Elsevier

Contraception

Volume 59, Issue 4, April 1999, Pages 237-243
Contraception

Original Research Articles
Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives

https://doi.org/10.1016/S0010-7824(99)00025-6Get rights and content

Abstract

This study was performed to evaluate pituitary-ovarian recovery in the pill-free interval during use of three low-dose combined oral contraceptives (COC). Either the estrogen component or the progestin component was comparable in the study groups, to evaluate their relative influence. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) levels were measured and follicle number and size estimated by transvaginal sonography daily during the 7-day pill-free interval in 44 healthy volunteers using three different low-dose oral contraceptives. Healthy volunteers were enrolled using 20 μg ethinyl estradiol (EE) + 75 μg gestodene (GSD) (Harmonet®, Wyeth-Lederle; n = 15), 20 μg EE + 150 μg desogestrel (DSG) (Mercilon®, Organon n = 17), or 30 μg EE + 150 μg DSG (Marvelon®, Organon, n = 12) given according to the usual regimen of one tablet daily during 3 weeks and 1 week pill-free interval.

No ovulations were observed. Pituitary hormones were not statistically significantly different at the beginning of the pill-free interval between the study groups. FSH concentrations were significantly higher at the end of the pill-free interval in the 30 μg EE group compared with both 20 μg EE groups (7.0 [0.6–12.4] IU/L vs 4.9 [1.4–6.1] IU/L and 4.5 [2.4–7.4] IU/L; p = 0.001). In both 20 μg EE groups, a single persistent follicle (24 and 28 mm) was present in one subject. Follicle diameters were statistically significantly smaller at the beginning and at the end of the pill-free period in the 30 μg EE group compared with both 20 μg EE study groups. Dominant follicles (defined as follicle diameter ≥10 mm) were observed at the end of the pill-free interval in both 20 μg EE groups (in 27% and 18% of women, respectively) but not in the 30 μg EE group. Finally, the area-under-the-curve for E2 was statistically significantly lower in the 30 μg EE group compared with both 20 μg EE groups.

In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval. Dominant follicles were encountered only in the 20 μg EE study groups.

Introduction

The contraceptive effect during the use of combined oral contraceptives (COC) is predominantly established as a result of inhibition of the hypothalamic-pituitary-ovarian axis. Follicle growth is prevented and ovulation inhibited. The estrogen component is considered to inhibit follicle stimulating hormone (FSH) production and consequently to diminish FSH-dependent follicle growth. Should, however, a dominant follicle emerge, inhibition of the luteinizing hormone (LH) surge and thus ovulation is prevented through the progestin component. The progestin component alone does not seem to have a prominent effect on basal concentrations of LH and FSH but, notably, inhibits peak concentrations.1 Although not completely understood, inhibitory effects of both components in COC are established through synergistic interactions at the hypothalamic-pituitary level.2, 3

The 7-day pill-free period of most currently used regimens allows for withdrawal bleeding and serves the purpose of mimicking the normal menstrual cycle. In addition, it allows reduction of the overall amount of steroids administered over a 4-week period. During the pill-free interval, pituitary-ovarian activity is allowed to resume in the absence of inhibitory steroids until the next medication strip is initiated. Numerous publications have described recovery of ovarian activity during the pill-free interval or after pill omissions.4, 5 However, daily blood sampling together with ultrasound has rarely been performed. Few data are available to determine whether the magnitude of pituitary-ovarian suppression significantly differs among users of various low-dose COC. The present study compared resumption of pituitary-ovarian activity in women using three different low-dose COC to determine: 1) the maximum extent of suppression at the beginning of the pill-free interval, 2) the magnitude of recovery of pituitary-ovarian activity during the pill-free interval, and 3) the extent of pituitary-ovarian activity at the end of the pill-free interval, a starting point for the next cycle.

Section snippets

Subjects and study protocol

A total of 44 women using low-dose oral contraception were included in this single-center group comparative study in healthy female volunteers. The human ethics committee of the Dijkzigt Academic Hospital approved the study and all women gave written informed consent. The study was conducted according to the Declaration of Helsinki and the Good Clinical Practice (GCP) recommendations of the European Committee. Inclusion criteria were: age between 18 and 39 years; weight between 50 and 75 kg;

Results

All 44 volunteers completed the study. Age, weight, and body mass index were not statistically significantly different among the study groups (data not shown). All women did use the studied COC for ≥2 months before the assessments in this study and there were no pill omissions reported. Figure 1, Figure 2, Figure 3 show the study parameters throughout the pill -free interval. Table 1 shows pituitary-ovarian activity at the beginning and end of the pill-free interval as well as parameters for

Discussion

During the luteal-follicular transition of the normal menstrual cycle, FSH levels surpass the threshold for stimulating ovarian activity. This intercycle rise in FSH elicits recruitment of a cohort of synchronous follicles from which a single dominant follicle is selected later in the follicular phase of the cycle.5

Conventional combined oral contraceptives act primarily through inhibition of follicular growth in combination with peripheral progestin effects. In any situation in which medication

Acknowledgements

We thank the staff of the Clinical Research Unit, Dijkzigt Hospital, for their logistic support.

This study was financially supported by Stichting Voortplantingsgeneeskunde Rotterdam, Organon NV, and Wyeth-Ayerst.

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