Ovarian Follicular Development During the Use of Oral Contraception: A Review

Abstract

Over the past 40 years, alterations to the composition of oral contraceptives (OCs) have been made in attempts to reduce adverse effects and to improve patient compliance while maintaining contraceptive efficacy. However, there is growing evidence to indicate that reducing the estrogen dose to minimize adverse effects may have compromised the degree of hypothalamo-pituitary-ovarian suppression, particularly during the hormone-free interval (HFI) or following missed doses. Follicle development during OC use appears to occur in association with a loss of endocrine suppression during the HFI. This information provides a rationale for reducing or eliminating the HFI in OC regimens. There is also evidence for an increased risk of follicle development and ovulation in women who use delayed OC initiation schemes, such as the “Sunday Start” method. It is not currently known why some follicles ovulate during OC use while others regress or form anovulatory follicle cysts. Continued research about follicle development during OC use would provide insight into understanding the precise mechanisms of action underlying combined OCs, as well as those of continuous OC formulations and emergency contraceptive regimens.

INTRODUCTION

The development of oral contraceptives (OCs) in 1958¹ dramatically changed the way in which couples worldwide viewed family planning. OCs are among the most widely used and studied pharmaceuticals. Combined OC preparations contain orally active exogenous estrogen and progestin. Supra-physiologic levels of estrogen and progestin have been shown to provide a negative feedback effect on the hypothalamo-pituitary axis.² Reductions in the endogenous gonadotropin-releasing hormone (GnRH), the follicle-stimulating hormone (FSH), and the luteinizing hormone (LH) are believed to suppress ovarian follicular development, and thus prevent ovulation and conception. The progestin component of OCs is believed to inhibit the LH surge and ovulation.^3–5 In primates, estrogens have been shown to inhibit the growth of pre-antral and medium-sized antral follicles,^6,7 presumably through inhibition of FSH secretion. Estrogen is also required to provide satisfactory bleeding patterns in women during regular OC use. Furthermore, it is believed that OCs elicit secondary inhibitory effects on endometrial development, cervical mucus viscosity, cervical dilation, and oviductal motility.⁸ The first approved OC contained 150 μg of mestranol, as its estrogen component, and 9.85 mg of norethynodrel, as its progestin component. Many hormonal contraceptive regimens have since been developed. Concerns about estrogen-related thromboses led to a marked reduction in the estrogen dose from 150 μg to 30 μg, and unproven concern about liver tumours caused a switch from the use of mestranol to ethinyl estradiol (EE).⁹ More recent OC formulations contain EE doses as low as 20 μg, and clinical trials are underway to determine the safety and efficacy of formulations containing 15 μg EE. Progestin development has also occurred in pursuit of better-tolerated and more effective OC regimens.⁸

Most combined OC regimens consist of 21 days of hormonally active pills followed by a 7-day hormone-free interval (HFI) during which a withdrawal menstrual bleed normally occurs. The first OC regimens used were “monophasic,” in that the same doses of estrogen and progestin were administered throughout the cycle.¹ Biphasic¹⁰ and triphasic^11,12 regimens were later developed by changing the individual doses of estrogen and progestin during the cycle. Continuous OC regimens may also be used, in which women take OC continuously for months at a time and, if they choose, discontinue for a withdrawal bleed only a few times a year.^13,14

There is growing evidence to indicate that reducing the estrogen dose to minimize adverse effects may have compromised the degree of hypothalamo-pituitary-ovarian suppression, in particular during the hormone-free interval (HFI) or following missed doses. The objective of this review article is to provide a comprehensive understanding of the current knowledge of ovarian follicular development during OC use.

METHODS

A critical review of the literature on ovarian follicular development during oral contraceptive use was performed, employing the National Library of Medicine PubMed electronic database. The key words used for the search were contraceptive, contraception, cyst, endocrine, estrogen, follicle, follicular, FSH, hormone, LH, oral, ovary, ovulation, pill-free interval, and progesterone. Electronic versions of journal articles were obtained. Hand searches of library holdings, books, and other related publications were used when references were not available on-line.

QUALITY OF EVIDENCE

The quality of evidence of the articles reviewed on ovarian follicular development during OC use was Level I for the randomized controlled trials (approximately 50%) and Level II-2 for the cohort and case-control studies (approximately 50%). Levels of evidence were determined using the criteria described by the Canadian Task Force on the Periodic Health Examination.¹⁵

OVARIAN FOLLICULAR DEVELOPMENT AND OVULATION DURING COMBINED ORAL CONTRACEPTIVE USE

Ovarian follicular development is not completely inhibited during standard use of combined OCs.¹⁶ The degree of follicular activity that occurs during OC use depends on the type and dose of steroids used, the administration regimen, user compliance, and the individual responsiveness of the woman taking the hormones.¹⁷ Twenty-nine studies were found in which pituitary-ovarian activity was evaluated in women using OC containing 20 μg to 40 μg EE and various progestins. In 20 of the 29 studies, the development of follicles to diameters of 10 mm or greater was detected using ultrasonography.^18–38 At a diameter of approximately 10 mm, follicles become physiologically selected for preferential growth and ovulation during natural menstrual cycles.³⁹ Selected dominant follicles are those that have acquired morphologic and functional dominance over other follicles of the cohort, and therefore have the greatest potential to ovulate.⁴⁰ In a recent study, 8 of 17 women (47%) using various OCs for a 3-month period developed dominant follicles that regressed before reaching 14 mm in diameter.³⁶ The remaining 9 women (53%) developed dominant follicles that grew to diameters of 14 mm or greater and either regressed (11 of 12 follicles) or formed a hemorrhagic anovulatory follicle (1 of 12 follicles).³⁶

In 10 of the 29 studies, ovulation was detected by endocrine assessment with or without ultrasonographic visualization of follicle growth and luteal formation.^{18,27,29,31,37,38,41–44} Pregnancy rates in these studies were reported to be low, with Pearl Indices of less than 1.0. In 17 of the 29 studies, ovulations were not detected during OC use.^{19–21,23,24,26,28,32–36,45–49} In the remaining 2 studies, 2 pregnancies were reported despite failure to detect ovulation.^25,30 Although it is believed that ovulation during OC use is prevented by inhibition of the LH surge, it is not currently known why some follicles ovulate during OC use while other follicles do not.^{3–5,22,23,49,50} Considering the variability in serum sex steroid levels and day of ovulation during the menstrual cycle,^51,52 accurate detection of ovulation may require frequent and comprehensive ultrasonographic and endocrinologic evaluation of ovarian status; prior to our studies,^36,38 serial high-resolution ovarian ultrasonographic examinations and endocrinologic evaluations had not been utilized to assess ovulation during OC use.

Follicles have been reported to develop to pre-ovulatory diameters, in association with pre-ovulatory levels of endogenous estradiol during OC use.^{20,31,36,45,53} However, most dominant follicles failed to ovulate and regressed.^{13,14,19–21,23,26,28,32–36,45–49} Large antral follicles that developed under the suppressive effects of OC appeared ultrasonographically indistinguishable from pre-ovulatory follicles observed during spontaneous menstrual cycles.^20,36 The ultrasonographic and endocrinologic similarities between large antral follicles developed during natural menstrual cycles and during OC cycles support the notion that follicles developed to pre-ovulatory diameters during OC use will retain their ovulatory potential.

FOLLICLE DEVELOPMENT AND STEROID DOSE

The extent of pituitary-ovarian suppression during combined OC use appears to be related to the dose of EE, rather than to the type and dose of progestin^54–56; the maximum diameter of detected follicles and number of follicles observed were greater in women taking 20 μg EE regimens than in women taking 30 μg to 35 μg EE regimens.^17,30,36 In addition, the 20 μg EE formulations have been associated with greater levels of serum FSH and LH.⁵⁴ No studies have been reported on the use of ultrasonographic and endocrinologic measures to evaluate the effect of different progestins on ovarian function, while properly controlling for the estrogen component.

FOLLICLE CYSTS AND ORAL CONTRACEPTIVE USE

Follicle cysts, including functional ovarian cysts, luteinized unruptured follicles (LUFs), and enlarged follicles, have been documented during OC use.^{26–28,31,33,36,38,57,58} The definition used to describe follicle cysts varies among reports. Functional ovarian cysts have been described as nonpathologic follicular cysts (i.e., anovulatory), corpus luteum cysts, or other unspecified ovarian cysts measuring more than 20 mm in diameter, as detected by ultrasonographic or surgical examination.⁵⁷ Functional ovarian cysts have also been described as follicles that failed to ovulate, developed beyond 30 mm in diameter, and persisted for more than 2 cycles.²⁸ This latter definition contrasts that of enlarged follicles, which have been described as follicles that developed beyond 30 mm in diameter and failed to ovulate, but failed to persist for more than 2 cycles.²⁸ LUFs are defined as follicles that have reached pre-ovulatory diameters, failed to ovulate, and became luteinized.⁵⁹ Follicle cysts usually regress within days or weeks of their development.^59,60 An increased incidence of functional ovarian cysts has been documented in women taking progesterone-only OCs.^61,62 There is also evidence to indicate that women taking multiphasic and low-dose monophasic combined OCs may be at greater risk of developing follicle cysts than women taking moderate-dose monophasic OCs.^28,58 The significance of follicle cysts and the mechanisms underlying their development during combined OC use have not been fully elucidated.

FOLLICLE DEVELOPMENT AND ORAL CONTRACEPTIVE ADMINISTRATION SCHEMES

The day of the cycle on which OC use is initiated influences the risk of follicle development and ovulation.²⁰ Delaying the initiation of OC use may fail to inhibit endogenous FSH, LH, and estradiol concentrations during the early follicular phase and thus increases the likelihood that a dominant follicle will develop. This concept is supported by the finding that women who initiated OC use on day 5 of the menstrual cycle developed more dominant follicles, in association with higher concentrations of serum estradiol and gonadotropin, than women who started OCs on day 1.²⁰ It has also been reported that dominant follicles 10 mm or greater in diameter continued to develop following initiation of OC use when follicles reached diameters of 10 mm, 14 mm, or 18 mm.³⁷ Ovulations occurred when OC use was initiated at follicle diameters of 14 mm and 18 mm, despite blunted LH levels.³⁷ Follicles 10 mm or greater in diameter, and occasionally those 14 mm or greater in diameter, have been reported in the first 7 days of spontaneous menstrual cycles.³⁹ Therefore, women who use “Sunday Start” regimens, in which OC use may be prolonged for up to 7 days following menses, appear to be at an increased risk of developing follicles and ovulating.^37,63–65 These data provide rationale to support the use of day 1 OC initiation schemes, rather than delayed initiation protocols, to ensure optimal ovarian suppression.

FOLLICLE DEVELOPMENT DURING THE HORMONE-FREE INTERVAL

The strategy of a 7-day HFI within a 28-day OC cycle was implemented in the 1960s, so that menstrual bleeding during OC use would mimic that observed during natural menstrual cycles. Several years later, researchers expressed concern over the degree of follicle development that was observed during the HFI, particularly with low EE dose formulations.^15,34 Elevated concerns about follicle development during the HFI of OC use were the result of advancements in our ability to monitor ovarian function using high-resolution transvaginal ultrasonography.

Dominant follicles of 10 mm and greater have been ultra-sonographically detected during the HFI, in as many as 86% of OC users.^{36,50,56,66–68} Similarly, endogenous FSH and estradiol levels at the end of the HFI have been reported to reach levels comparable to those observed during the early follicular phase of the natural menstrual cycle and following 7 days of recombinant FSH.^{20,36,50,55,69} Resumption of OCs at the end of the HFI decreased FSH levels.^50,56 If no dominant follicles developed during the HFI, follicular suppression was maintained.^50,56 However, if a dominant follicle developed during the HFI, follicle growth continued despite declining FSH concentrations.⁵⁰ Of the 6 studies^{36,50,56,66–68} in which follicle development during the HFI was observed, ovulation was detected in only 1 study.⁶⁸

Shortening the HFI from 7 days to 3 or 4 days has been shown to provide a greater suppressive effect on ovarian follicular development.^68,70 A new OC regimen, in which unopposed EE is administered for the last 5 days of the 7-day HFI, has also been associated with more effective suppression of ovarian follicular activity than a standard monophasic regimen.⁷¹ Reduction or elimination of the HFI in combined OC regimens appears to promote optimal ovarian suppression.

FOLLICLE DEVELOPMENT FOLLOWING MISSED DOSES OF ORAL CONTRACEPTIVES

The effect of missed OC doses on pituitary-ovarian activity is related to the number of doses missed and the cycle days when doses are missed. A greater number of missed doses and a greater number of consecutive days of missed doses are associated with increased risk of follicle development and ovulation.^16,72–77 The risk of follicular development and ovulation following missed doses is likely greater in women taking low EE dose formulations of 20 μg or less, compared to women taking higher doses of EE.¹⁶

The risk of contraceptive failure is greatest when the first or last dosing pill is missed and the HFI is extended,^{21,67,78–80} resulting in a prolonged interval during which follicle growth is not suppressed. Follicle growth to a potentially ovulatory diameter and increased estradiol levels were observed when the HFI was extended from 1 day to 11 days.^{21,67,78–80} Ovulation following the extension of the HFI was reported in 3 of 5 studies.^21,79,80 In a separate study, human chorionic gonadotropin (hCG) induced ovulation of follicles that reached 18 mm in diameter after extension of the HFI.²² It was concluded that follicles that developed to pre-ovulatory diameters following an extended HFI had the potential to ovulate.

In a more recent study, in which dominant follicles were detected ultrasonographically in 17 of 36 (47%) OC users, no ovulations were observed.³⁶ Although 1 to 2 missed pills were reported in 9 out of 108 cycles of OC use, missed doses were not associated with the growth of dominant follicles.³⁶ However, missing multiple doses, especially those that extend the HFI, may increase the risk of dominant follicle development.

SUPPRESSION OF FOLLICLE DEVELOPMENT OVER SUBSEQUENT ORAL CONTRACEPTIVE CYCLES

The consistency of ovarian suppression over the course of several cycles of OC use is not fully understood. The growth of follicles to diameters of 10 mm or more in the first cycle of combined OC has been shown to be greatest in the first week.²⁰ However, follicle growth was recently reported to be greatest during the HFI of the first and subsequent cycles of combined OC use.³⁶ Ovarian suppression has been reported to be greatest in the first treatment cycle in some studies^17,23,26 and in the second and third cycles of OC use compared to the first cycle in other studies.^21,36,38 It appears that the degree of follicle suppression, regardless of the cycle being studied, is related to the loss of endocrine suppression during the HFI.³⁶ Follicle development during the first cycle of OC use is also related to the OC initiation scheme used.^36,37

CONCLUSIONS

Ovarian follicular development is not completely suppressed during the use of currently available combined OC formulations. Alterations to the composition of OC formulations have been made in attempts to reduce adverse effects and improve patient compliance while maintaining contraceptive efficacy. However, there is growing evidence to indicate that reducing the estrogen dose may have compromised the degree of hypothalamo-pituitary-ovarian suppression, in particularly during the HFI or following missed doses. As follicle development during combined OC use appears to occur in association with a loss of endocrine suppression during the HFI, reducing or eliminating the HFI may provide optimal suppression of folliculo-genesis and ovulation. There is evidence for an increased risk of follicle development and ovulation in women who use delayed OC initiation schemes, such as the “Sunday Start” method. It is not currently known why some follicles ovulate during OC use while others regress or form anovulatory follicle cysts. Continued research on follicle development during OC use would enhance our understanding of the precise mechanisms of action underlying combined OC, as well as of continuous OC formulations and emergency contraceptive regimens.