The prevalence of polycystic ovaries in healthy women

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1 Acta Obstet Gynecol Scand 1999; 78: Copyright C Acta Obstet Gynecol Scand 1999 Printed in Denmark all rights reserved Acta Obstetricia et Gynecologica Scandinavica ISSN ORIGINAL ARTICLE The prevalence of polycystic ovaries in healthy women RIITTA KOIVUNEN 1,TIMO LAATIKAINEN 2,CANDIDO TOMÁS 1,ILPO HUHTANIEMI 3, JUHA TAPANAINEN 1 AND HANNU MARTIKAINEN 1 From the Department of Obstetrics and Gynecology, 1 University Hospital of Oulu, Oulu, 2 Helsinki City Maternity Hospital, Helsinki, and the 3 Department of Physiology, University of Turku, Turku, Finland Acta Obstet Gynecol Scand 1999; 78: C Acta Obstet Gynecol Scand 1999 Background. To study the prevalence of polycystic ovaries (PCO) in women of reproductive age. Methods. A total of 189 healthy volunteers aged years were examined. The subjects were divided into two groups according to age: Æ35 and Ø36 years. Transvaginal ultrasonography was performed and blood samples were collected on cycle day 1 6. Results. The prevalence of PCO in the entire study population was 14.2% (27/189). In the age group of Æ35 years the prevalence was 21.6% (19/88) and in the age group of Ø36 years 7.8% (8/101). Compared to women with normal ovaries, those with PCO had significantly higher serum testosterone (T) concentrations. Women with PCO tended to have lower serum FSH concentrations and higher LH/FSH ratios than controls. Women with PCO had significantly more irregular cycles (44% vs. 19%, pω0.001) and problems in conceiving (25.9% vs. 9.2%, pω0.01) than women with normal ovaries. Conclusions. The findings demonstrate that the prevalence of PCO in healthy women varies with age, being more common among women aged Æ35 years than in those aged Ø36 years. Although the hormonal parameters and clinical findings among women with PCO mimicked those of PCOS, it remains unclear if these women will later develop full-blown syndrome. Key words: polycystic ovaries (PCO); prevalence; ultrasonography Submitted 14 May, 1998 Accepted 7 September, 1998 Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of fertile age. The classical diagnosis of PCOS includes oligomenorrhea or amenorrhea, hirsutism and/or acne, infertility, an elevated LH/FSH ratio and/or hyperandrogenism and enlarged, rounded ovaries with numerous subcapsular follicles (1). The prevalence of PCOS varies depending on the diagnostic criteria used. When biochemical Abbreviations: BMI: body mass index; FSH: follicle-stimulating hormone; LH: luteinizing hormone; NIDDM: non-insulin dependent diabetes mellitus; NS: not statistically significant; PCO: polycystic ovaries; PCOS: polycystic ovary syndrome; s.d.: standard deviation; SHBG: sex hormone-binding globulin; T: testosterone; TA: total area. parameters were used, the prevalence of PCOS varied from 2.5% to 7.5% (2). When characterized by anovulation and hyperandrogenism, the prevalence of PCOS was about 6% (3). Recent refinements in ultrasound technology have remarkably improved the detection of ovarian morphology, particularly in obese patients. In previous studies using transabdominal ultrasonography, the prevalence of PCO among normal women has varied between 16% and 23% (4 8). A higher prevalence of PCO (27%) has been observed, however, using transvaginal ultrasonography (9). So far, age dependence of PCO has not been investigated among women of reproductive age. To explore this issue, we examined healthy women by transvaginal ultrasonography and di-

2 138 R. Koivunen et al. vided the subjects into two different age-groups. We also correlated the findings with endocrine markers of PCOS. Material and methods The study population consisted of 189 volunteers aged years. They were all healthy and had not been treated for menstrual disturbances, infertility or hirsutism. When these women were recruited, it was decided that only women without gynecological problems would be included in the study. Subjects using medication (including oral contraceptives), pregnant subjects or subjects using a hormonal intrauterine device were excluded. Transvaginal ultrasonography was performed and blood samples obtained on cycle day 1 6. Fasting venous blood samples were collected at a.m. after a rest for 30 min. The blood was allowed to clot and serum was separated and stored at ª20æC until later hormonal analyses. All the women filled in a questionnaire which included details of their menstrual cycle and reproductive history and a subjective assessment of hirsutism and acne. Obesity was assessed by body mass index (BMI, kg/m 2 ). Forty-two (22.2%) women were obese with a BMI ±25 kg/m 2. Hirsutism was graded using the Ferriman-Gallwey scoring system (10); the subject was considered hirsute if the score exceeded 7. A regular menstrual cycle was defined as a cycle with a maximum minus minimum length of 4 days and with an intermenstrual interval of 21 to 35 days (5). A menstrual cycle was considered irregular if the maximum minus minimum length of the cycle was ±4 days even though the intermenstrual interval was 36 days. If the woman had failed to conceive within a period of one year during her reproductive history, she was considered to have a subfertility problem. The study protocol was approved by the Ethics Committee of the University of Oulu, Finland. Transvaginal ultrasonography Transvaginal ultrasound scanning was performed by one observer (R.K.) (Toshiba SSA-270A; transvaginal probe PVF-651VT, 6 MHz). Polycystic ovaries were defined as 10 or more follicles 2 8 mm in diameter in one plane of each ovary in association with increased and/or hyperechogenic ovarian stroma, which was evaluated visually, using the criteria described by Adams et al. (11). The total area (TA) of the ovaries, which can be easily assessed by carefully shaping a strict longitudinal cut, was also noted. An increased total ovarian area (±5.5 cm 2 ) has been shown to have the same diagnostic value as an increased stromal area detected by computerized measurement (12). Ovarian volumes were calculated using a simplified formula for a prolate ellipse (1/2 X maximal longitudinal X maximal anteroposterior X transverse diameters) (13). The volume and the TA of the ovaries in women with ovarian cysts Ø30 mm in diameter were not included. Hormone analysis Serum concentrations of immunoreactive FSH and LH were measured with immunofluorometric assays (IFMAs) using Delfia A reagent kits (Wallac OY, Turku, Finland). Testosterone concentrations were measured using an Auto Delphia fluoroimmunoassay kit (Orion Diagnostica, Turku, Finland). Statistical analysis The reproductive histories of normal women and those with PCO, and the prevalence of PCO between the age groups were compared using the Chi-square test. The hormonal data were analyzed by using the Mann-Whitney U-test for comparisons between normal and PCO women in both age groups. All analyses were done using Stat View tm II for Macintosh (StatView tm II, Abacus Concepts, inc., California, USA). Results PCO vs. normal ovaries The clinical and hormonal data of the women with normal ovaries and the women with PCO are shown in Table I. The prevalence of PCO in the entire study group was 14.2% (27/189). BMI did Table I. Clinical and hormonal data in women with normal and polycystic ovaries. (The results are presented as mean s.d. or percentages). For the comparison of menstrual irregularities and infertility the X 2 -test was used. All the other data were analyzed using the Mann-Whitney U-test Normal PCO Age BMI (kg/m 2 ) Menstrual irregularities (%) a Infertility (%) a Ovarian volume (sum, cm 3 )* a Total area of ovary (sum, cm 2 )* a FSH (U/L) a LH (U/L) LH/FSH a Testosterone (nmol/l) a SHBG (nmol/l) a p 0.05 compared to women with normal ovaries. * ovarian cysts were excluded.

3 Prevalence of PCO 139 Table II. Hormonal and clinical parameters ( mean s.d.) in the different age groups. Volume and total area (TA) were not considered in women with cysts Ø30 mm in diameter. For the comparison of prevalences between the age groups the X 2 -test was used. All the other data were analysed using the Mann-Whitney U- test Æ35 Ø36 Age-group Normal PCO Normal PCO n (21.6%) 94 8 (7.8%) a BMI (kg/m 2 ) Volume (sum, cm 3 ) b TA (sum, cm 2) b FSH (U/L) LH (U/L) LH/FSH c Testosterone (nmol/l) SHBG (nmol/l) a p 0.05 compared to PCO women in the age group Æ35 years. b p 0.01 compared to normal women in the age group Æ35 years. c p 0.05 compared to normal women in the age group Ø36 years. not differ significantly between the normal and PCO women ( (s.d.) vs kg/m 2, NS) (Table I). One woman with PCO and one with normal ovaries were hirsute, with Ferriman- Gallwey scores ±7. Women with PCO had significantly more irregular cycles than women with normal ovaries (12/27 PCO vs. 31/162 normal, pω0.001). None of the women had oligomenorrhea. Women with PCO significantly more often had subfertility problems than normal women (25.9% vs. 9.3%, pω0.01). Despite this, all of the women who failed to conceive within a year, conceived spontaneously within 3 years without any infertility treatment (Table I). In our study population 130 women had tried to conceive (112 with normal ovaries and 18 with PCO). All of them had succeeded by the time of study. Eleven percent of the women with PCO had had a miscarriage, compared with 17% of the women with normal ovaries (NS). The volume and the total area of the ovaries (sums of both ovaries) were significantly higher in women with PCO compared with normal women (volume: (s.d.) vs cm 3, pω 0.03; TA: vs cm 2, pω0.001) (Table I). Of the entire study population, women with PCO had significantly lower FSH concentrations than normal women ( vs U/L, pω 0.03). The serum LH level tended to be higher and the LH/FSH ratio was significantly higher in women with PCO compared with normal women ( vs , pω0.006). Women with PCO also had significantly higher T-levels than normal women ( vs nmol/l, pω 0.01) (Table I). Effect of age The prevalence of PCO was 21.6% (19/88) in women aged Æ35 years and 7.9% (8/93) in women aged Ø36 (pω0.04) (Table II). The mean sum ovarian volume and TA (sum of both ovaries) were significantly higher in women with PCO than in normal women in the age group of Æ35 years. In the age group of Ø36 years, only the LH/FSH ratio was significantly higher in women with PCO compared with normal women (Table II). The hormonal parameters showed a tendency towards changes characteristic of PCOS. However, only in the age group of Ø36 was the LH/FSH ratio significantly higher among women with PCO than in normal women ( vs ) (Table II). Discussion The present results demonstrate that the prevalence of PCO is dependent on age among healthy women, the prevalence being significantly higher in the younger age group (Æ35 years) than among older women (Ø36). The prevalence of PCO in the entire study population was 14.2%, which is slightly lower than that reported (16 23%) in previous studies (4 8). The selection criteria of the study subjects have varied in the different studies, which makes any comparison difficult. In our study, all subjects were healthy and without the typical symptoms of PCOS, which may explain the lower prevalence of PCO compared with that in unselected populations. In a study by Polson et al. (5), where the selection criteria were similar to ours, the prevalence of PCO was 23%. The ages of

4 140 R. Koivunen et al. their patients varied from 18 to 36 years, so the prevalence of PCO is comparable to that in our study, where the prevalence of PCO in women Æ35 years old was 21.6%. Differences in age distributions of study populations, which have not usually been mentioned, may at least partly explain the variability in previous studies. The 88 women aged Ø36 years in our study may explain the lower prevalence of PCO in comparison with earlier studies. However, there is also a study where polycystic ovaries were found in 37% of postmenopausal women (14). The ultrasonographic technique may also affect the results obtained. Transabdominal ultrasonography was used in most previous studies (4 8). By using transvaginal ultrasonography the prevalence of PCO has been found to be higher (27%) than by using the transabdominal method (21%) (9). Our criteria for polycystic ovaries were very strict, which may have had an effect on the relatively low prevalence of PCO observed in the present study. At the moment, the prognostic significance of PCO among asymptomatic women is unclear. Women with PCO appear to have a higher incidence of minor cycle irregularities and significantly more problems in conceiving than normal women. Despite this, all of the women who failed to conceive within a year conceived spontaneously within 3 years without any infertility treatment. By the time of this study, equal numbers of women in the PCO and control groups had proved their fertility, which is in accordance with results published by Clayton et al. (7). The number of subjects suffering from subfertility was small in the present study, as it was in the study by Clayton et al., which makes it difficult to draw any definitive conclusions. PCOS is commonly related to obesity (15). The present results revealed no tendency towards an elevated BMI in women with PCO compared with normal women in the two age groups. It has earlier been postulated that some women with mild or occult PCO may be symptomless until gradually accumulating adiposity begins to contribute to ovarian dysfunction (16). It is unclear if lean women with PCO may later develop PCOS by gaining weight. The hormonal parameters in women with PCO showed a tendency towards changes characteristic of PCOS patients. In both age groups, serum SHBG levels tended to be lower in women with PCO than in normal women. Although not examined in this study, this tendency may reflect increased insulin secretion, which is known to inhibit SHBG synthesis (17). Women with PCOS are known to have profound peripheral insulin resistance and hyperinsulinemia and to be at risk of non-insulin-dependent diabetes mellitus (NIDDM) (18). It has been shown that full-blown PCOS with hyperandrogenism and anovulation only exists in women with PCO and hyperinsulinemia (19 21). In conclusion, the prevalence of PCO appears to be dependent on age among healthy women, the prevalence being significantly higher in younger (Æ35) than in older women (Ø36). The hormonal parameters and clinical findings among women with PCO mimicked those associated with PCOS. Longitudinal studies are needed to clarify the question of whether these women will later develop full-blown syndrome or if the ultrasonographic appearance of PCO disappears with increasing age in clinically symptomless women. References 1. Futterweit W, Mechanick JI. Polycystic ovarian disease: etiology, diagnosis and treatment. Compr Ther 1988; 14: Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: Goldzieher J. Polycystic ovarian disease. Fertil Steril 1981; 35: Gadir AA, Khatim MS, Mowafi RS, Alnaser HMI, Muharib NS, Shaw RW. 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5 Prevalence of PCO 141 polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 1995; 15: Dahlgren E, Johansson S, Lindstedt G, Knutsson F, Oden A, Janson PO et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992; 57: Singh A, Hamilton-Fairley D, Koistinen R, Seppälä M, James VH, Franks S et al. Effect of insulin-like growth factor type I (IGF-I) and insulin on the secretion of sex hormone binding globulin and IGF-I binding protein (IGBP- I). J Endocrinol 1990; 124: R Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in the polycystic ovary syndrome. Diabetes 1989; 38: Conway CS. Polycystic ovary syndrome: clinical aspects. Bailliere s Clin Endocrinol Metab 1996; 10: Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance and/ or hyperinsulinemia. J Clin Endocrinol Metab 1987; 65: Sharp ES, Kiddy DS, Reed MJ, Anyaoku V, Johnston DG, Franks S. Correlation of plasma insulin and insulin like growth factor-i with indices of androgen transport and metabolism in women with polycystic ovary syndrome. Clin Endocrinol 1991; 35: Address for correspondence: Riitta Koivunen, M.D. Department of Obstetrics and Gynecology University Hospital of Oulu PL Oulu, Finland