Effects on serum hormone levels of low-dose estrogen in place of placebo during the hormone-free interval of an oral contraceptive

doi:10.1016/j.contraception.2007.09.010

Contraception

Volume 77, Issue 1, January 2008, Pages 34-39

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Abstract

Background

The study was conducted to evaluate the effects of low-dose estrogen compared to placebo on ovarian activity during the traditional 7-day hormone-free interval (HFI) of an oral contraceptive (OC).

Study Design

Women were randomized to placebo or low-dose estrogen for 7 days during the HFI. Serum levels of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone and inhibin B were obtained before, during and after treatment.

Results

Mean hormone levels remained constant or only increased slightly for the low-dose estrogen group compared to greater more sustained increases observed for the placebo group. Estradiol, FSH and inhibin B levels were substantially higher for those on placebo. Differences were most noticeable by the end of the HFI and persisted into the subsequent cycle.

Conclusion

Subjects receiving low-dose estrogen for 7 days during the HFI demonstrated more pronounced ovarian suppression compared to placebo as evidenced by attenuation of increases in serum inhibin B, FSH and estradiol levels.

Introduction

Oral contraceptives (OCs) are an effective method of birth control and are utilized by a large number of women in the United States at some time during their reproductive years. Despite excellent efficacy, it is recognized that OCs do not provide complete suppression of ovarian follicular development [1], [2], [3]. During the standard 7-day hormone-free interval (HFI) of a conventional 28-day OC regimen, ethinyl estradiol (EE) and the progestin component are cleared from the circulation approximately 2 to 3 days after the last active combination pill is taken, allowing several hormone-free days during which recovery of the hypothalamic–pituitary–ovarian axis occurs [1], [4], [5]. The pituitary gland begins to secrete gonadotropins and levels of follicle-stimulating hormone (FSH), inhibin B and estradiol increase. As a result, ovarian follicular growth may occur. The hormonal events that take place during the 7-day HFI resemble those observed during the early follicular phase of a normal spontaneous menstrual cycle and could lead to an increased risk of escape ovulation [4], [5].

Ovarian activity during use of OCs has been correlated with increased intermenstrual bleeding, and enhanced ovarian suppression may result in improved cycle control [6]. Also, it has been suggested that the 7-day HFI may be associated with hormone-withdrawal symptoms (due to fluctuations in endogenous hormone levels) that could potentially be minimized by modification of the placebo interval [5], [7], [8], [9]. Increased pituitary–ovarian suppression may decrease the risk of follicular development, escape ovulation and unintended pregnancy and potentially contribute to improvements in hormone-related symptoms and breakthrough bleeding.

Methods for maintaining pituitary–ovarian suppression by modification of the HFI have included shortening the duration of the HFI to less than 7 days, continuous administration of active combination tablets and using low-dose estrogen in place of placebo during the usual HFI [5], [10], [11], [12], [13], [14]. This report describes the impact on ovarian activity of supplementing the usual 7-day HFI with 10 mcg/day EE compared to placebo in women using a 28-day conventional OC containing 150 mcg of levonorgestrel (LNG)/30 mcg of EE.

Section snippets

Study design and population

This was a prospective, multicenter, randomized, open-label study conducted at three sites in the United States from July 2005 to November 2005. The study was conducted in accordance with the Declaration of Helsinki and applicable guidelines for Good Clinical Practice; the Novum Independent Institutional Review Board reviewed and approved the protocol and informed consent prior to study initiation.

Premenopausal, nonpregnant, nonlactating females 18 to 35 years old, with no history of ovarian

Study population

Twenty-six subjects were enrolled and randomized to one of two treatment arms (10 mcg of EE, n=11; or placebo, n=15). Randomization was stratified by site, and there were incomplete randomization blocks at each site, so slightly more subjects were treated with placebo than with EE. All randomized subjects completed the study. The demographic characteristics of the subjects are summarized in Table 1. There were no differences between the two treatment groups.

The intent-to-treat (ITT) cohort

Discussion

Based on the endocrine data obtained during this study (estradiol, FSH, LH and inhibin B levels), the administration of 10 mcg/day of EE during the traditional 7-day HFI was associated with substantially greater and more persistent suppression of ovarian function than provided by placebo in women who were already taking a 28-day OC with active combination tablets containing 150 mcg of LNG/30 mcg of EE for the preceding 21 days. While this study evaluated hormone levels in users of a

Acknowledgment

This study was funded by Duramed Research, Bala Cynwyd, PA. The data were presented as an oral presentation on October 23, 2006, at the 62nd Annual Meeting of the American Society of Reproductive Medicine in New Orleans, LA.

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Effect of Extended 30 μg Ethinyl Estradiol with Continuous Low-Dose Ethinyl Estradiol and Cyclic 20 μg Ethinyl Estradiol Oral Contraception on Adolescent Bone Density: A Randomized Trial
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Citation Excerpt :
Seasonique (Teva Branded Pharmaceutical Products R&D, Inc, Frazer, PA) is an 84/7 regimen currently approved in the United States and Canada that includes 84 days of levonorgestrel (LNG) 150 μg and ethinyl estradiol (EE) 30 μg followed by 7 days of EE 10 μg (LNG/EE ER). Substituting low-dose EE for placebo or no treatment in the hormone-free interval has been shown to increase ovarian suppression and might decrease the risk of unscheduled bleeding, a side effect frequently reported in early cycles of extended COC use.12,13 Despite their increasing popularity, data on the skeletal effects and skeletal safety of extended COC regimens are limited.
To compare changes in lumbar spine bone mineral density after 12 months of a 91-day extended regimen or 28-day combined oral contraceptive with those in a healthy reference group not using hormonal contraceptives.
Phase 2, multicenter, open-label, randomized, controlled study.
Forty-five academic centers, clinical research centers, and community practices in the United States.
Eight hundred twenty-nine postmenarcheal adolescent girls aged 12-18 years.
Adolescents were randomly assigned to 91-day levonorgestrel (LNG)/ethinyl estradiol (EE) extended regimen (84 days of LNG 150 μg/EE 30 μg with 7 days of EE 10 μg [LNG/EE extended regimen]) or 28 days of LNG/EE (21 days of LNG 100 μg/EE 20 μg with 7 days of placebo [LNG/EE 21/7]) for 12 months. A reference group not seeking hormonal contraception was also evaluated.
The primary end point was mean percent change in lumbar spine bone mineral density measured using dual-energy x-ray absorptiometry.
Of 1361 adolescents randomized/enrolled, 829 were included in the primary analysis. Mean changes in lumbar spine bone mineral density were +2.26% with LNG/EE extended regimen, +1.45% with LNG/EE 21/7, and +2.50% in the reference group. Noninferiority of the LNG/EE extended regimen compared with the reference group was shown. A statistically significant treatment difference was found between LNG/EE 21/7 and the reference group (1.05%; 95% confidence interval, 0.61%-1.49%) but not between LNG/EE extended regimen and the reference group (0.23%; 95% confidence interval, −0.20% to 0.67%). No new safety signals were noted.
Compared with the reference group, bone accrual was statistically significantly lower among LNG/EE 21/7 users but not among LNG/EE 30-μg extended regimen users. Additional research is needed to clarify the clinical relevance of these findings.
Rationale for eliminating the hormone-free interval in modern oral contraceptives
2016, International Journal of Gynecology and Obstetrics
Although most low-dose combined oral contraceptives (COCs) include 7-day hormone-free intervals (HFIs), these COCs could incompletely suppress ovarian activity.
To review the impact of HFIs on ovarian suppression and tolerability, and evaluate the utility of COCs without traditional 7-day HFIs.
PubMed was searched for clinical studies published in English between January 1980 and April 2015 on the impact of HFIs and HFI modifications in COCs.
Articles assessing contraceptive efficacy or tolerability as the primary focus were included.
Abstracts of 319 articles were screened.
Analysis of the 161 articles selected revealed that suppression of ovarian activity with low-dose COCs with 7-day HFIs is suboptimal. Loss of ovarian suppression during 7-day HFIs is commonly associated with follicular development, and most dominant follicles appear during this period. By contrast, increased ovarian suppression was noted in regimens that shortened or eliminated the HFI, or that substituted low-dose ethinyl estradiol for the HFI.
Extended regimens with modified HFIs may provide greater ovarian suppression with the potential for increased contraceptive effectiveness. Additional research is needed to evaluate whether COC regimens that include 10 μg ethinyl estradiol instead of an HFI may improve tolerability.
Efficacy and safety of a 21/7-active combined oral contraceptive with continuous low-dose ethinyl estradiol
2016, Contraception
Citation Excerpt :
One such modification is to use low-dose ethinyl estradiol (EE) (10 mcg) instead of placebo or no treatment during the last 7 days of the cycle. Studies comparing 28-day regimens with and without low-dose EE during the traditional HFI demonstrate that low-dose EE during the last week of the cycle suppresses pituitary–ovarian activity and ovarian follicular activity [6,9,10]. COCs that incorporate both newer progestins and changes to the traditional HFI may provide useful and well-tolerated options for women seeking pregnancy prevention.
Substituting low-dose ethinyl estradiol (EE) for the hormone-free interval in combined oral contraceptives (COCs) may enhance ovarian suppression and improve tolerability. This noncomparative phase 3 study evaluated the efficacy and safety of a 21/7-active COC regimen including 21 days of desogestrel (DSG)/EE followed by 7 days of EE.
This multicenter, open-label, phase 3, single-arm study enrolled sexually active women aged 18–40 years at risk for pregnancy. Women received up to 1 year, or 13 consecutive 28-day cycles, of DSG 150 mcg/EE 20 mcg for 21 days and EE 10 mcg alone for 7 days. Participants kept diaries to record compliance, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index (PI) and life-table approach. Safety and tolerability were assessed primarily through reported adverse events (AEs).
A total of 2858 women enrolled and 1680 completed the study. Forty-six pregnancies in 2401 women aged 18–35 years occurred after COC initiation and up to 7 days after last DSG/EE or EE-only tablet was taken. When cycles in which another contraceptive method was used were excluded, the PI was 2.68 [95% confidence interval (CI), 1.96–3.57]. The cumulative pregnancy rate after 1 year of treatment was 2.47% (95% CI, 1.85–3.29) for all users aged 18–35 years. When only cycles during which women considered compliant were included, the PI was 2.00 (95% CI, 1.39–2.80). AEs were similar to those seen with other oral contraceptives.
This 21/7-active DSG/EE COC with 7 days of low-dose EE was efficacious and well tolerated for pregnancy prevention.
This phase 3 open-label study demonstrated that a 21/7-active COC regimen including 21 days of DSG 150 mcg/EE 20 mcg and 7 days of EE 10 mcg was efficacious and well tolerated for pregnancy prevention.
Ovulatory effects of three oral contraceptive regimens: A randomized, open-label, descriptive trial
2015, Contraception
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Adherence to COC treatment regimens is variable, and poor adherence increases the risk of reduced ovarian suppression and escape ovulation, especially if the missed pills extend the HFI within a low-dose EE regimen [19,20]. The current study findings are consistent with previous studies showing that the addition of low-dose EE during the traditional HFI results in a delay in the rise of estradiol and provides effective suppression of ovarian follicular activity [8,13,14]. In the current study, similar patterns of hormonal suppression, including E2, P, FSH and LH, were shown in the subjects who received the 21/7-active COC regimen with only low-dose EE during the traditional HFI and the subjects who received extended COC in the 24/4 DRSP/EE+4 days PBO regimen.
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.
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 3 mg 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.
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+4 days PBO and 1% (95% CI 0–3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17β-estradiol, follicle-stimulating hormone and luteinizing hormone levels.
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+7 days PBO) regimens.
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+4 days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens.
Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive
2014, Contraception
To evaluate the efficacy and safety of an ascending-dose, extended-regimen (ADER) combined oral contraceptive consisting of levonorgestrel (LNG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 42 days, LNG 150 mcg/EE 25 mcg for 21 days, LNG 150 mcg/EE 30 mcg for 21 days and EE 10 mcg for 7 days.
This was a multicenter, open-label, phase 3, single-arm study. Sexually active women aged 18–40 years were enrolled and received ADER for up to 1 year (4 consecutive 91-day cycles). Participants kept diaries to record adherence, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index and the life-table method; safety and tolerability were assessed through reported adverse events (AEs).
A total of 3701 women were enrolled and 2144 completed the study. The Pearl Index was 3.19 [95% confidence interval (CI), 2.49–4.03], based on 70 pregnancies that occurred after ADER initiation and ≤ 7 days after the last LNG/EE or EE-only pill in women aged 18–35 years, excluding cycles in which another contraceptive method was used. Life-table pregnancy rate was 2.82% (95% CI, 2.23%–3.57%) for all users aged 18–35 years. Unscheduled bleeding/spotting decreased with increasing EE doses within each cycle and decreased after cycle 1. No unexpected AEs or changes in laboratory parameters were reported.
This study demonstrated that ADER effectively prevented pregnancy with a favorable safety and tolerability profile.
Comparison of pregnancy rates in users of extended and cyclic combined oral contraceptive (COC) regimens in the United States: A brief report
2014, Contraception
To evaluate pregnancy rates with 84/7, 21/7, and 24/4 combined oral contraceptives (COCs).
Data were obtained from the i3Invision Data Mart^TM retrospective claims database. Subjects were 15 to 40 years; first prescribed COCs between January 1, 2006 and April 1, 2011; and continuously insured for ≥ 1 year. Eighty four over seven users (84/7) were matched 1:1 to 21/7 and 24/4 users.
One-year pregnancy rates were significantly lower with 84/7 than with 21/7 (4.4% vs. 7.3%; p<.0001) and 24/4 (4.4% vs. 6.9%, p<.0001) regimens.
Preliminary results suggest fewer pregnancies with 84/7 versus 21/7 or 24/4 regimens.
While newer COCs, including 84/7 and 24/4 regimens, potentially improve efficacy and alter bleeding profiles compared to 21/7 regimens, few data on comparative pregnancy rates with these regimens are available. In this retrospective claims analysis, real-world pregnancy rates were lower with 84/7 regimens versus 21/7 and 24/4 regimens.

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Original research articleEffects on serum hormone levels of low-dose estrogen in place of placebo during the hormone-free interval of an oral contraceptive

Abstract

Background

Study Design

Results

Conclusion

Introduction

Section snippets

Study design and population

Study population

Discussion

Acknowledgment

J Obstet Gynaecol Can

Contraception

Contraception

Obstet Gynecol

Am J Obstet Gynecol

Contraception

Am J Obstet Gynecol

Contraception

Original research article
Effects on serum hormone levels of low-dose estrogen in place of placebo during the hormone-free interval of an oral contraceptive