Original Research ArticlesActivity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives
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.
References (18)
- et al.
Is the contraceptive effect of 300 mcg of norethisterone mainly peripheral or central?
Contraception
(1992) - et al.
Pituitary response to LHRH stimulation in women on oral contraceptivesa follow-up dose response study
Contraception
(1981) - et al.
Anti-estrogenic effects of contraceptive progestins on the dynamics of gonadotropin release
Contraception
(1982) - et al.
Growth patterns of nondominant ovarian follicles during the normal menstrual cycle
Fertil Steril
(1990) - et al.
Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle
Fertil Steril
(1995) - et al.
The effect of follicular growth and luteal function of ’missing the pill’. A comparison between a monophasic and a triphasic combined oral contraceptive
Contraception
(1991) - et al.
The effect of deliberate omission of Trinordiol® or Microgynon® on the hypothalamo-pituitary-ovarian axis
Contraception
(1986) - et al.
Studies on low-dose oral contraceptivesplasma hormone changes in relation to deliberate pill (Microgynon 30) omission
Contraception
(1979) - et al.
Comparative studies of ethynyl estrogens used in oral contraceptives. III. Effect on plasma gonadotropins
Am J Obstet Gynecol
(1975)
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