A randomized single-blind non-inferiority trial of delayed start with drospirenone-only and ethinyl estradiol-gestodene pills for ovulation inhibition.

We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18-45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and - 0.11 (95% CI: - 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7-9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001 .

Oral medroxyprogesterone acetate for the use of ovulation suppression in in vitro fertilization: a cohort trial.

OBJECTIVE: To broadly assess the efficacy of medroxyprogesterone acetate (MPA) for ovulatory suppression during in vitro stimulation compared with gonadotropin-releasing hormone (GnRH) antagonist cycles. DESIGN: Cohort trial. SETTING: A single academic-affiliated private fertility practice. PATIENTS: Patients of all diagnoses aged 18-44 years undergoing autologous in vitro fertilization (IVF) for fertility treatment between 2020 and 2023. INTERVENTIONS: Comparison of MPA vs. antagonist IVF stimulation cycles. MAIN OUTCOME MEASURES: Rates of premature ovulation, oocyte and embryo yield, embryo quality, pregnancy rates, and logistical benefits. RESULTS: Prospective data was collected on 418 patients who underwent MPA protocol ovarian stimulation (MPA group), which was compared with 419 historical control gonadotropin hormone-releasing hormone antagonist cycles (control group). Age was similar between groups (35.6 ± 4.6 vs. 35.7 ± 4.8 years; P = .75). There were no cases of premature ovulation in the MPA group compared with a total of five cases in the control group (0% vs. 1.2%; risk ratio [RR] = 0.09; 95% confidence interval [CI], 0.01, 1.66). No differences were seen between number of oocytes retrieved (14.3 ± 10.2 vs. 14.3 ± 9.7; P = .83), blastocysts (4.9 ± 4.6 vs. 5.0 ± 4.6; P = .89), or euploid blastocysts (2.4 ± 2.6 vs. 2.2 ± 2.4; P = .18) in the MPA vs. control group respectively. Clinical pregnancy rate was similar between groups (70.4% vs. 64.2%; RR = 0.92; 95% CI, 0.72, 1.18). There was no difference in length of IVF stimulation or dose of stimulation medications. Patients in the MPA group saved an average of $491 ± $119 on medications, had an average of one less monitoring visit (4.4 ± 0.9 vs. 5.6 ± 1.1; P<.01), and 5.0 ± 1.2 less injections per cycle. When adjusting for age and ovarian reserve, protocol group (MPA vs. control) did not influence having an embryo available for transfer (76.6% vs. 73.4%; adjusted RR = 1.05; 95% CI, 0.94, 1.14). CONCLUSION: For ovulatory suppression during IVF cycles, MPA was effective at preventing ovulation while demonstrating similar cycle and reproductive outcomes, with the additional benefits of patient cost savings, increased convenience with decreased number of visits, and fewer injections.

Anticoncepção oral e hipotrofia muscular: existe correlação? / Oral contraception and muscle atrophy: is there a correlation?

As pílulas anticoncepcionais consistem na formulação combinada de um estrogênio e um progestagênio ou em apresentações simples de progestagênio isolado com a finalidade de bloquear a ovulação e alterar as condições do útero e das tubas uterinas, bloqueando parcialmente a foliculogênese e a inibição do pico de gonadotrofinas. Desse modo, no que concerne à temática, diversas publicações na mídia de ampla divulgação afirmam que os anticoncepcionais orais têm papel importante na sarcopenia e na hipotrofia, incluindo perda de força muscular e redução do desempenho físico. Assim, o presente trabalho tem por objetivo avaliar, por meio de pesquisas de artigos, a correlação entre anticoncepcionais hormonais orais e hipotrofia muscular. Foi concluído que os artigos científicos especializados no tema são ainda bastante inconclusivos, sugerindo que há indicações de que usuárias de anticoncepcional oral sejam mais suscetíveis ao dano muscular induzido por exercícios, contudo ainda não há consenso.

Anticonception pills consist of a combined formulation of an estrogen and a progestogen or simple presentations of progestogen alone with the purpose of blocking ovulation and altering the conditions of the uterus and uterine tubes, partially blocking folliculogenesis and inhibiting the gonadotropin peak. Thus, with regard to the subject, several widely publicized media publications claim that oral contraceptives play an important role in sarcopenia and hypotrophy, including loss of muscle strength and reduced physical performance. So, the present work aims to evaluate through article searches the correlation between oral hormonal contraceptives and muscle hypotrophy. It was concluded that scientific articles specialized on the subject are still quite inconclusive, suggesting that there are indications that oral contraceptive users are more susceptible to exercise-induced muscle damage, however there is still no consensus.

The effectiveness of quick starting oral contraception containing nomegestrol acetate and 17-ß estradiol on ovulation inhibition: A randomized controlled trial.

To determine the effectiveness of quick starting combined oral contraception (COC) contain 2.5 mg nomegestrol acetate and 1.5 mg estradiol (NOMAC/E2) comparing with 0.075 mg gestodene and 0.02 mg ethinyl estradiol (GS/EE) on ovarian ovulation inhibition rate, we conducted a non-inferiority randomized controlled trial involving 69 healthy female volunteers aged 18-40 years who had normal menstrual history and were randomized at a 2:1 ratio to take one pack of COC containing either NOMAC/E2 (study group) or GS/EE (control group) starting on menstrual cycle Day7-9. The ovarian activity was assessed by using Hoogland and Skouby grading. Forty-six and 23 participants were randomized to NOMAC/E2 and GS/EE groups, respectively. Baseline characteristics were similar between groups. No significant difference was observed between the study and control groups for ovulation inhibition rate (93.4% vs. 95.6%, risk difference: -2.2%, 95% CI: -13.1, 8.8), ovarian quiescence rate (91.2% vs. 91.2%, P = 1.000), persistent cyst rate (2.2% vs. 4.4%, P = 1.000), and ovulation rate (6.6% vs. 4.4%, P = 1.000). Quick starting COC during day7-9 of menstrual cycle can inhibit ovulation for more than 90%. The quick starting NOMAC/E2 is non-inferior to GS/EE for preventing ovulation and suppressing follicular growth.

Oestrogen-free oral contraception with a 4 mg drospirenone-only pill: new data and a review of the literature.

Purpose: The contraceptive pill is an effective and safe method of preventing pregnancy. The progestins used for contraception either are components of a combined hormonal contraceptive (tablets, patches or vaginal rings) or are used alone in progestin-only formulations. Progestin-only contraceptives are available as daily oral preparations, subcutaneous or intramuscular injectables (every 1-3 months), subdermal implants (every 3-5 years) and intrauterine systems (every 3-5 years). Long-acting progestins are highly effective in typical use and have a very low risk profile and few contraindications.Material and Methods: A new progestin-only, oestrogen-free contraceptive, drospirenone, in a dosage of 4 mg/day in a 24/4 regimen, has received regulatory approval in the USA and the EU. The molecule has antigonadotropic, antimineralocorticoid, antiestrogenic and antiandrogenic properties.Results: The regimen was chosen to improve the bleeding profile; maintain plasma oestradiol levels at those of the early follicular phase, to avoid hypoestrogenism; and preserve efficacy even with a missed pill, as drospirenone has a half-life of 30-34 h.Conclusions: Clinical studies have shown good efficacy, very low cardiovascular side effects and a favourable bleeding pattern, as well as maintenance of ovulation inhibition after scheduled 24 h delays in pill intake.

Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17ß-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing.

PURPOSE: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%. METHODS: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17ß-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles. RESULTS: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups. CONCLUSIONS: Contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or 500-900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.

Missed pills: frequency, reasons, consequences and solutions.

OBJECTIVES: Oral hormonal contraception is an effective contraceptive method as long as regular daily intake is maintained. However, a daily routine is a constraint for many women and can lead to missed pills, pill discontinuation and/or unintended pregnancy. This article describes the frequency of inconsistent use, the consequences, the risk factors and the possible solutions. METHODS: The article comprises a narrative review of the literature. RESULTS: Forgetting one to three pills per cycle is a frequent problem among 15-51% of users, generally adolescents. The reasons for this are age, inability to establish a routine, pill unavailability, side effects, loss of motivation and lack of involvement in the initial decision to use oral contraceptives. The consequences are 'escape ovulations' and, possibly, unintended pregnancy. Solutions are either to use a long-acting method or, for women who prefer to take oral contraceptives, use a continuous or long-cycle regimen to reduce the risks of follicular development and thus the likelihood of ovulation and unintended pregnancy. A progestogen with a long half-life can increase ovarian suppression. CONCLUSIONS: For women deciding to use oral contraceptives, a shortened or eliminated hormone-free interval and a progestogen with a long half-life may be an option to reduce the negative consequences of missed oral contraceptive pills.

Serum caffeine and paraxanthine concentrations and menstrual cycle function: correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study.

BACKGROUND: Clinicians often recommend limiting caffeine intake while attempting to conceive; however, few studies have evaluated the associations between caffeine exposure and menstrual cycle function, and we are aware of no previous studies assessing biological dose via well-timed serum measurements. OBJECTIVES: We assessed the relation between caffeine and its metabolites and reproductive hormones in a healthy premenopausal cohort and evaluated potential effect modification by race. DESIGN: Participants (n = 259) were followed for ≤2 menstrual cycles and provided fasting blood specimens ≤8 times/cycle. Linear mixed models were used to estimate associations between serum caffeine biomarkers and geometric mean reproductive hormones, whereas Poisson regression was used to assess risk of sporadic anovulation. RESULTS: The highest compared with the lowest serum caffeine tertile was associated with lower total testosterone [27.9 ng/dL (95% CI: 26.7, 29.0 ng/dL) compared with 29.1 ng/dL (95% CI: 27.9, 30.3 ng/dL), respectively] and free testosterone [0.178 ng/mL (95% CI: 0.171, 0.185 ng/dL) compared with 0.186 ng/mL (95% CI: 0.179, 0.194 ng/dL), respectively] after adjustment for age, race, percentage of body fat, daily vigorous exercise, perceived stress, depression, dietary factors, and alcohol intake. The highest tertiles compared with the lowest tertiles of caffeine and paraxanthine were also associated with reduced risk of anovulation [adjusted RRs (aRRs): 0.39 (95% CI: 0.18, 0.87) and 0.40 (95% CI: 0.18, 0.87), respectively]. Additional adjustment for self-reported coffee intake did not alter the reproductive hormone findings and only slightly attenuated the results for serum caffeine and paraxanthine and anovulation. Although reductions in the concentrations of total testosterone and free testosterone and decreased risk of anovulation were greatest in Asian women, there was no indication of effect modification by race. CONCLUSION: Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women.

A two-centre, open-label, randomised study of ovulation inhibition with three transdermal contraceptive patches, each containing different amounts of ethinyl estradiol and gestodene in healthy, young women.

Here we report the findings of a two-centre, open-label, randomised, Phase IIa study designed to investigate whether an ethinyl estradiol (EE)/gestodene (GSD) patch that has been developed (referred to herein as the 'EE/GSD patch') reliably inhibits ovulation in comparison with patches delivering lower doses of these hormones. The study rationale was to provide justification of the doses of EE and GSD selected for the EE/GSD patch. Healthy women, aged 18-35 years, were randomised to receive treatment with either the EE/GSD patch, a 'reduced-GSD patch' (delivering similar amounts of EE and approximately half the amount of GSD) or a 'reduced-EE/GSD patch' (delivering half the amount of EE and GSD). Treatment was administered for three 28-day cycles (three × 7 patch-wearing days, plus a 7-day patch-free interval). The primary pharmacodynamic variable was the percentage of women with ovulation in at least one of Cycles 2 and/or 3, as indicated by Hoogland score. Pharmacokinetic parameters for EE and GSD were also measured. Results indicated that the EE/GSD patch effectively suppressed ovulation, while patches delivering lower doses of EE and GSD were less effective for this purpose. All three patches showed comparable tolerability.

Emergency contraception: Focus on the facts.

Significant progress on contraception, and in particular emergency contraception, has been made in the past decade. Emergency contraception was first introduced as a stand-alone prescription in 1998, and the interaction of politics and medicine meant a tumultuous course to the drug becoming available over the counter. This article reviews how emergency contraception works, the effectiveness of different methods, pros and cons, and the history of emergency contraception.

A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen.

OBJECTIVES: Progestogen-only pills (POPs) are safer with respect to cardiovascular risks than contraceptives containing estrogens. Despite the increased contraceptive efficacy of a desogestrel-only pill compared with a traditional POP, POPs are still not widely used due to an unpredictable bleeding pattern. A new POP containing 4 mg drospirenone has been developed with a 24/4 intake regimen which may improve the bleeding pattern. The objectives of this study were to investigate ovulation inhibition with the new drospirenone-only pill in comparison with the desogestrel-only pill and, in addition, to assess the effects on cervical mucus permeability and bleeding. METHODS: Sixty-four healthy volunteers with proven ovulatory cycles were randomised and treated with either the drospirenone-only or the desogestrel-only pill during two 28-day cycles. Follicular diameter, endometrial thickness, and serum estradiol (E2) and progesterone concentrations were measured and Hoogland scores were determined. Additionally, cervical mucus scores, bleeding and return of ovulation were assessed. RESULTS: Both treatments effectively inhibited ovulation. Follicular diameter, E2 levels and Hoogland scores were equal, demonstrating efficient ovarian suppression. One subject in each group had a Hoogland score of 6, but the criteria for normal luteal activity were not fulfilled. In both groups, ovulation did not occur before day 9 of the post-treatment cycle. Cervical mucus permeability was suppressed in both groups. The median number of bleeding and spotting days was lower in the drospirenone group. CONCLUSIONS: The new drospirenone-only pill inhibited ovulation as effectively as the desogestrel-only pill despite the 4-day hormone-free interval.

Formulation and testing of a non-steroidal aromatase inhibitor intravaginal device for the control of ovarian function in cattle.

The study was designed to formulate intravaginal devices that provide biologically active circulating concentrations of an aromatase inhibitor for a minimum of 4 days, and to determine their physiologic effects in cattle. Three compounds with estradiol inhibitory capability (letrozole, anastrozole and fenbendazole) were tested in vitro using bovine granulosa cell culture. Letrozole was found to be the most efficient and potent inhibitor. A wax-based vehicle was selected for further development of a letrozole intravaginal device based on its steady release rate. Cycling heifers were assigned randomly to be given an intravaginal device containing wax plus gel coat (n=4), wax formulation (n=4), no formulation (blank device, control, n=4). Intravaginal devices were inserted on Day 3 (Day 0=ovulation) and kept in place for 8 days. The addition of a letrozole-containing gel coating hastened the initial increase on plasma concentrations, while the letrozole-containing wax-based vehicle maintained prolonged delivery from the intravaginal device. The dominant follicle diameter profile was larger in heifers treated with the wax plus gel coat device (P<0.04), and the interwave interval was prolonged in heifers in the letrozole-treated groups compared to controls (P<0.001). Plasma estradiol concentrations were reduced significantly in the letrozole-treated groups. Plasma progesterone concentrations were lower in the wax letrozole-treated group (P<0.02). We concluded that wax base plus gel coat intravaginal devices are suitable for the development of a letrozole-based protocol for the synchronization of ovulation in cattle. It effectively reduced estradiol production resulting in prolonged dominant follicle growth and lifespan, without adversely affecting progesterone production.

Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial.

OBJECTIVE: This study describes ovarian activity suppression of a 21/7-active low-dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. STUDY DESIGN: The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. RESULTS: Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17ß-estradiol, follicle-stimulating hormone and luteinizing hormone levels. CONCLUSIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. IMPLICATIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens.

On-label and off-label drug use in the treatment of endometriosis.

Endometriosis, characterized by the presence of endometrial glands and stroma in extrauterine locations, is a significant cause of pelvic pain and infertility, as well as a major health care burden. Although Food and Drug Administration (FDA)-approved treatments are available, the use of "off-label" medications for endometriosis is widespread. In this review, we provide an overview of the current FDA-approved treatments, followed by a detailed review of the major "off-label" treatments being used in the United States and worldwide, including efficacy, side effects, drug interactions, contraindications, and anomaly risks.

A phase 1, multicentre, open-label study to evaluate ovarian follicular activity and hormone levels with an extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation.

OBJECTIVES: To evaluate the effect on ovarian follicular activity of the 91-day extended-regimen combined oral contraceptive (COC), consisting of 84 days of levonorgestrel (LNG)/ethinylestradiol (EE) 150 µg/30 µg tablets plus seven days of EE 10 µg tablets in place of placebo. METHODS: This was a phase 1, open-label study. Ovarian follicular activity was classified via the Hoogland and Skouby method. Safety and tolerability as well as return to ovulation were assessed. RESULTS: Of the 35 subjects included in the efficacy analysis, luteinized, unruptured follicles, or ovulation were detected in 0 of 35 cycles during the first 28-day interval; 1 of 35 cycles (2.9%) in the second 28-day interval; and 2 of 35 cycles (5.7%) in the final 35-day interval. The ovarian activity rate over the entire 91-day treatment period was 2.9%. There was a low incidence of treatment-emergent adverse events. Ovulation returned in most subjects (77.1%, 27/35) within 32 days following the last dose of COC. CONCLUSIONS: The 91-day extended-regimen COC with low-dose EE supplementation was found to be effective in suppressing ovarian activity and inhibiting ovulation and was well tolerated. Return to ovulation was rapid, occurring within approximately one month after discontinuation of COC.

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception.

OBJECTIVE: To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles. STUDY DESIGN: This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 µg/day) or a high-dose (2500 µg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns. RESULTS: All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding. CONCLUSION: The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-µg/day ring. IMPLICATIONS: The 3-month CVR delivering UPA 2500 µg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment.

Impact of body mass index on suppression of follicular development and ovulation using a transdermal patch containing 0.55-mg ethinyl estradiol/2.1-mg gestodene: a multicenter, open-label, uncontrolled study over three treatment cycles.

BACKGROUND: Body mass index (BMI) may influence ovulation inhibition resulting from transdermal hormone delivery. Investigation of this effect is important given the high prevalence of obesity in the US. STUDY DESIGN: This open-label, uncontrolled, Phase 2b trial stratified 173 women (18-35 years) according to three BMI groups (Group 1, n = 56, ≤ 30 kg/m²; Group 2, n = 55, > 30 kg/m² and ≤ 35 kg/m²; and Group 3, n = 47, > 35 kg/m²). Women used a contraceptive patch containing 0.55-mg ethinyl estradiol (EE) and 2.1-mg gestodene (GSD). The EE/GSD patch was used weekly for three 28-day cycles (one patch per week for 3 consecutive weeks followed by a 7-day, patch-free interval), and its effect on ovulation was assessed by the Hoogland score, a composite score that comprises transvaginal ultrasound and estradiol (E2) and progesterone levels every 3 days in Cycles 2 and 3. Evaluation of pharmacokinetic parameters was a secondary aim of the study, and blood samples for analytic determination of EE, GSD and sex hormone-binding globulin were taken during the pretreatment cycle, Cycle 2 and Cycle 3. Compliance was assessed using diary information and serum drug levels. RESULTS: In the per-protocol set, there were only six ovulations during the study, and no participant ovulated in both study cycles. One ovulation occurred in Group 1, three in Group 2 and two in Group 3. Ovulation inhibition was unaffected by BMI; in all groups, most participants had Hoogland scores of 1 or 2 (i.e., follicle-like structures < 13 mm: Group 1, ≤ 30 kg/m², 80.0% in Cycle 2, 85.7% in Cycle 3; Group 2, > 30 kg/m² and ≤ 35 kg/m², 61.4% in Cycle 2, 75.0% in Cycle 3; Group 3, > 35 kg/m², 78.0% in Cycle 2, 72.5% in Cycle 3). Serum levels of follicle-stimulating hormone, luteinizing hormone, E2 and progesterone were similar between groups. Body weight had a limited effect on EE clearance that was unlikely to be clinically relevant. CONCLUSION: The EE/GSD patch provided effective ovulation inhibition, even in women with higher BMI. IMPLICATIONS: This is the largest-to-date study of physiologic endpoints and found no clinically important differences in ovarian suppression among obese and normal-weight users of the EE/GSD contraceptive patch, thus providing reassurance that obese women can achieve the same high level of contraceptive protection as normal-weight users.

Efficacy and safety of a combined oral contraceptive containing estradiol valerate/dienogest: results from a clinical study conducted in North America.

BACKGROUND: This study investigated the efficacy and safety of a combined oral contraceptive (COC) containing estradiol valerate/dienogest (E2V/DNG). METHODS: This was a multicenter, noncomparative, 13-cycle (extended to 28 cycles) study conducted in the United States and Canada. Contraceptive efficacy was calculated as a Pearl Index for 13 cycles, based on all on-treatment pregnancies; bleeding patterns were calculated based on bleeding and spotting information recorded daily in diary cards. Safety events during a 16-month extension study were added to the 1-year data. RESULTS: In total, 499 women, aged 18-35 years, were enrolled, and 490 of them were included in the full analysis set for contraceptive efficacy. Five pregnancies occurred in the first year (unadjusted Pearl Index=1.64). In cycles 1-12, an average 23.5% of women had absent scheduled (withdrawal) bleeding. Among women with scheduled (withdrawal) bleeding, bleeding started after a median of 2 days after intake of the last DNG-containing pill. For safety, data included from 147 women followed over an additional 16 months were added to the original 13-cycle data set. Treatment-related adverse events (AEs) occurred in 51.8% of women; 14.9% discontinued because of AEs over the entire 28-month study period. CONCLUSION: A COC with E2V and DNG was shown to provide effective contraception in women aged 18-35 years in North America.

Aromatase inhibitor treatment with an intravaginal device and its effect on pre-ovulatory ovarian follicles in a bovine model.

BACKGROUND: Letrozole, a non-steroidal aromatase inhibitor, prevents the body from producing its own estrogen. The objectives of the present study were to test the hypotheses that letrozole treatment, initiated prior to selection of the preovulatory dominant follicle, will induce the growth of more than one follicle to a pre-ovulatory size, and will delay ovulation. METHODS: Post-pubertal beef heifers were given two luteolytic doses of PGF (12 h apart) and monitored by ultrasonography for ovulation. Five to eight days later, ovarian follicular wave emergence was synchronized by ultrasound-guided transvaginal follicular ablation (Day 0=wave emergence) and a luteolytic dose of PGF was given 60 and 72 h later. On Day 1, heifers were divided randomly into two groups (n=15/group) and an intravaginal device containing 1 g of letrozole or a blank device (control) was inserted. The intravaginal devices were removed on Day 7, or at the time of ovulation, whichever occurred first. Transrectal ultrasonography and blood sample collection were performed daily from the day of ablation to 12 days after subsequent ovulation. RESULTS: The mean (+/-SEM) interval from device placement to ovulation was longer in letrozole-treated animals compared to controls (6.1+/-0.25 vs 5.1+/-0.26 days, respectively; P<0.01). Single dominant follicles were present in both groups. The day-to-day diameter profiles of the dominant follicles of the ovulatory wave were larger (P<0.05) and the maximum diameters greater in letrozole-treated heifers (14.6+/-0.51 vs 12.4+/-0.53 mm, respectively; P<0.01). The diameter profile of the corpus luteum (CL) that formed after treatment did not differ between groups; however, plasma progesterone concentrations were higher (P<0.01) in heifers treated with letrozole. Estradiol concentrations were reduced following letrozole treatment (P<0.05), although a preovulatory rise of estradiol occurred in both groups. CONCLUSIONS: Administration of letrozole with an intravaginal device during growth of the ovulatory follicle delayed ovulation by 24 h and resulted in the formation of a CL that secreted higher levels of progesterone. A sustained-release intravaginal device may be useful for the development of an aromatase inhibitor-based protocol to control ovulation for herd synchronization and to enhance fertility by increasing circulating progesterone concentrations during the first 7 days post-ovulation in cattle.