- Email: [email protected]
Ovarian volume in normal and hyperandrogenic adolescent women
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
Ovarian volume in normal and hyperandrogenic adolescent women Franca Fruzzetti, M.D.,a Anna Maria Campagna, M.D.,b Daria Perini, M.D.,a and Enrico Carmina, M.D.b a Department of Obstetrics and Gynecology, University of Pisa, Pisa; and Palermo, Palermo, Italy
b
Endocrinology and Metabolism, University of
Objective: To study the threshold for increased ovarian size during different periods of adolescence. Design: Cross sectional study with retrospective analysis. Setting: University center. Patient(s): A total of 146 hyperandrogenic adolescent women and 72 healthy adolescent controls. Intervention(s): Intravaginal or transabdominal ovarian sonography. Main Outcome Measure(s): Determination of normal ovarian size during the different phases of adolescence calculated using the ellipsoid formula; calculation of threshold for increased ovarian size during different adolescent gynecologic ages and prevalence of increased ovarian size for hyperandrogenic girls at different gynecologic ages. Result(s): In adolescent women, the threshold for increased ovarian size was 11.5 cm3 during first 2 years from menarche, 10.5 cm3 during the third year from menarche, and 10 cm3 during the fourth and fifth years from menarche. The prevalence of increased ovarian size in hyperandrogenic adolescents was around 50% from the third to fifth years from menarche and 35% during the first 2 years from menarche. Conclusion(s): After the first 2 years from menarche, the thresholds for increased ovarian size are similar to those used among adults. During first 2 years from menarche, ovarian size is larger, and differentiation between normal or increased ovarian sizes may be more difficult. In hyperandrogenic adolescent patients, the prevalence of increased ovarian size is relatively low (ranging from 35% to 50% during the different periods of adolescence). In these patients, increased ovarian size may have low sensitivity as a criterion for the diagnosis of possible polycystic ovary syndrome. (Fertil Use your smartphone SterilÒ 2015;-:-–-. Ó2015 by American Society for Reproductive Medicine.) to scan this QR code Key Words: Adolescence, adolescent ovarian size, adolescent PCOS, hyperandrogenism, and connect to the increased ovarian size, PCOS Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/fruzzettif-ovarian-volume-adolescent-girls/
T
he possibility making a diagnosis of polycystic ovary syndrome (PCOS) in adolescents remains controversial (1). In fact, the same criteria—anovulation, hyperandrogenism, and polycystic ovaries—that are used for diagnosis in adults may be transitory or in evolution, in adolescents (2–4). In our literature review several years ago we suggested that the diagnosis of PCOS during adolescence may be reasonably suspected if the same three criteria are contemporaneously present in girls
who are at least 2 years past menarche (1). However, the definition of polycystic ovaries can be difficult at this age. In adult women, follicular count seems to be a more useful measure than increased ovarian size for defining polycystic ovaries (5), but during adolescence the number of follicles is particularly high (6), so the threshold for defining increased follicular count used in adult women may be incorrect. In addition, a precise follicular count may require transvaginal ovarian so-
Received December 6, 2014; revised March 7, 2015; accepted March 24, 2015. F.F. has nothing to disclose. A.M.C. has nothing to disclose. D.P. has nothing to disclose. E.C. has nothing to disclose. Reprint requests: Enrico Carmina, M.D., Endocrinology and Metabolism, University of Palermo, Via delle Croci, 47, 90139 Palermo, Italy (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.03.026 VOL. - NO. - / - 2015
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
nography, a methodology that is often not possible in young girls. Thus, it has been suggested that increased ovarian size may be of more use in the diagnosis of polycystic ovaries in adolescent girls (7). However, ovarian size is larger during adolescence than adulthood (8), and its progressive reduction with gynecologic age (9, 10) complicates its use for diagnosing polycystic ovaries. Our previous review suggested using the same cutoff of 10 cm3 in adolescents and adults (1), but the available data to support this cutoff are few (11) and are mainly based on a magnetic resonance imaging (MRI) study of adolescent ovaries (9). In this study, we assessed ovarian size in a group of healthy adolescent girls and for comparison in a large group of hyperandrogenic adolescent 1
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY girls. Because the available data show that ovarian size decreases with the progression of adolescence, we divided our controls and patients according their gynecologic age and determined the ovarian size cutoffs during the different phases of adolescence.
Biochemical hyperandrogenism was defined as serum T >60 ng/dL (R2.08 nmol/L) and/or serum DHEAS 3 mg/mL (R7.8 mmol/L). These values for hyperandrogenism had been previously validated in adult women with the use of the previously described assays.
MATERIALS AND METHODS
Ovarian Ultrasound
This study was conducted in two Italian university centers between 2011 and 2013. The healthy adolescent women (controls) were students in two local schools who volunteered for the study. The young hyperandrogenic women were consecutive patients at the two participating institutions being treated as outpatients for clinical or biochemical signs of hyperandrogenism. We enrolled 72 healthy, menstruating, nonhyperandrogenic women, aged 11 to 17 years (mean age 13.7 1 years) of gynecologic age (time in years elapsed since menarche) of 1 to 5 years. The patients were 146 hyperandrogenic adolescents aged 11–17 years (mean age 14.1 1 years) of gynecologic ages 1 to 5 years who were retrospectively evaluated. The large majority of the young hyperandrogenic women studied (138 out of 146) had irregular menses. The two groups were not matched for age or body weight. The project design included a medical examination, biochemical analyses, and ovarian sonography. The procedures we adopted were in agreement with the Helsinki Declaration of 1975 as revised in 1983, and the study was approved by the local ethics councils. All participants in the study gave their informed consent. Because of the age of the controls and patients, legal informed consent was also obtained from authorized representatives (parents), who also were present during all stages of the medical examination, including the laboratory analyses and ovarian ultrasounds. At admission all participants underwent a medical examination and answered a questionnaire on their personal and medical information, including age, past medical history, and use of medications. All controls were studied in a single institution (Endocrinology and Metabolism, University of Palermo). None of patients or controls were taking medication from at least 3 months before entering the study. Menstrual cycles were recorded for R3 months, and normal menses were defined as a menstrual cycle interval of 24 to 35 days.
In all patients and controls, on days 3 to 6 of the cycle the ovarian morphology was assessed by intravaginal or transabdominal ultrasound using a transducer frequency of 6–10 MHz. In both centers, the same machine (MyLab 50 Xvision, Esaote) was used. Ovarian volume was calculated by the formula p/6 (DB1 DB2 DB3), where the dimensions (D) of length, width, and thickness were used. The size of both ovaries was assessed, and the mean ovarian size was calculated. In no instance did the ovarian ultrasound have to be repeated because of the finding of a dominant follicle. Both data obtained by transabdominal and intravaginal ultrasound were considered useful for the diagnosis. However, in all controls and in the large majority of hyperandrogenic adolescent patients (n ¼ 117, 80%) a transabdominal ultrasound scan was performed.
Laboratory Analyses In all patients and controls the serum levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) were determined on days 3–5 of the cycle. In non-menstruating women the blood samples were drawn after the menstrual cycle had been induced by progesterone administration. Serum hormone levels were quantified by wellestablished methods that had been validated previously in our laboratories. The total T concentrations were determined by use of a competitive immunoassay (Johnson & Johnson/ Ortho Clinical). The DHEAS concentrations were determined by use of radioimmunoassay (Orion Diagnostics). In all assays, the intra-assay and interassay coefficients of variation did not exceed 6% and 15%, respectively. 2
Statistical Analyses Statistical analyses were performed using Statview 5.0 (SAS Institute). Univariate analyses were performed using an unpaired t test for the numeric variables. Bonferroni correction for multiple comparisons was applied. Thresholds for increased ovarian size were calculated as mean 2 standard deviation (SD) of the values of the healthy controls. The results are expressed as mean SD.
RESULTS Table 1 shows the clinical data, hormone levels, and mean ovarian size of the healthy and hyperandrogenic girls. Although the two groups were not matched for age or body weight, their mean ages were similar; the hyperandrogenic adolescent girls had statistically significantly (P< .01) higher body mass index (BMI), hirsutism scores, total testosterone levels, DHEAS levels, and ovarian size compared with the healthy adolescent girls. All controls had normal menses whereas the large majority of hyperandrogenic patients had irregular menses (n ¼ 134, 92%). Table 2 reports the ovarian sizes of the healthy and the hyperandrogenic girls, divided according their gynecologic age. Because there were fewer healthy girls of gynecologic age 1, the patients of gynecologic ages 1 and 2 were regrouped. It may be observed that the younger girls (1– 2 years after the menarche) had a higher threshold (95 percentile of values of ovarian size) for increased ovarian size (11.5 cm3), but then the threshold was around 10 cm3. At any gynecologic age, the hyperandrogenic adolescents had larger ovarian sizes (P< .01) than the healthy adolescent controls (Table 2). According to these thresholds, 66 (45.2%) hyperandrogenic adolescents had increased ovarian size. VOL. - NO. - / - 2015
Fertility and Sterility®
TABLE 1 Clinical data, hormone levels, and ovarian size in healthy versus hyperandrogenic adolescent women. Adolescent girls
No.
Age (y)
BMI (kg/m2)
Total T (ng/mL)
Hirsutism scores
DHEAS (mg/mL)
Ovarian size (cm3)
Normal Hyperandrogenic
72 146
13.7 1 14.1 1
22.8 3 25.1 5.3a
36 13 68 24b
21 12.5 2.8b
2.2 0.4 2.9 1.5a
6.7 2.2 10.1 4.7b
Note: BMI ¼ body mass index; DHEAS ¼ dehydroepiandrosterone sulfate; T ¼ testosterone. a P< .01 versus healthy adolescent women. b P< .0001 versus healthy adolescent women. Fruzzetti. Ovarian size in adolescent girls. Fertil Steril 2015.
DISCUSSION It is generally reported that ovarian size is larger during the early adolescent years and then progressively reduces until reaching the size found in adult women (8, 9, 12). This complicates the use of ovarian size for diagnosing possible PCOS in adolescents because the same threshold that is used in adults may not be applicable in adolescents. However, a previous study using MRI technique determined a threshold between normal and increased ovarian size of 10 cm3 (9), the same that is generally used in adult women (5). In our study, we assessed ovarian size in a group of healthy adolescent women and in hyperandrogenic adolescent patients. Most hyperandrogenic adolescent patients had irregular menses. When the healthy (regular menses and no hyperandrogenism) adolescents were divided according their gynecologic age (time in years elapsed since menarche), the threshold for increased ovarian size was the same as found in adult women with the exception of the younger adolescents. In fact, during the first 2 years since menarche, the cutoff value between normal and increased ovarian size was 11.5 cm3 whereas in the following years the threshold was around 10 cm3 (10.5 cm3 in the third year, and 10 cm3 in the fourth and fifth years). It may be concluded that there is a need to use a higher threshold for increased ovarian size only during first 2 years from menarche. After that time, the same threshold may be used in adolescents that is generally used in adults.
Increased ovarian size has been used for diagnosis of PCOS during adolescent years (1, 7). In our study, the hyperandrogenic adolescents as group had a larger ovarian size than the normally menstruating nonhyperandrogenic controls. However, only 45% of the hyperandrogenic patients had increased ovarian size. The prevalence of increased ovarian size in hyperandrogenic adolescents was lower (35%) during the first 2 years after menarche and then approached about 50%, a prevalence similar to that recently reported by Youngster et al. (13) who found an increased ovarian size in about 50% of 54 adolescents selected for possible PCOS (hyperandrogenism but also chronic anovulation). In adults, increased ovarian size is more common (14) and may reach 80% to 85% in patients with severe forms of PCOS (chronic anovulation and hyperandrogenism) (5). Although our study was performed in hyperandrogenic adolescents independent of their menstrual cycle regularity, the large majority of our patients had irregular menses, which was suggestive of chronic anovulation. This indicates that although increased ovarian size is useful in the diagnosis of PCOS in adolescence, it may have low sensitivity as a criterion for individuating possible PCOS patients. The sensitivity also seems to be lower in the 2 years immediately after menarche; in fact, only 35% of adolescents during this period of life had increased ovarian size. That enforces the concept that assessment of ovarian function may be particularly difficult in the period immediately after the menarche. Of course, in young women who present all the characteristics of PCOS, including
TABLE 2 Ovarian size in 72 healthy adolescent women and in 146 hyperandrogenic adolescent patients, divided according their gynecologic age. Gynecologic age (y) Ovarian characteristics Healthy controls Number Mean ovarian size (cm3) Ovarian size threshold (cm3) Hyperandrogenic patients Number Mean ovarian size (cm3) Prevalence of increased ovarian size (%) P value
1–2
3
4
5
12 7.9 1.8 11.5
20 6.7 1.9 10.5
20 6.3 1.8 10
20 6.1 2 10
30 12.6 4a 35 .0004
40 9.7 3a 50 .0002
52 9.4 3a 46 .0001
24 9.2 3a 48 .0004
Note: Thresholds for increased ovarian size were calculated as 95th percentile of values of healthy controls. a Bonferroni correction P< .007. Fruzzetti. Ovarian size in adolescent girls. Fertil Steril 2015.
VOL. - NO. - / - 2015
3
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY increased ovarian size, the definitive diagnosis should wait until the end of adolescence. These patients require careful follow-up observation. The limitations of our study must be noted. The hyperandrogenic patients were adolescents studied retrospectively with a cross sectional approach. Only prospective studies and long-term follow-up observations may give definitive information about the role of ovarian size assessment in diagnosis of PCOS during adolescence. In conclusion, after the first 2 years of menarche, the same cutoffs for increased ovarian size that are used for adult women may be used in adolescents as well. However, in adolescent patients increased ovarian size appears to have low sensitivity as a criterion for the diagnosis of PCOS.
REFERENCES 1. 2. 3.
4.
5.
4
Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol 2010;203:201–5. Hickey M, Balen A. Menstrual disorders in adolescence: investigation and management. Hum Reprod Update 2003;9:493–5. Van Hoof MH, Voorhost FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries for oligomenorrhea at age 18 years. Hum Reprod 2004;19:383–92. Viksten-Almstromer M, Hirschberg AL, Hagenfeltk K. Prospective follow-up of menstrual disorders in adolescence and prognostic features. Acta Obstet Gynecol Scand 2007;87:1162–8. Dewailly D, Lujan M, Carmina E, Cedars M, Laven J, Norman R, et al. Definition and significance of polycystic ovarian morphology: a task force report
6.
7.
8.
9.
10. 11.
12.
13.
14.
from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2014;20:334–52. Venturoli S, Porcu E, Fabbri R, Pluchinotta V, Ruggeri S, Macrelli S, et al. Longitudinal change of sonographic ovarian aspects and endocrine parameters in irregular cycles of adolescence. Pediatr Res 1995; 38:974–80. Herter LD, Magalhaes JA, Spritzer PM. Relevance of the evaluation of ovarian volume in adolescent girls with menstrual disorders. J Clin Ultrasound 1996;24:243–8. Mortensen M, Rosenfield RL, Littlejohn E. Functional significance of polycystic size ovaries in healthy adolescents. J Clin Endocrinol Metab 2006;911: 3786–90. Well D, Yang H, Houseni M, Iruvuri S, Alzeair S, Sansovini M, et al. Agerelated structural and metabolic changes in the pelvic reproductive end organs. Semin Nucl Med 2007;37:173–84. Blank SK, Helm KD, McCartney CR, Marshall JC. Polycystic ovary syndrome in adolescence. Ann NY Acad Sci 2008;1135:76–84. Mortensen M, Ehrmann DA, Littlejohn E, Rosenfield RL. Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population. J Clin Endocrinol Metab 2009;94:1579–86. Radivojevic UD, Lazovic BC, Kravic-Stevovic TK, Puzigace ZD, Canovic FM, Nikolic RR, et al. Differences in anthropometric and ultrasonographic parameters between adolescent girls with regular and irregular menstrual cycles: a case-study of 835 cases. J Pediatr Adolesc Gynecol 2014;27:227–31. Youngster M, Ward VI, Blood EA, Barnewolf CE, Emans SJ, Divasta AD. Utility of ultrasound in the diagnosis of polycystic ovary syndrome in adolescents. Fertil Steril 2014;102:1432–8. Carmina E, Orio F, Palomba S, Longo RA, Lombardi G, Lobo RA. Ovarian size and blood flow in women with polycystic ovary syndrome (PCOS) and their correlations with some endocrine parameters. Fertil Steril 2005;84:413–9.
VOL. - NO. - / - 2015
Ovarian volume in normal and hyperandrogenic adolescent women Franca Fruzzetti, M.D.,a Anna Maria Campagna, M.D.,b Daria Perini, M.D.,a and Enrico Carmina, M.D.b a Department of Obstetrics and Gynecology, University of Pisa, Pisa; and Palermo, Palermo, Italy
b
Endocrinology and Metabolism, University of
Objective: To study the threshold for increased ovarian size during different periods of adolescence. Design: Cross sectional study with retrospective analysis. Setting: University center. Patient(s): A total of 146 hyperandrogenic adolescent women and 72 healthy adolescent controls. Intervention(s): Intravaginal or transabdominal ovarian sonography. Main Outcome Measure(s): Determination of normal ovarian size during the different phases of adolescence calculated using the ellipsoid formula; calculation of threshold for increased ovarian size during different adolescent gynecologic ages and prevalence of increased ovarian size for hyperandrogenic girls at different gynecologic ages. Result(s): In adolescent women, the threshold for increased ovarian size was 11.5 cm3 during first 2 years from menarche, 10.5 cm3 during the third year from menarche, and 10 cm3 during the fourth and fifth years from menarche. The prevalence of increased ovarian size in hyperandrogenic adolescents was around 50% from the third to fifth years from menarche and 35% during the first 2 years from menarche. Conclusion(s): After the first 2 years from menarche, the thresholds for increased ovarian size are similar to those used among adults. During first 2 years from menarche, ovarian size is larger, and differentiation between normal or increased ovarian sizes may be more difficult. In hyperandrogenic adolescent patients, the prevalence of increased ovarian size is relatively low (ranging from 35% to 50% during the different periods of adolescence). In these patients, increased ovarian size may have low sensitivity as a criterion for the diagnosis of possible polycystic ovary syndrome. (Fertil Use your smartphone SterilÒ 2015;-:-–-. Ó2015 by American Society for Reproductive Medicine.) to scan this QR code Key Words: Adolescence, adolescent ovarian size, adolescent PCOS, hyperandrogenism, and connect to the increased ovarian size, PCOS Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/fruzzettif-ovarian-volume-adolescent-girls/
T
he possibility making a diagnosis of polycystic ovary syndrome (PCOS) in adolescents remains controversial (1). In fact, the same criteria—anovulation, hyperandrogenism, and polycystic ovaries—that are used for diagnosis in adults may be transitory or in evolution, in adolescents (2–4). In our literature review several years ago we suggested that the diagnosis of PCOS during adolescence may be reasonably suspected if the same three criteria are contemporaneously present in girls
who are at least 2 years past menarche (1). However, the definition of polycystic ovaries can be difficult at this age. In adult women, follicular count seems to be a more useful measure than increased ovarian size for defining polycystic ovaries (5), but during adolescence the number of follicles is particularly high (6), so the threshold for defining increased follicular count used in adult women may be incorrect. In addition, a precise follicular count may require transvaginal ovarian so-
Received December 6, 2014; revised March 7, 2015; accepted March 24, 2015. F.F. has nothing to disclose. A.M.C. has nothing to disclose. D.P. has nothing to disclose. E.C. has nothing to disclose. Reprint requests: Enrico Carmina, M.D., Endocrinology and Metabolism, University of Palermo, Via delle Croci, 47, 90139 Palermo, Italy (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.03.026 VOL. - NO. - / - 2015
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
nography, a methodology that is often not possible in young girls. Thus, it has been suggested that increased ovarian size may be of more use in the diagnosis of polycystic ovaries in adolescent girls (7). However, ovarian size is larger during adolescence than adulthood (8), and its progressive reduction with gynecologic age (9, 10) complicates its use for diagnosing polycystic ovaries. Our previous review suggested using the same cutoff of 10 cm3 in adolescents and adults (1), but the available data to support this cutoff are few (11) and are mainly based on a magnetic resonance imaging (MRI) study of adolescent ovaries (9). In this study, we assessed ovarian size in a group of healthy adolescent girls and for comparison in a large group of hyperandrogenic adolescent 1
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY girls. Because the available data show that ovarian size decreases with the progression of adolescence, we divided our controls and patients according their gynecologic age and determined the ovarian size cutoffs during the different phases of adolescence.
Biochemical hyperandrogenism was defined as serum T >60 ng/dL (R2.08 nmol/L) and/or serum DHEAS 3 mg/mL (R7.8 mmol/L). These values for hyperandrogenism had been previously validated in adult women with the use of the previously described assays.
MATERIALS AND METHODS
Ovarian Ultrasound
This study was conducted in two Italian university centers between 2011 and 2013. The healthy adolescent women (controls) were students in two local schools who volunteered for the study. The young hyperandrogenic women were consecutive patients at the two participating institutions being treated as outpatients for clinical or biochemical signs of hyperandrogenism. We enrolled 72 healthy, menstruating, nonhyperandrogenic women, aged 11 to 17 years (mean age 13.7 1 years) of gynecologic age (time in years elapsed since menarche) of 1 to 5 years. The patients were 146 hyperandrogenic adolescents aged 11–17 years (mean age 14.1 1 years) of gynecologic ages 1 to 5 years who were retrospectively evaluated. The large majority of the young hyperandrogenic women studied (138 out of 146) had irregular menses. The two groups were not matched for age or body weight. The project design included a medical examination, biochemical analyses, and ovarian sonography. The procedures we adopted were in agreement with the Helsinki Declaration of 1975 as revised in 1983, and the study was approved by the local ethics councils. All participants in the study gave their informed consent. Because of the age of the controls and patients, legal informed consent was also obtained from authorized representatives (parents), who also were present during all stages of the medical examination, including the laboratory analyses and ovarian ultrasounds. At admission all participants underwent a medical examination and answered a questionnaire on their personal and medical information, including age, past medical history, and use of medications. All controls were studied in a single institution (Endocrinology and Metabolism, University of Palermo). None of patients or controls were taking medication from at least 3 months before entering the study. Menstrual cycles were recorded for R3 months, and normal menses were defined as a menstrual cycle interval of 24 to 35 days.
In all patients and controls, on days 3 to 6 of the cycle the ovarian morphology was assessed by intravaginal or transabdominal ultrasound using a transducer frequency of 6–10 MHz. In both centers, the same machine (MyLab 50 Xvision, Esaote) was used. Ovarian volume was calculated by the formula p/6 (DB1 DB2 DB3), where the dimensions (D) of length, width, and thickness were used. The size of both ovaries was assessed, and the mean ovarian size was calculated. In no instance did the ovarian ultrasound have to be repeated because of the finding of a dominant follicle. Both data obtained by transabdominal and intravaginal ultrasound were considered useful for the diagnosis. However, in all controls and in the large majority of hyperandrogenic adolescent patients (n ¼ 117, 80%) a transabdominal ultrasound scan was performed.
Laboratory Analyses In all patients and controls the serum levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) were determined on days 3–5 of the cycle. In non-menstruating women the blood samples were drawn after the menstrual cycle had been induced by progesterone administration. Serum hormone levels were quantified by wellestablished methods that had been validated previously in our laboratories. The total T concentrations were determined by use of a competitive immunoassay (Johnson & Johnson/ Ortho Clinical). The DHEAS concentrations were determined by use of radioimmunoassay (Orion Diagnostics). In all assays, the intra-assay and interassay coefficients of variation did not exceed 6% and 15%, respectively. 2
Statistical Analyses Statistical analyses were performed using Statview 5.0 (SAS Institute). Univariate analyses were performed using an unpaired t test for the numeric variables. Bonferroni correction for multiple comparisons was applied. Thresholds for increased ovarian size were calculated as mean 2 standard deviation (SD) of the values of the healthy controls. The results are expressed as mean SD.
RESULTS Table 1 shows the clinical data, hormone levels, and mean ovarian size of the healthy and hyperandrogenic girls. Although the two groups were not matched for age or body weight, their mean ages were similar; the hyperandrogenic adolescent girls had statistically significantly (P< .01) higher body mass index (BMI), hirsutism scores, total testosterone levels, DHEAS levels, and ovarian size compared with the healthy adolescent girls. All controls had normal menses whereas the large majority of hyperandrogenic patients had irregular menses (n ¼ 134, 92%). Table 2 reports the ovarian sizes of the healthy and the hyperandrogenic girls, divided according their gynecologic age. Because there were fewer healthy girls of gynecologic age 1, the patients of gynecologic ages 1 and 2 were regrouped. It may be observed that the younger girls (1– 2 years after the menarche) had a higher threshold (95 percentile of values of ovarian size) for increased ovarian size (11.5 cm3), but then the threshold was around 10 cm3. At any gynecologic age, the hyperandrogenic adolescents had larger ovarian sizes (P< .01) than the healthy adolescent controls (Table 2). According to these thresholds, 66 (45.2%) hyperandrogenic adolescents had increased ovarian size. VOL. - NO. - / - 2015
Fertility and Sterility®
TABLE 1 Clinical data, hormone levels, and ovarian size in healthy versus hyperandrogenic adolescent women. Adolescent girls
No.
Age (y)
BMI (kg/m2)
Total T (ng/mL)
Hirsutism scores
DHEAS (mg/mL)
Ovarian size (cm3)
Normal Hyperandrogenic
72 146
13.7 1 14.1 1
22.8 3 25.1 5.3a
36 13 68 24b
21 12.5 2.8b
2.2 0.4 2.9 1.5a
6.7 2.2 10.1 4.7b
Note: BMI ¼ body mass index; DHEAS ¼ dehydroepiandrosterone sulfate; T ¼ testosterone. a P< .01 versus healthy adolescent women. b P< .0001 versus healthy adolescent women. Fruzzetti. Ovarian size in adolescent girls. Fertil Steril 2015.
DISCUSSION It is generally reported that ovarian size is larger during the early adolescent years and then progressively reduces until reaching the size found in adult women (8, 9, 12). This complicates the use of ovarian size for diagnosing possible PCOS in adolescents because the same threshold that is used in adults may not be applicable in adolescents. However, a previous study using MRI technique determined a threshold between normal and increased ovarian size of 10 cm3 (9), the same that is generally used in adult women (5). In our study, we assessed ovarian size in a group of healthy adolescent women and in hyperandrogenic adolescent patients. Most hyperandrogenic adolescent patients had irregular menses. When the healthy (regular menses and no hyperandrogenism) adolescents were divided according their gynecologic age (time in years elapsed since menarche), the threshold for increased ovarian size was the same as found in adult women with the exception of the younger adolescents. In fact, during the first 2 years since menarche, the cutoff value between normal and increased ovarian size was 11.5 cm3 whereas in the following years the threshold was around 10 cm3 (10.5 cm3 in the third year, and 10 cm3 in the fourth and fifth years). It may be concluded that there is a need to use a higher threshold for increased ovarian size only during first 2 years from menarche. After that time, the same threshold may be used in adolescents that is generally used in adults.
Increased ovarian size has been used for diagnosis of PCOS during adolescent years (1, 7). In our study, the hyperandrogenic adolescents as group had a larger ovarian size than the normally menstruating nonhyperandrogenic controls. However, only 45% of the hyperandrogenic patients had increased ovarian size. The prevalence of increased ovarian size in hyperandrogenic adolescents was lower (35%) during the first 2 years after menarche and then approached about 50%, a prevalence similar to that recently reported by Youngster et al. (13) who found an increased ovarian size in about 50% of 54 adolescents selected for possible PCOS (hyperandrogenism but also chronic anovulation). In adults, increased ovarian size is more common (14) and may reach 80% to 85% in patients with severe forms of PCOS (chronic anovulation and hyperandrogenism) (5). Although our study was performed in hyperandrogenic adolescents independent of their menstrual cycle regularity, the large majority of our patients had irregular menses, which was suggestive of chronic anovulation. This indicates that although increased ovarian size is useful in the diagnosis of PCOS in adolescence, it may have low sensitivity as a criterion for individuating possible PCOS patients. The sensitivity also seems to be lower in the 2 years immediately after menarche; in fact, only 35% of adolescents during this period of life had increased ovarian size. That enforces the concept that assessment of ovarian function may be particularly difficult in the period immediately after the menarche. Of course, in young women who present all the characteristics of PCOS, including
TABLE 2 Ovarian size in 72 healthy adolescent women and in 146 hyperandrogenic adolescent patients, divided according their gynecologic age. Gynecologic age (y) Ovarian characteristics Healthy controls Number Mean ovarian size (cm3) Ovarian size threshold (cm3) Hyperandrogenic patients Number Mean ovarian size (cm3) Prevalence of increased ovarian size (%) P value
1–2
3
4
5
12 7.9 1.8 11.5
20 6.7 1.9 10.5
20 6.3 1.8 10
20 6.1 2 10
30 12.6 4a 35 .0004
40 9.7 3a 50 .0002
52 9.4 3a 46 .0001
24 9.2 3a 48 .0004
Note: Thresholds for increased ovarian size were calculated as 95th percentile of values of healthy controls. a Bonferroni correction P< .007. Fruzzetti. Ovarian size in adolescent girls. Fertil Steril 2015.
VOL. - NO. - / - 2015
3
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY increased ovarian size, the definitive diagnosis should wait until the end of adolescence. These patients require careful follow-up observation. The limitations of our study must be noted. The hyperandrogenic patients were adolescents studied retrospectively with a cross sectional approach. Only prospective studies and long-term follow-up observations may give definitive information about the role of ovarian size assessment in diagnosis of PCOS during adolescence. In conclusion, after the first 2 years of menarche, the same cutoffs for increased ovarian size that are used for adult women may be used in adolescents as well. However, in adolescent patients increased ovarian size appears to have low sensitivity as a criterion for the diagnosis of PCOS.
REFERENCES 1. 2. 3.
4.
5.
4
Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol 2010;203:201–5. Hickey M, Balen A. Menstrual disorders in adolescence: investigation and management. Hum Reprod Update 2003;9:493–5. Van Hoof MH, Voorhost FJ, Kaptein MB, Hirasing RA, Koppenaal C, Schoemaker J. Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries for oligomenorrhea at age 18 years. Hum Reprod 2004;19:383–92. Viksten-Almstromer M, Hirschberg AL, Hagenfeltk K. Prospective follow-up of menstrual disorders in adolescence and prognostic features. Acta Obstet Gynecol Scand 2007;87:1162–8. Dewailly D, Lujan M, Carmina E, Cedars M, Laven J, Norman R, et al. Definition and significance of polycystic ovarian morphology: a task force report
6.
7.
8.
9.
10. 11.
12.
13.
14.
from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2014;20:334–52. Venturoli S, Porcu E, Fabbri R, Pluchinotta V, Ruggeri S, Macrelli S, et al. Longitudinal change of sonographic ovarian aspects and endocrine parameters in irregular cycles of adolescence. Pediatr Res 1995; 38:974–80. Herter LD, Magalhaes JA, Spritzer PM. Relevance of the evaluation of ovarian volume in adolescent girls with menstrual disorders. J Clin Ultrasound 1996;24:243–8. Mortensen M, Rosenfield RL, Littlejohn E. Functional significance of polycystic size ovaries in healthy adolescents. J Clin Endocrinol Metab 2006;911: 3786–90. Well D, Yang H, Houseni M, Iruvuri S, Alzeair S, Sansovini M, et al. Agerelated structural and metabolic changes in the pelvic reproductive end organs. Semin Nucl Med 2007;37:173–84. Blank SK, Helm KD, McCartney CR, Marshall JC. Polycystic ovary syndrome in adolescence. Ann NY Acad Sci 2008;1135:76–84. Mortensen M, Ehrmann DA, Littlejohn E, Rosenfield RL. Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population. J Clin Endocrinol Metab 2009;94:1579–86. Radivojevic UD, Lazovic BC, Kravic-Stevovic TK, Puzigace ZD, Canovic FM, Nikolic RR, et al. Differences in anthropometric and ultrasonographic parameters between adolescent girls with regular and irregular menstrual cycles: a case-study of 835 cases. J Pediatr Adolesc Gynecol 2014;27:227–31. Youngster M, Ward VI, Blood EA, Barnewolf CE, Emans SJ, Divasta AD. Utility of ultrasound in the diagnosis of polycystic ovary syndrome in adolescents. Fertil Steril 2014;102:1432–8. Carmina E, Orio F, Palomba S, Longo RA, Lombardi G, Lobo RA. Ovarian size and blood flow in women with polycystic ovary syndrome (PCOS) and their correlations with some endocrine parameters. Fertil Steril 2005;84:413–9.
VOL. - NO. - / - 2015