly associated with increasing odds of reporting abnormal bleeding (adjusted odds ratio [aOR] 1.005, P=.015) and increasing odds of having received an oral contraceptive pill prescription (aOR 1.008, P=.002). For every 100 pg/mL increase in serum etonogestrel concentration, contraceptive implant users in this study had 1.6 times the odds of reporting abnormal bleeding and 2.3 times the odds of having received a prescription as treatment for bothersome bleeding. CONCLUSION: We found both objective and subjective evidence that higher levels of progestin from the contraceptive implant were associated with bleeding side effects experienced by women in this study. Pharmacologic variation may influence the side effects women experience with a variety of hormonal contraceptive methods, in turn affecting patient satisfaction and discontinuation rates.

Relationship between patient characteristics and serum etonogestrel concentrations in contraceptive implant users.

OBJECTIVE: To determine whether serum etonogestrel concentrations in contraceptive implant users are associated with certain individual patient characteristics. STUDY DESIGN: We enrolled reproductive-age women using etonogestrel contraceptive implants between 12-36 months duration and measured a single serum etonogestrel concentration. Participants also completed a questionnaire about demographics. RESULTS: We enrolled 350 participants; median age was 22.5 years (range 18.0-39.1), median months of implant use was 26.0 (range 12.0-36.0), and median body mass index was 25.7 kg/m2 (range 18.5-52.0). Our study population was primarily white/Caucasian (46.6% [163/350]) and Hispanic/Latina ethnicity (51.4% [180/350]). The median serum etonogestrel concentration was 137.4 pg/ml and etonogestrel concentrations varied 12.4 fold in the population (range 55.8-695.1 pg/ml). Using forward stepwise linear regression, months of implant use (ß=-1.74, p<.001) and body mass index (ß=-3.10, p<.001) were both significantly associated with decreased serum etonogestrel concentration with Black/African American race as a positive effect modifier (ß=18.24, p=.099); R-squared for the model=0.13. CONCLUSIONS: Individuals demonstrated a wide variability in serum etonogestrel concentrations, which can potentially affect side-effect profiles and efficacy. Increasing body mass index and longer duration of implant use were associated with small decreases in serum etonogestrel concentrations, while self-reported Black/African American race was associated with a non-significant increase. Despite these findings, most of etonogestrel variability was unaccounted for, suggesting that other clinical, pharmacologic, and genetic factors contributing to variability in etonogestrel concentrations remain to be determined. IMPLICATIONS: Although increases in body mass index are associated with lower etonogestrel levels in contraceptive implant users, the majority of women will maintain serum concentrations that consistently suppress ovulation. Furthermore, certain patient characteristics can only explain a small portion (13%) of the variability in serum etonogestrel levels among contraceptive implant users.

Influence of Genetic Variants on Steady-State Etonogestrel Concentrations Among Contraceptive Implant Users.

OBJECTIVE: To identify genetic variants that influence steady-state etonogestrel concentrations among contraceptive implant users. METHODS: We enrolled healthy, reproductive-age women in our pharmacogenomic study using etonogestrel implants for 12-36 months without concomitant use of hepatic enzyme inducers or inhibitors. We collected participant characteristics, measured serum etonogestrel concentrations, and genotyped each participant for 120 single nucleotide variants in 14 genes encoding proteins involved in steroid hormone (ie, estrogens, progestins) metabolism, regulation, or function. We performed generalized linear modeling to identify genetic variants associated with steady-state etonogestrel concentrations. RESULTS: We enrolled 350 women, who had a median serum etonogestrel concentration of 137.4 pg/mL (range 55.8-695.1). Our final generalized linear model contained three genetic variants associated with serum etonogestrel concentrations: NR1I2(PXR) rs2461817 (ß=13.36, P=.005), PGR rs537681 (ß=-29.77, P=.007), and CYP3A7*1C (ß=-35.06, P=.025). Variant allele frequencies were 69.4%, 84.9%, and 5.1%, respectively. Our linear model also contained two nongenetic factors associated with etonogestrel concentrations: body mass index (BMI) (ß=-3.08, P=7.0×10) and duration of implant use (ß=-1.60, P=5.8×10); R for the model =0.17. CONCLUSION: Only BMI and duration of implant use remained significantly associated with steady-state etonogestrel concentrations. Of the three novel genetic associations found, one variant associated with increased etonogestrel metabolism (CYP3A7*1C) causes adult expression of fetal CYP3A7 proteins and can consequently alter steroid hormone metabolism. Women with this variant may potentially have increased metabolism of all steroid hormones, as 27.8% (5/18) of CYP3A7*1C carriers had serum etonogestrel concentrations that fell below the threshold for consistent ovulatory suppression (less than 90 pg/mL). More pharmacogenomic investigations are needed to advance our understanding of how genetic variation can influence the effectiveness and safety of hormonal contraception, and lay the groundwork for personalized medicine approaches in women's health. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03092037.

Plasma concentrations of etonogestrel in women using oral desogestrel before and after Roux-en-Y gastric bypass surgery: a pharmacokinetic study.

OBJECTIVE: To investigate whether Roux-en-Y gastric bypass (RYGB) affects oral desogestrel (etonogestrel) pharmacokinetics. DESIGN: Single centre, open label, phase-2 pharmacokinetic study. SETTING: University hospital of Linköping, Sweden. POPULATION: Fourteen women with planned RYGB surgery were included; nine women aged 18-45 years using 75 micrograms desogestrel completed the study. METHODS: Steady-state etonogestrel pharmacokinetic (PK) parameters were measured on three occasions for each individual (at 8 ± 6 weeks before surgery, and at 12 ± 2 and 52 ± 2 weeks after surgery). Each patient served as her own control. On each occasion, serum samples were collected during a 24-hour period and etonogestrel concentrations were determined with ultra-performance liquid chromatography/tandem mass spectrometry. MAIN OUTCOME MEASURES: Area under the plasma concentration time curve of etonogestrel (AUC0-24 hours ). RESULTS: All women had significant postoperative weight loss. There were no significant differences in AUC0-24 hours , terminal half-lives (t½ ), time to peak serum concentrations (Tmax ), or apparent oral clearances of etonogestrel (CLoral ) before and after gastric bypass surgery on any occasion. Peak serum concentrations (Cmax ) increased after 52 ± 2 weeks compared with preoperative values (0.817 ng/ml versus 0.590 ng/ml, P = 0.024). CONCLUSION: To our knowledge, this is the first study to investigate the effects on desogestrel pharmacokinetics after RYGB. This study did not reveal any clinically significant changes in etonogestrel pharmacokinetics, suggesting that oral desogestrel may be used by women after RYGB surgery. The sample size was limited, however, and therefore the results should be interpreted cautiously. TWEETABLE ABSTRACT: The pharmacokinetics of oral desogestrel does not appear to change after gastric bypass surgery.

Simultaneous determination of etonogestrel and ethinyl estradiol in human plasma by UPLC-MS/MS and its pharmacokinetic study.

A selective, sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for the simultaneous determination of etonogestrel (ENG) and ethinyl estradiol (EE) in human plasma. The analytes and their deuterated internal standards, ENG-d7 and EE-d4, were extracted from plasma samples by solid-phase extraction on HyperSep™ Retain PEP cartridges. The chromatographic analysis was performed on an Acquity UPLC HSS Cyano column, 100 Å (50 × 2.1 mm, 1.8 µm), column using gradient mobile phase, acetonitrile and 2.0 mm ammonium trifluoroacetate at 0-1.7 min (65:35, v/v) and 1.8-2.7 min (95:5, v/v) with 0.250 mL/min flow rate. Analytes and IS protonated precursor → product ion transitions (ENG, m/z 325.2 → 257.2; EE, m/z 530.2 → 171.2; ENG-d7, m/z 332.2 → 263.2; EE-d4, m/z 534.2 → 171.2) were monitored on a Triple Quadrupole Mass spectrometer (TQMS), operating in multiple reaction monitoring and positive ionization mode. The calibration curves were established at 10.00-2500 pg/mL for ENG and 1.500-150.0 pg/mL for EE with a correlation coefficient (r2 ) ≥0.9996 for both. The validated method was successfully applied to support a bioequivalence study of 0.15 mg ENG and EE 0.03 mg tablet formulation, administered in 24 healthy Indian females. Method reliability was assessed by reanalysis of 94 incurred study samples.

The effect of carbamazepine on etonogestrel concentrations in contraceptive implant users.

OBJECTIVE: The objective was to determine the impact of carbamazepine on the pharmacokinetics and pharmacodynamics of the etonogestrel contraceptive implant. STUDY DESIGN: We enrolled healthy, reproductive-age women using an etonogestrel implant for 1-3 years. We measured etonogestrel levels at baseline and following 3 weeks of coadministered carbamazepine titrated up to 300 mg twice daily. We also evaluated for ovarian follicle-like structures and endometrial thickness using transvaginal ultrasound at the baseline and 3-week visits. RESULTS: We enrolled 13 women; 10 completed study procedures. Participants' mean age was 25.6 years (±5.6), mean body mass index was 30.4 (±7.3), and median duration of implant use was 23 months (range 15-35). The median etonogestrel concentrations before and after carbamazepine coadministration were 158.1 pg/mL (range 128-347) and 50.9 pg/mL (range 39-202), respectively (p=.005). In 8 of 10 subjects, the etonogestrel concentration was below the threshold for ovulatory suppression (<90 pg/mL) after carbamazepine coadministration. The number of ovarian follicle-like structures and endometrial thickness did not significantly change before and after carbamazepine coadministration. CONCLUSIONS: Women using a contraceptive implant experienced significant reductions in etonogestrel concentrations following coadministration of 600 mg of carbamazepine. We did not find significant pharmacodynamic changes during this abbreviated follow-up period. IMPLICATIONS: Carbamazepine use significantly reduces serum etonogestrel concentrations in women using an etonogestrel contraceptive implant, with the majority of participants having etonogestrel concentrations below the threshold for ovulatory suppression. Our findings suggest that treatment with carbamazepine might increase the risk of pregnancy in etonogestrel implant users.

The sexuological impact of hormonal contraceptives based on their route of administration.

Evidence on the effects of hormonal contraceptives on female sexuality is conflicting. We enrolled 556 women, divided into six groups: two composed of subjects using a combined hormonal contraceptive (COC) containing 0.020 ("COC20") and 0.030 ("COC30") mg of ethynyl estradiol (EE), "natural", using COC containing 1.5 mg of estradiol (E2), "ring", using a vaginal ring releasing each day 0.015 mg of EE + 0.120 of etonogestrel, "subcutaneous", using a progestin only subcutaneous contraceptive implant releasing etonogestrel and "controls", using no hormonal contraceptive methods. The subjects were required to answer to the McCoy female sexuality questionnaire and were subjected to a blood test for hormonal evaluation. An ultrasound evaluation of the dorsal clitoral artery was also performed. The higher McCoy sexological value were recorded in the subdermal group; significant differences were recorded among the groups in terms of hormone distribution, with the higher levels of androstenedione in subdermal and control groups. The ultrasound evaluation of dorsal clitoral artery shows a significative correlation between pulsatility and resistance indices and orgasm parameters of McCoy questionnaire. The recorded difference in the sexual and hormonal parameters among the studied hormonal contraceptives may guide toward the personalization of contraceptive choice.

Relationship between etonogestrel level and BMI in women using the contraceptive implant for more than 1 year.

Progestin-only contraceptive methods, including the 3-year, single-rod etonogestrel (ENG) implant, may be preferred for obese women to avoid additional estrogen-related thrombosis risk; however, whether obese women receive an ENG sufficient dose to suppress ovulation is understudied. Our analysis expands on the limited information currently available by studying ENG levels related to body mass index (BMI) in a community sample of primarily Hispanic women. This cross-sectional, descriptive study of 52 long-term implant users found comparable ENG levels across a wide BMI range (p=.1). These results further support that ENG levels are independent of BMI through 3 years of implant use and are thus reassuring that ENG implants will be effective for women of all BMIs.

Contraceptive vaginal ring effectiveness is maintained during 6 weeks of use: a prospective study of normal BMI and obese women.

BACKGROUND: A single study shows that contraceptive vaginal ring (CVR) use for up to 35 days in women with a normal body mass index (BMI) maintains serum hormone levels sufficient to suppress ovulation. This study is intended to confirm those results and to evaluate prolonged CVR use up to 42 days in both normal BMI and obese women. STUDY DESIGN: Twenty women with a normal BMI and 20 obese women enrolled in a prospective open label clinical study of ethinyl estradiol (EE) and etonogestrel (ENG) pharmacokinetics during six weeks of use of a single CVR. Participants underwent twice-weekly evaluations to determine serum hormone concentrations, ovarian follicle development, endometrial thickness and bleeding patterns. RESULTS: Thirty-seven women completed follow-up including eighteen women with a normal BMI and nineteen obese women. EE and ENG concentrations remained in therapeutic range for all women. Follicular development and endometrial proliferation were minimal. By the sixth week, 30% of participants reported spotting or bleeding. CONCLUSIONS: A single CVR used for 6 weeks demonstrates therapeutic serum levels of EE and ENG among women with normal and obese BMI. Women who forget to remove the CVR at day 21 may well have continued contraceptive protection during the next 3 weeks.

Endometrial histopathology, ovarian changes and bleeding patterns among users of long-acting progestin-only contraceptives in Egypt.

OBJECTIVE: To evaluate endometrial and ovarian effects, and bleeding patterns, among users of Depo-Provera(®), Norplant(®), and Implanon(®). STUDY DESIGN: One-hundred and fifty women, who had been using one of these long-acting progestin-only contraceptives (LAPCs) for at least the previous six months, with fifty in each of the groups, were assessed. RESULTS: All results are mentioned in the following sequence: (1) Depo-Provera(®), (2) Norplant(®), and (3) Implanon(®). Normal bleeding was reported by 0%, 52%, and 8%; amenorrhoea or infrequent bleeding by 68%, 24%, and 72%; and abnormal bleeding by 32%, 24%, and 20%, respectively (p < 0.001). Histological evaluation revealed an atrophic endometrium in 84%, 32%, and 28%, respectively (p < 0.0001); a progestin effect in 16%, 28%, and 62%, respectively (p < 0.0001), and a proliferative pattern in 0%, 40%, and 10%, respectively (p < 0.0001). Endometrial thickness was 3 ± 0.41 mm, 3.62 ± 0.65 mm, and 5.2 ± 0.84 mm, respectively (p < 0.0001). Follicular growth in the ovaries was observed at ultrasound in 12%, 40%, and 72%, respectively (p < 0.001). CONCLUSION: Bleeding patterns, endometrial thickness, ovarian activity, and endometrial histology among Egyptian users of LAPCs differed significantly depending on the nature of the contraceptive.

Pharmacokinetics of the etonogestrel contraceptive implant in obese women.

OBJECTIVE: We sought to examine the pharmacokinetics and acceptability of the etonogestrel contraceptive implant in obese women. STUDY DESIGN: We developed and validated a plasma etonogestrel concentration assay and enrolled 13 obese (body mass index ≥30) women and 4 normal-weight (body mass index <25) women, who ensured comparability with historical controls. Etonogestrel concentrations were measured at 50-hour intervals through 300 hours postinsertion, then at 3 and 6 months to establish a pharmacokinetic curve. RESULTS: All obese participants were African American, while all normal-weight participants were white. Across time, the plasma etonogestrel concentrations in obese women were lower than published values for normal-weight women and 31-63% lower than in the normal-weight study cohort, although these differences were not statistically significant. The implant device was found highly acceptable among obese women. CONCLUSION: Obese women have lower plasma etonogestrel concentration than normal-weight women in the first 6 months after implant insertion. These findings should not be interpreted as decreased contraceptive effectiveness without additional considerations.

Pharmacokinetics and ovarian suppression during use of a contraceptive vaginal ring in normal-weight and obese women.

OBJECTIVE: Many observational studies indicate higher oral contraceptive failure among obese women, but most clinical trials and physiologic studies do not support these differences. Limited data indicate higher failure rates among obese contraceptive patch users. Data regarding contraceptive vaginal ring performance in obese women are needed. STUDY DESIGN: Twenty normal weight (body mass index [BMI] 19.0-24.9; median, 21.65) and 20 obese (BMI 30.0-39.9; median, 33.7) women enrolled in a prospective study of ethinyl estradiol (EE(2)) and etonorgestrel pharmacokinetics and of ovarian follicle development, endometrial thickness, and bleeding patterns, all measured biweekly during the second cycle of contraceptive vaginal ring use. RESULTS: Thirty-seven women completed follow-up. Mean day 0-21 EE(2) concentrations were lower among obese vs normal weight women (15.0 vs 22.0 pg/mL, respectively, P = .004), whereas etonorgestrel concentrations were similar (1138 vs 1256 pg/mL, respectively, P = .39). Follicular development was minimal in both groups, with only 5 women achieving a maximum follicle diameter >13 mm at any time during 3 weeks follow-up (3 normal weight and 2 obese women); these women had serum progesterone levels <1.0. Obese women reported more bleeding or spotting than normal weight women (3.6 vs 1.4 days, respectively, P = .01). CONCLUSION: Although obese women had lower EE(2) levels during contraceptive vaginal ring use, they had excellent suppression of ovarian follicle development, similar to normal weight women. This predicts that contraceptive vaginal ring effectiveness will be similar in women with a BMI up to 39.9. The lower serum EE(2) levels in the obese women may explain the greater reported bleeding or spotting days.

Etonorgestrel concentrations in morbidly obese women following Roux-en-Y gastric bypass surgery: three case reports.

BACKGROUND: Pregnancy should be avoided for 12 to 18 months after Roux-en-Y gastric bypass (RYGB) surgery. The etonorgestrel (ENG)-releasing implant (Implanon®) may represent a safe and effective contraceptive method in morbidly obese women who are candidates for bariatric surgery. In addition, the subcutaneous delivery of steroid is unaffected by malabsorptive surgery. METHODS: Three cases of young women with ENG-releasing implant are reported. The device was inserted 1-2 months prior to RYGB. RESULTS: Their initial weights were 130 to 176 kg, and the mean weight loss was 33.6 kg at 6 months. The concomitant serum ENG concentrations decreased currently with weight loss but remained above the minimum concentration required for effective contraceptive effect of the implant for at least 6 months following RYGB (average, 170 pg/mL). The concentrations observed before weight loss were lower than in normal-weight women, but decreases in ENG concentrations following implant insertion were similar. CONCLUSION: These unique data in morbidly obese women highlight the need for further pharmacokinetic studies of contraceptive agents in obese women during weight loss.

No effect of Implanon® on inflammatory cardiovascular parameters.

OBJECTIVE: Recently, we found decreased levels of C-reactive protein (CRP) during use of the low-dosed contraceptive implant Implanon®. To further elucidate, whether this finding might be a sign for a lower inflammatory reaction and is associated with changes in levels of other cytokines, we investigated the effect of this implant on interleukin-6 (IL-6) and adiponectin. Plasma lipids and sex hormone levels have been shown to interact with the investigated parameters in vivo and in vitro. Therefore these parameters were measured as well. DESIGN: Prospective case-control study. SETTING: Family-planning centre, University hospital. SUBJECTS: Thirty-six non-smoking women with regular cycles. INTERVENTIONS: Blood samples for the measurements were taken in the early follicular phase of the cycle in both groups. A second sample was taken 12 weeks after Implanon insertion or in the controls during the early follicular phase of cycle 4. RESULTS: Implanon did not cause significant changes in IL-6, adiponectin or lipoprotein (Lp)(a). At baseline, there was a significant positive correlation between IL-6 and CRP and a negative correlation between adiponectin and CRP. CONCLUSION: We did not observe a negative impact of Implanon on risk markers for atherosclerotic disease such as IL-6, adiponectin, and Lp(a). These data are reassuring for clinicians who prescribe progestagen-only preparations as first choice contraceptives in females with cardiovascular risk factors.

Budesonide quantification by HPLC coupled to atmospheric pressure photoionization (APPI) tandem mass spectrometry. Application to a comparative systemic bioavailability of two budesonide formulations in healthy volunteers.

In the present study, a novel, fast, sensitive and robust method to quantify budesonide in human plasma using 3-keto-desogestrel as the internal standard (IS) is described. The analyte and the IS were extracted from human plasma by liquid-liquid extraction (LLE) using ether. Extracted samples were analyzed by high performance liquid chromatography coupled to Atmospheric pressure photoionization tandem mass spectrometry (HPLC-APPI-MS/MS). Chromatography was performed isocratically on a C18, 5 µm analytical column. The temperature of the autosampler was kept at 6 °C and the run time was 4.00 min. A linear calibration curve over the range 7.5-1000 pg ml⁻¹ was obtained and the lowest concentration quantified was 7.5 pg ml⁻¹, demonstrating acceptable accuracy and precision. This analytical method was applied in a relative bioavailability study in order to compare a test budesonide 64 µg/dose nasal spray formulation vs. a reference 64 µg/dose nasal spray formulation (Budecort Aqua) in 48 volunteers of both sexes. The study was conducted in an open randomized two-period crossover design and with a one-week washout period. Plasma samples were obtained over a 14 h interval. Since the 90% CI for both C(max), AUC(last) and AUC(0-inf) were within the 80-125% interval proposed by the Food and Drug Administration and ANVISA, it was concluded that budesonide 64 µg/dose nasal spray was bioequivalent to Budecort Acqua® 64 µg/dose nasal spray, according to both the rate and extent of absorption.

Hormonal synchronization of the menstrual cycles of pigtail macaques to facilitate biomedical research including modeling HIV susceptibility.

BACKGROUND: Menstrual cycle synchronization of female pigtail macaques could prove an invaluable resource in studies of the reproductive tract, associated infections, and other potential research fields. We tested whether use of an oral progesterone and estradiol combination tablet could synchronize menstrual cycles following treatment discontinuation. METHODS: Daily desogestrel 0.075 mg and ethinyl estradiol 0.01 mg were administered orally to three pigtail macaques at visual onset of perineal sex swelling and were continued until all animals had received it for at least 45 days. The hormones were discontinued, and these three macaques and three controls were observed for menstruation and had blood progesterone and estrogen measured over an additional 2-month period. RESULTS: All treatment animals showed spontaneous menstrual cycle synchronization for 2 months after menstrual cycling resumed. CONCLUSION: Progesterone and estradiol combination therapy can be used in pigtail macaques to induce synchronized cycling that persists in the absence of on-going hormone treatments.