1 Research Institute of Endocrinology, Reproduction and Metabolism, Department of Obstetrics and Gynaecology, Polikliniek VEVO and 2 Department of Clinical Epidemiology and Biostatistics, Free University Hospital, PO Box 7057, 1007 MB Amsterdam, The Netherlands
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Abstract |
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Key words: ageing/menstrual cycle/ovary/polycystic ovary syndrome
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Introduction |
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The treatment of enlarged polycystic ovaries by wedge-resection can lead to regular menstrual cycles in PCOS patients (Stein and Leventhal, 1935; Goldzieher et al., 1962; Buttram and Vaquero, 1975
; Goldzieher, 1981
; Dahlgren et al., 1992a
). These observations led us to postulate that the enlarged antral follicle cohort is an aetiological factor in PCOS and that a decrease in size of the cohort leads to restoration of the functional balance for regular ovulatory cycles in the PCO ovary.
Ovarian ageing is known to be a process of ovarian follicle loss starting even before birth. Faddy et al. (1992) constructed a mathematical model of follicle disappearance with age on the basis of pooled data from different studies on follicle numbers in ovaries of women of different ages (Faddy et al., 1992). There appears to be a gradual loss of follicles throughout the years and from ~37 years onwards there is an accelerated decline of the remaining follicles. Another proof of a reduced follicle cohort in ageing women was documented by Friedrich et al. (1975). He punctured all visible tertiary follicles of 220 mm during a gynaecological operation in 65 women and found an average of six oocytes in women aged up to 40 years as opposed to only three oocytes in older women (4153 years) (Friedrich et al., 1975
).
The aim of our study was to investigate if a reduction of the antral follicle cohort due to ageing, as described by the model for follicle disappearance, also leads to regular menstrual cycles in PCOS patients.
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Materials and methods |
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Patients and study design
Retrospectively, we traced all patients registered as having PCOS in the out-patient clinic of the Division of Reproductive Endocrinology and Fertility of the Free University Hospital in Amsterdam, by screening their medical charts for the combination of oligo- or amenorrhoea and an increased luteinizing hormone (LH) concentration in the presence of a normal follicle stimulating hormone (FSH) concentration.
We retrieved the current addresses of the patients by searching a computerized telephone book or by consultation of the records of municipal registry offices. We invited the patients to participate in our study by letter in which we did not mention the hypothesis: gaining regular menses with age. When the patient consented, one of the authors (T.J.M.K.) performed a structured interview by telephone. If no response was obtained to the first letter, a second mailing was sent.
Data from the charts
We screened the medical charts for the following items: dates of the first and last visit, oligo- or amenorrhoea and an elevated LH concentration, hirsutism, acne, body mass index (BMI), concentrations of FSH, prolactin, androstenedione, testosterone and oestradiol, treatment with clomiphene citrate or gonadotrophins for induction of ovulation.
Data from the questionnaire
We divided the questionnaire into several question categories as shown in Table I.
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Assays
The commercial assays used to determine LH and FSH changed in 1988 from polyclonal radioimmunoassay (Amerlex, Amersham, UK) to monoclonal radioimmunoassay (MAIA, Serono). Our endocrine laboratory tested the different assays in PCOS patients, and by means of linear regression lines found new thresholds for elevated LH and FSH concentrations. The upper limit of normal for LH changed from 12 IU/l to 6.5 IU/l, and for FSH from 12 IU/l to 10 IU/l. Later on, the MAIA assays were replaced by Amersham immunometric assays for LH and FSH which, however, did not lead to different thresholds.
Data analysis
We questioned and evaluated all patients of 30 years and older and analysed the actual menstrual cycle pattern at the time of the interview for each patient. The answer scores were categorized according to the age of the patient on the date of the interview in one of the following groups: 3035, 3638, 3941, 4245, 4650 and 5155 years. For analysis, we divided the cases with answer scores 1 to 5 in a regular group (score 1) and an irregular group (score 25). Regularity of the cycle was related to the age groups by means of a 2 test for a linear trend. To test if the relationship between age and regularity of the cycle could be confounded by one of the following variables: BMI, weight loss, hirsutism, ethnic origin, smoking, previous treatment with clomiphene citrate or gonadotrophins, previous pregnancy and the interaction of these variables with age, we performed a forward-stepwise logistic regression analysis. For all tests the significance level was 0.05.
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Results |
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Patients
The first visit was 12 years (mean) before the interview (range: 1.731.6). The patients' mean age was 26.7 years (range: 14.941.3) at that time. When interviewed the mean age was 38.7 years (range: 30.355.7). None of the patients was wedge-resected in the past.
Menstrual cycle pattern
Of the 346 patients, 121 patients (35%) used oral contraceptives (OC), 10 (3%) used hormones for infertility treatment, seven (2%) had a hysterectomy in the past, one had reached menopause and two had no cycle because they were breast-feeding. We excluded these women (141) from analysis. Of the remaining 205 patients, 123 (60%) had a menstrual cycle shorter than 6 weeks (score 1) and 82 patients had a score varying between 2 and 5. Analysis showed a strong inverse correlation between age and cycle length (P < 0.001). The proportion of women with regular menstrual cycles increased in the various age groups, from 40.6% in the group of 3035 years to 100% in the oldest group of 5155 years of age (Figure 1).
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Previous treatment with clomiphene citrate or with gonadotrophins for induction of ovulation did not differ between the regularly and the irregularly menstruating group (clomiphene citrate: P = 0.45, gonadotrophins: P = 0.84). Pregnancy (miscarriages and ectopic pregnancies included) occurred in 87.8% of the regularly menstruating group and in 84.1% in the irregularly menstruating group (P = 0.46). Ethnic origin or smoking habits (actual smoking or in smoking years) showed no differences between the groups. When performing logistic regression analysis for hirsutism, previous treatment with clomiphene citrate, previous treatment with gonadotrophins, previous pregnancy, ethnic origin, smoking or the interactions of these variables with age, none of the variables did influence the effect of age on the regularity of the menstrual cycle. In a step-forward logistic regression with all variables, age was the first and most significant variable, after which only BMI had some significance.
Change in menstrual cycle pattern according to the patient
Of the 205 patients, 144 answered that their menstrual cycle pattern changed, 137 (95%) found it to be shorter and seven (5%) to be longer. The remaining patients (n = 19) were not able to determine any change. Fifty patients mentioned that the pattern changed after a delivery, two after weight loss, two mentioned stress and 90 patients did not recognize any event after which the cycle pattern changed.
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Discussion |
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Several studies reported on the efficacy of wedge-resection in gaining regular cycles in PCOS patients. In a world-wide review of 1079 wedge-resected PCOS patients a wide range of normalization to regular cycles was reported in 695%, and pregnancies in 1389% (Goldzieher, 1981) (original study: Goldzieher and Green, 1962). In another study (Buttram and Vaquero, 1975
), 93.7% of 173 wedge-resected patients showed improvement of menstrual cyclicity (31.8% temporary). An explanation for this effect of wedge-resection on the menstrual cycle could be that an acute reduction of the follicle cohort leads to a new balance in the polycystic ovary between FSH and inhibin B. The combination of oligo- or amenorrhoea and the enlarged antral follicle cohort in PCOS can be caused by the production of inhibin B by antral follicles. Groome et al. (1996) found an increase in the early follicular phase of inhibin B in parallel with FSH, but with a peak value 4 days after the peak of FSH. They suggested that inhibin B might be produced by the small antral follicles as well as by the selected dominant follicle (Groome et al., 1996
). The production of inhibin B by the small antral follicles is supported by the observation of mRNA production of the ß-B subunit of inhibin in these follicles (Roberts et al., 1993
). As previously reported (Anderson et al., 1998
; Lockwood et al., 1998
), the basal inhibin B is elevated in patients with PCOS. This elevated inhibin B, produced by the enlarged antral follicle cohort, explains the relatively low FSH in women with PCOS and the stagnation of the selection process of the dominant follicle leading to arrested follicle growth and consequently cycle disturbances. A reduction in the number of antral follicles as done by wedge-resection would lead to a lower basal inhibin B concentration and consequently to a relative increase in FSH, inducing follicular growth and spontaneous ovulations. Supportive for this explanation are the findings of Lockwood et al. (1998) who treated four PCOS women with a laparoscopic diathermy and found a normalization of the inhibin B concentration post-operatively (Lockwood et al., 1998
).
Dahlgren et al. (1992a) mentioned for the first time the occurrence of regular menstrual cycles in older patients with PCOS. In a long-term follow-up study she examined 33 patients of 4459 years of age, wedge-resected 2030 years earlier. When pre-operatively 81% and post-operatively 61% of these patients were oligomenorrhoeic, there were only 28% left to have an oligomenorrhoea in their latest decade (Dahlgren et al., 1992). This report points in the direction of the influence of age on the normalization of menstrual cycles in PCOS patients. Our study confirms this in PCOS patients not previously wedge-resected. We suggest that this phenomenon is related to the decline of the follicle cohort because of ageing (Faddy et al., 1992). Also ovarian ageing leads to a new balance between inhibin B and FSH in the early follicular phase. This can be concluded from recent publications (Klein et al., 1996
; Reame et al., 1998
; Welt et al., 1999
) that compared FSH, inhibin A and B concentrations in the early follicular phase of older ovulatory women with that of younger ovulatory women. In all three studies the mean inhibin B concentration was significantly lower in the older women. The longitudinal study of Welt et al. (1999) showed that the decrease in inhibin B precedes that of inhibin A and appears to be the earliest marker of the decline in the follicle cohort (Welt et al., 1999
).
Furthermore, the data from our study suggest that treatment with oral contraceptives in ageing women with PCOS is not always necessary, which is of clinical importance regarding the increased risk for cardiovascular disease and diabetes in women with PCOS (Mattson et al., 1984; Wild et al., 1985; Conway et al., 1992
; Dahlgren et al., 1992b
; Talbott et al., 1995
; McKeigue, 1996
).
In conclusion, our study shows that women with PCOS gain regular menstrual cycles when ageing. We suggest that the development of a new balance between inhibin B and FSH in the polycystic ovary, solely caused by follicle loss through the process of ovarian ageing, can explain the occurrence of these regular cycles. Measurements of inhibin B and FSH in older PCOS women need to be done to confirm this. Finally, our findings support the hypothesis that the enlarged antral follicle cohort is a main factor in the aetiology of the PCOS.
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Acknowledgments |
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Notes |
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References |
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Submitted on May 5, 1999; accepted on October 12, 1999.