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BOR - Papers in Press, published online ahead of print May 14, 2003.
Biol Reprod 2003, 10.1095/biolreprod.103.017772
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BIOLOGY OF REPRODUCTION 69, 1023–1031 (2003)
DOI: 10.1095/biolreprod.103.017772
© 2003 by the Society for the Study of Reproduction, Inc.

Ovary

Characterization of Ovarian Follicular Wave Dynamics in Women1

Angela R. Baerwald3, Gregg P. Adams4, and Roger A. Pierson2,3

Women's Health Imaging Research Laboratory,3 Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W8 Department of Veterinary Biomedical Sciences,4 Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B4


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A wave phenomenon of ovarian follicular development in women has recently been documented in our laboratory. The objective of the present study was to characterize follicular waves to determine whether women exhibit major and minor wave patterns of follicle development during the interovulatory interval (IOI). The ovaries of 50 women with clinically normal menstrual cycles were examined daily using transvaginal ultrasonography for one IOI. Profiles of the diameters of all follicles >=4 mm and the numbers of follicles >=5 mm were graphed during the IOI. Major waves were defined as those in which one follicle grew to >=10 mm and exceeded all other follicles by >=2 mm. Minor waves were defined as those in which follicles developed to a diameter of <10 mm and follicle dominance was not manifest. Blood samples were drawn to measure serum concentrations of estradiol-17ß, LH, and FSH. Women exhibited major and minor patterns of follicular wave dynamics during the IOI. Of the 50 women evaluated, 29/34 women with two follicle waves (85.3%) exhibited a minor-major wave pattern of follicle development and 5 women (14.7%) exhibited a major-major wave pattern. Ten of the 16 women with three follicle waves (62.5%) exhibited a minor-minor-major wave pattern, 3 women (18.8%) exhibited a minor-major-major wave pattern, and 3 women (18.8%) exhibited a major-major-major wave pattern. Documentation of major and minor follicular waves during the menstrual cycle challenges the traditional theory that a single cohort of antral follicles grows only during the follicular phase of the menstrual cycle.

follicle, menstrual cycle, ovary


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ovarian follicular development in women during the menstrual cycle has not been fully elucidated. The traditional theory of human folliculogenesis, developed over the past 50 yr, holds that a single cohort of 3–11 antral follicles is recruited to grow in each ovary during the late luteal phase of the human menstrual cycle [1]. A single dominant follicle is believed to be selected from this cohort for preferential growth in the early- to mid-follicular phase. The dominant follicle continues to develop and ovulate, while all other subordinate follicles regress [2–4]. Follicular development to an ostensibly ovulatory diameter in women has been believed to occur exclusively in the follicular phase [5–7], while follicular quiescence has been thought to occur during the luteal phase due to the inhibitory effects of luteal progesterone production [8–13]. Antral follicles have been reported in the luteal phase of the menstrual cycle occasionally [14–16]. However, only 6% of follicles in luteal phase were believed to be healthy, as determined by oocyte viability and granulosa cell number [10]. In other reports, it appeared as though luteal phase follicular development represented an abnormal reproductive event [14–16].

Much of the current understanding of ovarian follicular development during the menstrual cycle has been based on studies in which measurements of urine and serum endocrine levels were used to indirectly assess follicle growth and ovulation [17]. Histologic evaluation of ovaries during laparotomy and laparoscopy or following ovariectomy have also been reported, sometimes in association with endocrine measurements [9, 10, 14, 18–29]. Transabdominal and transvaginal ultrasonography have also been used intermittently during the menstrual cycle (usually only during the follicular phase) to assess follicle development [15, 16, 30–54]. The traditional model of human folliculogenesis has been proposed based on limited studies in women and extrapolations from studies performed in rodents, nonhuman primates, and domestic animal species [7, 26, 55–63].

Successive waves of ovarian follicular development during the menstrual cycle have recently been documented in our laboratory using serial high-resolution transvaginal ultrasonographic evaluation of follicle growth and regression [64]. Thirty-four of 50 women (68%) with normal menstrual cycles exhibited two waves of follicular development during an interovulatory interval and 16 women (32%) exhibited three waves [64]. Only the final wave of each cycle was ovulatory; all preceding waves were anovulatory. Three-wave cycles were associated with longer interovulatory intervals and shorter interwave intervals than two-wave cycles [64]. Documentation of a follicular wave phenomenon in women challenges the traditional notion that a single cohort of antral follicles grows only during the follicular phase of the menstrual cycle and has provided a new model for studying ovarian follicular development.

The development of two and three ovarian follicular waves in women [64] is comparable with the follicular wave phenomenon described in domestic animal species [65, 66]. In the cow, two and three waves of follicular development were observed during the estrous cycle [67–71]. The final wave was ovulatory, while all preceding waves were anovulatory. In the mare, major and minor follicular waves have been documented [72]. Major follicular waves were defined as the synchronous growth of a group of follicles followed by selection of a follicle for continued growth and regression of all other ‘subordinate’ follicles of the wave. Major waves were either anovulatory or ovulatory, depending on the stage of the cycle during which they developed. Minor follicle waves in mares were characterized by the failure of any one follicle to become dominant over other follicles of the wave.

Follicle-wave dynamics in domestic animals have been associated with cyclic changes in reproductive steroid and glycoprotein hormones. The emergence of follicular waves in cows [73] and mares [72] was preceded by a rise in the circulating concentrations of FSH. After wave emergence, selection of a dominant follicle was associated with a decline in circulating concentrations of FSH, acquisition of granulosa LH receptors, and rising circulating concentrations of estradiol [74–79]. Progesterone production from the corpus luteum in cows elicited a suppressive effect on LH and inhibited ovulation of dominant follicles from waves that developed in the luteal phase [80, 81].

The objective of the present study was to characterize ovarian follicular-wave activity in women by evaluating changes in follicle diameter, number of follicles >=5 mm, and circulating concentrations of FSH, LH, and estradiol during one interovulatory interval. We hypothesized that women would exhibit major and minor patterns of follicle-wave development.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Data obtained from 50 women enrolled in our initial study, which documented two and three follicular waves [64], were carefully evaluated to elucidate different patterns of follicle-wave development. Participants were assessed, by history and physical examination, to be healthy women of reproductive age (mean ± SD = 28.0 ± 6.9 yr, range = 19–43 yr). Women who were currently or recently pregnant or lactating, had used hormonal contraception within 3 mo of enrollment, had a history of irregular menstrual cycles, or were taking medication(s) known or suspected to interfere with reproductive function were not eligible to participate. Informed consent was obtained from all women prior to initiating study procedures. The study protocol was approved by the Institutional Review Board of the University of Saskatchewan.

Each volunteer underwent daily transvaginal ultrasonographic evaluation of her ovaries for one interovulatory interval (IOI). An IOI was defined as the interval from one ovulation to the subsequent ovulation. Ultrasound examinations were initiated 12 days after menses (i.e., a few days before the first ovulation) and were continued until 3 days after the second ovulation. Ovulation was defined as the disappearance of a large follicle (>15 mm) that had been identified by ultrasonography on the previous day, and the subsequent visualization of a corpus luteum [41, 82]. Follicles >=2 mm were measured during each examination, and the number of follicles >=5 mm tabulated. The length and width of each follicle were measured in both the sagittal and transverse planes. Follicle diameter was then calculated by averaging the mean measurement in the sagittal plane by the mean measurement in the transverse plane. The methods used for tracking follicle diameter and follicle number each day during the IOI are as described in Baerwald et al. [64].

High-resolution Ultramark 9 and ATL HDI 5000 ultrasound machines with 5–9 MHz multifrequency convex array transducers (Advanced Technologies Laboratories, Bothell, WA) were used to acquire follicular data. Approximately 90% of the examinations were performed by one sonographer (ARB). A second sonographer (RAP) was available when the primary sonographer was not available.

Follicular waves were characterized by an increase and subsequent decrease in the number of follicles >=5 mm, occurring in association with the growth of at least two follicles to >=6 mm, as documented in the previous report [64]. In the present analysis, major waves were defined as waves in which one follicle grew to >=10 mm and exceeded the next largest follicle by >=2 mm (i.e., development of a dominant follicle). Minor waves were defined as those in which the largest follicle developed to <10 mm and did not grow larger than all other follicles of the wave by >=2 mm (i.e., no evidence of follicular dominance). Wave emergence was defined as the day at which the largest follicle of each wave was first identified, retrospectively, at 4–5 mm. An interwave interval (IWI) was defined as the interval from the emergence of one wave to the emergence of the subsequent wave. Selection was defined as the day on which the prospective dominant follicle became, and remained, larger than all other follicles of a major wave.

Blood samples were drawn every third day during the IOI in a stratified manner among women so that each day of the IOI was represented. The stratification scheme was used to randomly assign one third of the women to have blood drawn on Days 1, 4, 7, etc., one third on Days 2, 5, 8, etc., and the remaining one third on days 3, 6, 9, etc. Blood was collected into a 7-ml clot-activated tube and allowed to sit at room temperature for 15–30 min before centrifugation for 10 min at 3000 rpm (700 x g). The serum was drawn off and stored at -20°C. Sequential competitive fluorescence immunoassays (Immulite; Diagnostic Products Corporation, Los Angeles, CA) were performed to measure serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol-17ß (E2). Interassay coefficients of variation were as follows: LH (low = 6.3%, medium = 4.0%, high = 4.5%), FSH (low = 8.0%, medium = 2.9%, high = 4.1%), and E2 (low = 9.8%, medium = 5.6%, high = 4.3%). Minimal detectable limits were 0.1 mIU/ml for FSH, 0.1 mIU/mL for LH, and 15 pg/ml for E2.

We initially categorized follicle diameter, follicle number, and endocrine data into two- or three-wave patterns [64]. In the present study, data were further partitioned into major and minor wave patterns: minor major (- +), major major (+ +), minor minor major (- - +), minor major major (- + +), and major major major (+ + +). Follicle and endocrine data were centralized to the day of wave emergence and normalized to the mean IOI of the respective wave patterns.

In women with two follicular waves, t-tests were used to compare - + and + + wave cycles with respect to days of wave emergence, IOI, IWI, maximum number of follicles >=5 mm, follicle diameter, growth rate, and regression rate (SPSS Version 11, 2002). In women with three follicular waves, analyses of variance with the Scheffe post hoc tests were used to compare endpoints between - - +, - + +, and + + + wave cycles (SPSS Version 11, 2002). Student t-tests and repeated measures analyses (SPSS Version 11, 2002; PROC MIXED, SAS/STAT Software, 2002) were used to compare IWI, follicle diameter, growth rate, and regression rate between waves. Repeated measures analyses (PROC MIXED, SAS/STAT Software, 2002) were also used to assess changes in follicle diameter, follicle number, and endocrine status during the IOI.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The proportions of women exhibiting major and minor wave patterns and the respective interovulatory and interwave intervals are shown in Table 1. Waves of follicle development emerged on Days 0 (i.e., day of first ovulation) and 14 (- +); -1, and 14 (+ +); -1, 11, and 17 (- - +); -1, 13, and 20 (- + +); and 1, 13, and 19 (+ + +). The days of wave emergence were not different between women with - + and + + wave patterns (P > 0.05), or among women with - - +, - + +, and + + + wave patterns (P > 0.05).


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  		TABLE 1. Interovulatory intervals (IOI) and interwave intervals (IWI) (mean ± SEM) for women with two- and three-wave patterns of follicular development during the ovarian cycle.a

Follicle diameter and number data during the IOI for the two- and three-wave patterns are shown in Figures 1 and 2, respectively (day effect: P < 0.0001). A nadir in follicle number was detected prior to the emergence of all major and minor waves.



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  		FIG. 1. Diameter of the largest follicle of each wave ({circ}) and the number of follicles >=5 mm () in women with two-wave interovulatory intervals (IOI). The majority of women exhibited a - + wave pattern (A; n = 29); all other women exhibited a + + wave pattern (B; n = 5). Follicle diameter and number data were normalized to the mean IOI for each wave pattern and centralized to wave emergence. Follicle number data were displayed from emergence of the first wave and midpoint of both waves.



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  		FIG. 2. Diameter of the largest follicle of each wave ({circ}) and the number of follicles >=5 mm () in women with three-wave interovulatory intervals (IOI). Women exhibited either a - - + wave pattern (A; n = 10), a - + + wave pattern (B; n = 3) or a + + + wave pattern (C; n = 3). Follicle diameter and number data were normalized to the mean IOI for each wave pattern and centralized to wave emergance. Follicle number data were displayed from emergence of the first wave and midpoint of all three waves

Peak diameters of the largest, second largest, and third largest follicles of each wave for the five different wave patterns are shown in Table 2. The peak diameters of the largest follicles from major waves were greater than those in minor waves (P < 0.05), and dominant follicles from major ovulatory waves were larger than those in major anovulatory waves (P < 0.05) in all five patterns of follicular growth.


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  		TABLE 2. Maximum diameter (mean ± SEM) of the largest (F1), second largest (F2), and third largest (F3) follicles of each wave in women with two- and three-wave patterns of follicular development during the ovarian cycle

Follicle diameter and number for major and minor waves are compared in Figure 3. In major waves, more follicles were recruited to grow and the largest follicle of the wave reached a greater peak diameter than in minor waves (follicle number, day effect: P < 0.0001; wave effect, P < 0.0001; day x wave effect, P = 0.64), (follicle diameter, day effect: P < 0.0001; wave effect, P < 0.0001; day x wave effect, P < 0.0001). The diameter of the largest follicle and number of follicles >=5 mm increased simultaneously (r = +0.99) in major waves until Day 4, when follicle diameter continued to increase and number decreased to Day 11 (r = -0.68). In contrast, follicle diameter and number data increased and decreased simultaneously throughout the duration of minor waves (r = +0.87). The growth rate of the largest follicle in major waves was slower than that in minor waves. No difference in regression rates was detected (Table 3). Day of selection, diameter of the dominant follicle at selection, and diameter of the largest subordinate follicle at selection are shown in Table 4. On the day of selection, the dominant follicle was 10 mm and the largest subordinate follicle was 8 mm in both major ovulatory and anovulatory waves (P > 0.05, respectively). The dominant follicle became larger than the first and second subordinate follicles 3 days after wave emergence in both major ovulatory waves and major anovulatory waves, indicating that selection occurred at this time (Fig. 4, P < 0.05). The dominant follicle emerged 3 days later than the first and second subordinate follicles in major ovulatory waves and 2 days later in major anovulatory waves.



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  		FIG. 3. Diameter of the largest follicle (A) and the number of follicles >=5 mm (B) for major waves (; n = 67) and minor waves ({circ}; n = 52)


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  		TABLE 3. Characteristics (mean ± SEM) of major and minor follicular waves during the ovarian cycle in women


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  		TABLE 4. Selection of the dominant follicle (mean ± SEM) of major waves (i.e., ovulatory and anovulatory) in women with two- and three-wave patterns of follicle development during the menstrual cycle



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  		FIG. 4. Diameter of the dominant ({block}), 1st subordinate ({circ}), and 2nd subordinate ({blacktriangledown}) follicles in major ovulatory waves (A; n = 52) and major anovulatory waves (B; n = 15). Asterisks indicate the first day at which a difference between the diameters of the two largest follicles was detected

Levels of FSH, LH, and E2 in women with two versus three follicular waves during the IOI are shown in Figure 5. No differences in FSH and LH profiles between women with two versus three follicle waves were detected prior to the preovulatory hormone surge (day effect, P < 0.0001, respectively). However, estradiol levels increased earlier during the follicular phase (day effect, P < 0.0001; wave effect, P = 0.30; day x wave effect, P = 0.007) in women with two versus three follicle waves. Similarly, the preovulatory estradiol peak occurred 2 days earlier (i.e., 26 versus 28 days after ovulation) and the FSH and LH peaks occurred 1 day earlier (i.e., 27 versus 28 days after ovulation) in women with two wave cycles compared with those with three wave cycles. No differences in LH or estradiol concentrations were detected among women with major and minor patterns of follicle-wave development (pattern effect, P > 0.05; pattern x day effect, P > 0.05).



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  		FIG. 5. Serum (A) FSH, (B) LH, and (C) estradiol-17ß concentrations during the interovulatory interval for women with two () and three ({circ}) waves of follicle development. Data were centralized to the days of wave emergence and normalized to the mean IOI for two-wave and three-wave cycles.

A nadir in FSH was detected 3 days before the emergence of all anovulatory and ovulatory follicular waves (day effect, P = 0.004; wave effect, P = 0.64; day x wave effect, P = 0.06) (Fig. 6). The FSH nadir occurred 2 days earlier for major waves (i.e, Day 3) compared with minor waves (i.e., Day 1) (day effect, P = 0.008; wave effect, P < 0.0001; wave x day effect, P = 0.006).



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  		FIG. 6. Serum FSH concentrations centralized to the day of wave emergence for A) ovulatory (n = 50; {circ}) and anovulatory (n = 66; {block}) waves and B) major (n = 67; {block}) and minor waves (n = 52; {circ})


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our evaluation of the changes in follicle diameter and the number of follicles >=5 mm during an interovulatory interval supported the hypothesis that women exhibit major and minor wave patterns of ovarian follicular development during the menstrual cycle. Major waves were those in which a single dominant follicle was selected to grow larger than all other subordinate follicles of the wave. Minor waves were those in which selection of a dominant follicle was not manifest. Anovulatory major waves were those in which the dominant follicle preferentially grew and then regressed. Ovulatory major waves were those in which the dominant follicle ovulated. In this regard, follicular dynamics in women is comparable with that described in the equine species [72].

In all 50 of the women evaluated, the final wave of the IOI was an ovulatory major wave, while preceding waves were either minor or major anovulatory waves. The dominant follicle of major ovulatory waves was larger than that in major anovulatory waves. Selection of the dominant follicle in both major anovulatory and ovulatory waves occurred at a diameter of approximately 10 mm, 3 days after wave emergence.

The dominant follicle of major waves emerged 2–3 days later than the first and second subordinate follicles. These findings in women are inconsistent with observations in other species (i.e., bovine, equine), in which the dominant follicle emerged earlier than subordinate follicles [79]. It seems unlikely that emergence of the dominant follicle would differ between species given the similarity in follicular wave dynamics. We attribute this discrepancy to limitations inherent to current ultrasound-imaging techniques. A human ovary contains, on average, more follicles >=4 mm than a bovine ovary [64, 67]. The multitude of follicles visualized on each ovary on any given day during a woman's cycle made it difficult to maintain the day-to-day identities of 4–5-mm follicles. Follow-up studies in women should be performed with an emphasis on the emergence of 2–5-mm follicles.

Follicle stimulating hormone, LH, and E2 are differentially involved in the regulation of ovarian follicular wave dynamics in women. The emergence of both major and minor follicular waves was preceded by an increase in FSH, which occurred in concert with an increase in the number of follicles >=5 mm. The nadir in FSH, which preceded wave emergence, occurred 2 days earlier in women with major versus minor follicular waves.

Estradiol levels increased earlier during the follicular phase in women with two versus three follicular waves, presumably due to earlier emergence of the dominant follicle. Similarly, preovulatory surges of FSH, LH, and E2 occurred earlier in women with two versus three follicle waves, resulting in a shorter IOI in women with two waves. We concluded that follicle development was the primary factor that determined the length of the menstrual cycle. It has previously been thought that the rise in circulating estradiol during the luteal phase of the menstrual cycle was due to the steroidogenic activity of the CL [83]. Although the CL does produce estradiol during the luteal phase, the levels observed in the present analysis are more consistent with the notion of a follicular, rather than luteal, origin of estradiol.

We were not able to identify differences in the concentrations of estradiol and LH in women exhibiting major versus minor patterns of follicle-wave development. In retrospect, the every-third-day stratification scheme used for drawing blood was insufficient to allow finely detailed correlations between reproductive hormone levels and the wavelike nature of follicular development we observed. These findings, taken together with observations from a recent study [84], indicate that more frequent (e.g., twice daily) venipuncture is necessary to quantify the precise changes in circulating concentrations of gonadotropins and steroid hormones during a woman's cycle and relate them to specific patterns of follicular growth. However, this approach is considered unfavorably by most research volunteers.

Human follicular development, in its entirety, occurs from a diameter of approximately 0.03 mm and continues for more than 150 days until ovulation is achieved [4]. We were able to examine follicles at only advanced stages of development (i.e., >=4 mm) over the course of only one cycle. It appeared, although we were not able to quantify, that follicular development in women may occur as a hierarchy. Follicles >=4 mm grew in minor and major waves of development while smaller follicles (i.e., <4 mm) appeared to grow and regress in a random fashion during the IOI. The growth dynamics of follicles <4 mm in women are not known. Future work in this area will provide valuable insight into understanding the mechanisms of follicle recruitment, selection, and endocrine regulation of follicular growth and atresia. We expect that the use of three-dimensional ultrasonographic imaging technologies will allow us to identify precise changes in the location and morphology of follicles and corpora lutea in the ovary, not currently possible using two-dimensional imaging techniques. Future studies should also evaluate whether luteal progesterone plays a role in regulating the development of major and minor follicular waves in women.

The discovery that major and minor waves of follicle development occur during the menstrual cycle provides a new model for understanding human ovarian follicular development. Selection of a dominant follicle for preferential growth and development to an ostensibly ovulatory diameter can occur at more than one time during the menstrual cycle. We anticipate that the knowledge of major and minor follicular waves in women will have profound implications for the study, diagnosis, and treatment of female infertility (i.e., ovarian stimulation for ovulation induction and in vitro fertilization) and the development of safer and more efficacious hormonal contraceptive formulations.


   ACKNOWLEDGMENTS
 
The authors would like to thank the volunteers whose participation and dedication was invaluable for the completion of this study. Appreciation is expressed to Dr. Norman Rawlings and Susan Cook at the Prairie Diagnostics Services Laboratory at the University of Saskatchewan for their expertise in endocrine immunoassays.


   FOOTNOTES
 
1 Supported by a grant from the Canadian Institutes of Health Research. Portions of these data were presented at the 48th Annual Meeting of the Canadian Fertility and Andrology Society, Charlevoix, Quebec, Canada, September 2002, and the 58th Annual Meeting of the American Society for Reproductive Medicine, Seattle, Washington, October 2002. Back

2 Correspondence: Roger A. Pierson, Department of Obstetrics, Gynecology and Reproductive Sciences, Room 4512 Royal University Hospital, Saskatoon, SK, Canada S7N 0W8. FAX: 306 966 8796; pierson{at}erato.usask.ca Back

Received: 31 March 2003.

First decision: 29 April 2003.

Accepted: 12 May 2003.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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