Histological Evidence of Alternating Ovulation in Women A
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Histological evidence of alternating ovulation in women A. Gougeon and Brigitte Lef\l=e`\vre Physiologie et psychologie de la reproduction humaine, INSERM U-187, 32 rue des Carnets, 92140 Clamart, France Summary. Detailed histological analysis of ovaries obtained from 25 women by ovariectomy for medical reasons demonstrated that the degeneration of the cyclic corpus luteum is a long process, taking several cycles. The ages of the various regressing corpora lutea were identified to permit classification of the side of ovulation during the preceding 4 or 5 cycles. In the 25 women studied, with regular menstrual cycles of 28 \m=+-\3 days (48 cycles), ovulation occurred most often (87\m=.\6%)in an alternating manner. Introduction It is not known whether the single follicle that ovulâtes in each cycle of primates does so by chance in either of the two ovaries or is influenced by the side of ovulation of the preceding cycle. The follicle destined to ovulate and/or the cyclic corpus luteum could influence follicular development in such a way that the selection of the dominant follicle is not by chance. Riihl (1925) suggested that ovulation in women was alternate, but his results, obtained from post-mortem ovaries, were not quantitative or illustrated. The question is also unresolved in non-human primates. Wallach, Virutamasen & Wright (1973) and Clark, Dierschke & Wolf (1978) reported that ovulation occurred by chance in either ovary, uninfluenced by the side of ovulation in the previous cycle in the rhesus monkey. However, Dukelow (1977) and Hodgen (1982) consider that ovulation in the cynomolgus monkey and rhesus monkey, respectively, occurs alternately as long as the cycles are not perturbed. The present study was undertaken to determine whether human ovulation is alternate and was based upon histological examination of pairs of ovaries. The studies of Corner, Bartelmez & Hartman (1936) and Corner (1942) have shown that the ages of involuting corpora lutea in rhesus monkeys can be determined. In the normal human ovary, this assessment is facilitated by the absence of the corpora aberrantia that occur in the rhesus monkey ovary (Corner, 1942) and the identification of corpora lutea of different ages permits deduction of the side of ovulation during the preceding cycles. Materials and Methods Sampling Pairs of ovaries were obtained during gynaecological surgery (ovariectomy for carcinoma of the breasts or cervix, hysterectomy for fibroids). They were fixed in Bouin's fluid or a mixture of alcohol, formaldehyde and acetic acid, processed by routine histological methods and then serially sectioned at 10 pm. 0022-4251 /84/010007-09S02-00/0 © 1984 Journals of Reproduction & Fertility Ltd Downloaded from Bioscientifica.com at 10/04/2021 04:33:08AM via free access Ovarian function was considered to be normal after verification of (i) the absence of morphological pathology of the ovary; (ii) regular cycles, i.e. 28 + 3 days, determined over the 2 previous cycles, and (iii) the occurrence of ovulation in each of the preceding 3 cycles, corroborated by the presence of corpora lutea at various stages of degeneration (see below). After verification of these criteria 25 pairs of ovaries were retained for study. The women were aged 19-52 years (mean + s.d. = 40-0 ± 8-5 years). Calculations Corpus luteum dimensions were measured using an eyepiece micrometer. The diameter was taken as the mean of three measurements: the first two being made at right angles to each other in the section showing maximal corpus luteum area and the third was the number of sections in which the corpus luteum was present, multiplied by 0-01 mm (the thickness of each section). Cellular and nuclear diameters were measured using an eyepiece micrometer and an oil immersion 100 objective. Methodology Histological examination of the 50 ovaries revealed the presence of large structures (2-10 mm in diameter) at various stages of involution. Comparison of the histological appearance of the functional corpus luteum of the cycle and the least involuted of these structures revealed similar histological characteristics, indicating that these involuting structures are corpora lutea at different stages of regression. All the ovaries taken during the same half of the cycle (i.e. follicular or luteal) showed an identical number of regressing corpora lutea (5 and 4 respectively), the difference indicating that the corpora lutea in samples taken during the follicular phase were, on average, half a cycle younger than those in luteal phase samples (Text-fig. 1). The oldest recognizable corpus luteum in the follicular phase therefore represents the last regression stage that can be dated reliably ; the ages of older corpora lutea cannot be estimated due to their transformation into corpora albicantia. Follicular 0 5 1-5 phase 2 5 3-5 4-5 ma _ _ _ [ _ F CL 2a CL 3a CL 4a CL 5a CL 6a CL1 CL 2b CL 3b_CL 4b CL 5b "ET w luteal phase Text-fig. 1. Age of the involuting corpus luteum observed in the samples obtained during the follicular or luteal phases of the menstrual cycle, m = menstruation. In each of the 25 pairs of ovaries, the 4 or 5 involuting corpora lutea could be distinguished from each other by their morphological characteristics, although fragmentation of the oldest corpora lutea, caused by follicular development, may have made estimation of their age more difficult, particularly from the stage 4a (Table 1). Each corpus luteum may therefore be considered as representative of a stage of luteal regression. These various stages of regression, showing the same morphological characteristics, were seen in all the samples taken in the same halfof the cycle (PI. 1, Figs 1-6; PI. 2, Figs 7-12). 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If this had not been the case then at least one involuting corpus luteum would have been absent, reflecting the existence of an anovulatory cycle. Such anovulatory cycles do exist in women. In several other ovaries that we have studied one or more involuting corpora lutea were missing, but since the aim of the present study was the investigation of normal folliculogenesis, which implies an ovulation in each cycle, such samples were excluded from the study material. After determination of the ages of the involuting corpora lutea it was necessary to identify the ovulating ovary during the cycle of ovariectomy. This ovary showed the following characteristics : (i) during the first half of the follicular phase it was the ovary that contained the largest healthy follicle (Gougeon & Lefèvre, 1983); (ii) during the second half of the follicular phase it was the ovary that contained a large healthy follicle which in turn showed the histological characteristics of follicles destined to ovulate (Bomsel-Helmreich et al, 1979); and (iii) during the luteal phase it was the ovary that contained the most recent corpus luteum. Together, the data relating to the side of ovulation during the cycle of ovariectomy and the ages and localization of the involuting corpora lutea permitted easy determination of the side of ovulation during the preceding 4 or 5 cycles. Results The side of ovulation was analysed for 5 consecutive cycles in 13 women operated on during the follicular phase, and for 4 consecutive cycles in 12 women operated on during the luteal phase (Table 2). The mean duration of the cycles in the whole group of 25 patients was 27-8 + 31 days (mean + s.d., 48 cycles). Table 2. Distribution of contralateral and ipsilateral ovulations during 4 or 5 consecutive cycles in 25 women Corpus luteum stage CL2 CL3 CL4 CL5 CL6 No. of contralateral ovulations* 20 22 22 23 12 No. of ipsilateral ovulations* 5 3 3 2 1 * Compared with corpus luteum or the dominant follicle. PLATE 1 Figs 1 & 2. CL 1 : a cyclic corpus luteum (Day 20-24 of a 28-day cycle). The central cavity is filled with a fibrin network (f.n.), and the luteal cell nuclei are spheroidal with many visible nucleoli.