Standards for ovarian volume in childhood and puberty*

Size: px

Start display at page:

Download "Standards for ovarian volume in childhood and puberty*"

Emily Edwards
5 years ago
Views:

FERTILITY AND STERILITY Copyright 1993 The American Fertility Society Printed on acid-free paper in U. S. A. Standards for ovarian volume in childhood and puberty* Nicola A. Bridges, B.M.

1 FERTILITY AND STERILITY Copyright 1993 The American Fertility Society Printed on acid-free paper in U. S. A. Standards for ovarian volume in childhood and puberty* Nicola A. Bridges, B.M.t Alex Cooke, M.B. B.Ch. Micheal J. R. Healy, M.A. Pliter C. Hindmarsh, M.D.t Charles G. D. Brook, M.D.:j: Endocrine Unit, The Middlesex Hospital, London, United Kingdom Objective: To examine the growth of the ovary and the prevalence of polycystic ovaries in childhood and to compare the ovarian volumes of girls with growth disorders. Design: A retrospective study of ovarian volume measurements made with ultrasound. Setting: Paediatric Endocrine Outpatient service at The Middlesex Hospital. Patients: The control group consisted of girls with no endocrine defect. The study group consisted of girls with GH insufficiency, treated and untreated; skeletal dysplasia (and no endocrine defect) on a trial of recombinant human GH; and tall stature. Methods: The prevalence of polycystic appearance ovaries in the control group was noted. Centiles were calculated for the volumes of normal appearance ovaries in the control group (428 scans from 358 girls). Standard deviation scores were calculated for the ovarian volumes in the study groups. Results: There was continuous growth of the ovaries throughout childhood. There was an increase in the prevalence of polycystic ovaries from 6% at 6 years of age, until 26% of the scans showed polycystic ovaries at 15 years of age. The ovarian volume SD score of untreated G H insufficient girls was less than controls but did not achieve statistical significance. It was significantly less than that of GH-insufficient girls on GH, girls with skeletal dysplasia on GH, and girls with tall stature. Tall girls had significantly greater ovarian volume than either of the GH-treated groups. Conclusions: Growth hormone appears to influence ovarian growth. Most women who have polycystic ovarian appearance develop this appearance during childhood and puberty. Fertil Steril 1993;60: Key Words: Ovary, growth hormone, puberty, polycystic ovaries, growth hormone insufficiency. Pelvic ultrasound is a safe, accurate, and noninvasive method of examining uterine and ovarian size and appearance. Its use in gynecology is well established (1, 2). Several investigators have documented increases in ovarian volume with age in childhood, with an increase in the number and size Received February 4th, 1993; revised and accepted May 7, * Presented at the 12th meeting of the British Endocrine Societies, Liverpool, United Kingdom March 29 to April 1, t Supported by Children Nationwide, Kabi Pharmacia, and the Special Trustees of the Middlesex Hospital, London, United Kingdom. =!: Reprint requests: Charles G. D. Brook, M.D., Middlesex Hospital, Mortimer Street, London, United Kingdom. of the developing follicles in the years leading up to puberty. The changes reported with ultrasound (3, 4) agree with those observed at postmortem (5). Polycystic ovaries (PCO) have increased echo dense stroma and a circumferential arrangement of follicles (;do follicles 2 to 10 mm in diameter) (6). They are larger than normal but their characteristic appearance distinguishes them from other large ovaries, which do not have increased stroma. Studies have shown the incidence of this appearance to be 22% to 25% in the adult female population (7,8). There is an increased incidence of infertility, amenorrhea, and hirsutism in women with PCO. Typical biochemical abnormalities reported are elevated serum LH, T, and insulin concentrations (9, 10), and it is possible that the raised levels of these 456 Bridges et al. Ovarian volume in childhood Fertility and Sterility

2 hormones are responsible for the polycystic appearance. Families have been reported in which the condition appears to be inherited (11), and a number of cases developing in childhood have been described (12). Ovarian ultrasound is of value in assessing girls with abnormalities of pubertal development, but data on normal girls are limited (4, 13). Many girls who attend endocrine outpatients do not have an endocrine disorder, and we have used ultrasound examinations performed on these girls to delineate the changes in ovarian volume during childhood and adolescence and to construct standards. We have also examined the timing of onset and incidence of PCO in childhood and compared the ovarian parameters of our control group with the results of girls with growth disorders. MATERIALS AND METHODS Ultrasound Examination and Measurements The study was approved by the Ethical Committee of the Middlesex Hospital. Ultrasound examinations were carried out on girls who attended the Paediatric Endocrine Outpatient service at the Middlesex Hospital over a period of 3 years. Each ovary was measured in three dimensions at right angles, and the ovarian volume (ml) was calculated using the formula for an ellipsoid ovoid (volume = dimension 1 X dimension 2 X dimension 3 X ) (2, 3). The ultrasonographer noted whether the ovary appeared polycystic using the criteria described by Adams et al. (6). The diameter of the largest follicle in each ovary (mm) was noted. Some subjects had more than one ultrasound examination, and each examination was assessed as a separate measurement. The measurements for each ovary were taken separately because there were variations between the volume and follicle diameter in pairs of ovaries. It was assumed that the ovaries not visualized were at random (i.e., not always the largest or the smallest). To assess the reproducibility of the measurements made, ultrasound examinations were performed twice on the same occasion on six individuals by two experienced operators who were unaware of the other's results. Seven ovaries were visualized by both observers, and the ovarian volume was calculated from the measurements of each observer. The two sets of volume measurements were regressed against each other. The correlation coefficient for the volume measurements was The mean between measurement (i.e., interobserver) coefficient of variation for volume measurements was 11.37%. Calculation of Centiles and SD Scores Data from 358 girls who were on no medication and who had no pubertal or endocrine disorder were used. There were 527 scans and at least one ovary was visualized and measured in 428. The number of scans that showed PCO at each age were counted. The volumes of ovaries that were normal (i.e., not polycystic) were used to calculate the centiles for age. The data were not normally distributed and were log transformed for analysis. Centiles were calculated using the log transformed data, by using the "moving box" method (14, 15), and smoothed. The log transformed (log 10) mean volume at each age and SD was calculated. Ovarian volume SD scores were calculated using the formula: SD score = [log 10 (measured value) -log 10 (mean for age)l/sd. The advantage of using this method of expressing data is that SD scores are independent of age and allow for the comparison of groups with different mean ages. Analysis of Ovarian Volume SD Scores for Girls with Growth Disorders Ultrasound data were collected from girls with a number of different growth disorders. Ovarian volume SD scores were calculated for each ovary. GH Insufficiency and GH Treatment Growth hormone insufficiency was diagnosed using standard criteria (16). Ovarian measurements were collected from girls with a diagnosis of GH insufficiency who were untreated and from those receiving recombinant human GH treatment in doses of 15 to 20 U 1m 2 per week. Data from a group of girls with skeletal dysplasia, who did not have G H insufficiency and who were treated with G H as part of a trial, were also available for analysis. Tall Stature Data from a group of girls who presented with tall stature were collected. Girls whose tall stature was secondary to precocious puberty were excluded. Statistical Analysis Mean and SEM were calculated for the ovarian volume SD score and maximum follicular diameter. Groups were compared using multiple analysis of Bridges et al. Ovarian volume in childhood 457

10 8 97 90 o Normal Dpca c 100% ~ ~ o 75% 15 () 1&)% 8.

3 o Normal Dpca c 100% ~ ~ o 75% 15 () 1&)% 8. '0 25% C " ~ 0% Age (years) o ~'----~--~'----~'----~ Age (years) Figure 1 Ovarian volume centiles derived from 327 scans (in which the ovaries were of normal appearance) in the control group. variance (MANOVA) or one-way analysis of variance with the Student-Newman-Keuls post hoc test applied. The groups were compared with the control group by t-test; the SD score of the control group was 0 and the SD 1. Calculation of Centiles RESULTS Figure 1 shows the smoothed centiles for the control group (using the normal appearance ovaries only) on a linear scale. Table 1 gives the means for volume by age, the log 10 transformed means, and the number of scans. The SD for log 10 of the means Table 1 Mean Ovarian Volumes for the Control Group No. of Mean Log 10 Age scans volume mean volume y ~ ~ ~ ~ Bridges et al. Ovarian volume in childhood ml Figure 2 Percentage of ovarian ultrasound scans in the control group in which the ovarian appearance was polycystic, plotted against age in years. is Of the 428 scans in which ovaries were visualized, the ovaries had a polycystic appearance in 101 (24%). Figure 2 shows the percentage of ovaries with a polycystic appearance in the control group at each age. The youngest at which polycystic appearance was demonstrated was 6 years and this increased until a plateau was reached in the early teenage years. We have not yet seen a girl with polycystic ovarian appearance whose ovaries have subsequently returned to a normal appearance. Follicular Diameter The mean maximum follicle diameter (for the ovaries of a normal appearance only) increased significantly with pubertal stage (F = 46.81, P = 0.001), with a significant increment at each pubertal stage (Student-Newman-Keuls, P < 0.05). There were 137 scans at Tanner breast stage 1, mean maximum follicular diameter was 4.65 mm (SD 1.70, range 2 to 12 mm); 56 scans at breast stage 2 with a mean maximum follicular diameter 6.00 mm (SD 1.75, range 2 to 11 mm); 43 scans at breast stage 3 with a mean maximum follicular diameter of 6.81 mm (SD 2.96, range 2 to 21 mm); and 22 scans at breast stage 4 or 5 with a mean maximum follicular diameter of 8.37 (SD 3.13, range 3 to 17 mm.) Growth Disorders Table 2 shows details of the groups examined. Data are presented with respect to mean age, ovarian volume SD score, percentage of ovaries with a polycystic appearance, and maximum follicular diameter. The ovarian volume SD score of GH-insufficient girls who were not treated with GH was less than Fertility and Sterility

4 Table 2 Ovarian Parameters for the Girls with Growth Disorders Diagnostic group Age* No. of scanst Volume Maximum SD score* Polycystic follicular diameter:j: GH insufficiency: no treatment GH insufficiency: on GH Skeletal dysplasia: on GH Tall stature y 9.94 ± ± ± ± (8) 83 (43) 41 (19) 59 (40) % mm ± (3-7) 0.39 ± (2-22) 0.58 ± (2-22) 1.36 ± (3-17) * Values are means ± SE. t Values in parentheses are the number of people. :j: Values in parenthesis are ranges. the control group but did not achieve statistical significance. The ovarian volume SD scores for the GH-insufficient girls on GH, the girls with skeletal dysplasia on GH, and the tall girls were greater than the control group (t-test, P = 0.001). The ovarian volume SD scores of the groups were compared using MANOV A. There was a significant difference between GH-insufficient girls not treated with GH and GH-insufficient girls treated with GH (F = 12.05, P = 0.001), girls with skeletal dysplasia treated with GH (F = 15.13, P = 0.001), and girls with tall stature (F = 46.31, P = 0.001). There was no difference between the two GH-treated groups. The girls with tall stature had larger ovaries for their age than either of the GH-treated groups (GH-insufficient group F = 43.57, P = 0.001; skeletal dysplasia group F = 14.06, P = 0.001). The maximum follicular diameters of ovaries in girls with skeletal dysplasia and those with tall stature were comparable with those of the control group girls in puberty. Thirty-one percent of the girls with tall stature had polycystic appearing ovaries, and this proportion increased to 50% in tall girls older than 12 years. The incidence in the other groups was no more than in the control group. DISCUSSION The ovaries grow in volume throughout childhood, and our centiles show two periods of increased growth rate. The first, at approximately 8 years of age, coincided with the rise in adrenal androgen secretion at adrenarche and may be caused by the action of adrenal androgens on ovarian growth. The second period occurred immediately before and during puberty. A number of different factors may be important in this period of growth; at the onset of puberty there is a rise in gonadotropin secretion, followed by increased concentrations of GH, insulin-like growth factor I (lgf-i), estrogen, and insulin. There is an increase in the mean maximum follicular diameter with progress in puberty. Follicles mature and regress continuously and the wide range of diameters observed at different pubertal stages indicates that a scan performed at breast stage 4 or 5 may sometimes demonstrate only small follicles. The lower level of gonadotropin secretion in prepubertal girls can also occasionally result in larger follicles, up to 12 mm across. This limits the usefulness of measurements of follicular diameter in the assessment of pubertal status. Exogenous GH accelerates progress through puberty but does not result in an earlier onset of puberty (17). Growth hormone has been demonstrated to augment the action of gonadotropins on the ovary when exogenous gonadotropins are used in the induction of ovulation (18). Our study suggests that G H is also important in ovarian growth and that the administration of exogenous G H may result in larger than normal ovaries. Insulin-like growth factor I is important in mediating the action of GH on the ovary, although there may be some direct effect of GH itself (19). IGF-I has an important paracrine role, amplifying the action of gonadotropins and promoting granulosa cell differentiation and steroidogenesis (20), whereas IGF binding proteins act to modulate the action of IGF I (21). The difference in the maximum follicular diameter between the GH-insufficient and GHtreated groups suggests that the difference in volume may be partly due to the action of GH in amplifying gonadotropin action. Another possible explanation for the smaller ovarian volume of the untreated GH-insufficient girls is these children have a higher prevalence of gonadotropin insufficiency. Longitudinal studies on larger numbers of subjects would be needed to test this hypothesis. Tall girls have large ovaries and are more likely to have ovaries with a polycystic appearance after approximately 12 years of age. Not all of the large ovaries in these girls are polycystic. Higher serum Bridges et al. Ovarian volume in childhood 459

5 concentrations of GH, increased IGF-I, or hyperinsulinemia may playa part in the increased ovarian volume observed in tall girls. Nutritional factors and insulin status can contribute to growth in childhood and these factors could also influence ovarian size. In the younger tall girls, gonadotropin levels are low and the increased ovarian size is unlikely to be because of the effect of GH in amplifying gonadotropin action. The cause of PCO is not known. It has been reported in the absence of gonadotropins (22), and our study confirms that a polycystic appearance is present in a few children at an age when gonadotropin concentrations are low. Adult women with PCO have elevated serum IGF-I levels and hyperinsulinemia, (10, 23, 24) but also have elevated IGF binding proteins within the follicles, which would diminish the action of IGF -I in augmenting gonadotropin action (25). The rise in IGF-I and insulin during puberty may be related to the increase in prevalence at this time. Because we have yet to find a girl whose polycystic ovarian appearance at ultrasound has reverted to normal, this raises the question as to whether most adult women with polycystic appearance have in fact developed this appearance by the end of puberty. Acknowledgments. We are grateful to the members of the Ultrasound Department at The Middlesex Hospital for performing the scans, particularly Ms. Anita Patel, Ms. Claire Webber, Ms. Jan Oliver, Ms. Judy Adams, and Ms. Sandra Mather. REFERENCES 1. Saxton DW, Farquhar CM, Rae T, Beard RW, Anderson MC, Wadsworth J. Accuracy of ultrasound measurement of female pelvic organs. Br J Obstet GynaecoI1990;97: Sample WF, Lippe BM, Gyeppes MT. Grey scale ultrasonography of the normal female pelvis. Radiology 1977;125: Salardi S, Forsini L, Cacciari E, Bovicelli L, Tassoni P, Regianni A. Pelvic ultrasonography in premenarcheal girls: relation to puberty and sex hormone concentrations. Arch Dis Child 1985;60: Stanhope R, Adams J, Jacobs HS, Brook CDG. Ovarian ultrasound assessment in normal children, idiopathic precocious puberty and during low dose pulsatile GnRH treatment of hypogonadotrophic hypogonadism. Arch Dis Child 1985;60: Peters H, Himelstein-Braw R, Faber M. The normal development of the ovary in childhood. Acta Endocrinol (Copenh) 1976;82: Adams J, Polson DW, Abdulwahid N, Morris DV, Franks S, Mason HD, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet 1985;2: Clayton RN, Ogden V, Hodgkinson J, Worswick L, Rodin DA, Dyer S, et al. How common are polycystic ovaries in normal women and what is their significance for the fertility of the population? Clin Endocrinol (Oxf) 1992;37: Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries: a common finding in normal women. Lancet 1988;1: Eden JA, Place J, Carter GD, Alaghband-zaden J, Pawson M. Is the polycystic ovary a cause of infertility in the ovulatory woman? Clin Endocrinol (Oxf) 1989;30: Conway GS, Honour JW, Jacobs HS. Heterogeneity of the polycystic ovary syndrome: clinical, endocrine and ultrasound features in 556 patients. Clin Endocrinol (Oxf) 1989;30: Givens JR. Familial polycystic ovarian disease. Endocrinol Metab Clin North Am 1988;17: Rao JK, Chinal HJ, Johnson CM. Primary polycystic ovary syndrome in a premenarcheal girl. J Reprod Med 1985;30: Ivarsson SA, Nilsson KO, Persson PH. Ultrasonography of the pelvic organs in prepubertal and postpubertal girls. Arch Dis Child 1983;58: Healy MJR, Rasbash J, Yang M. Distribution free estimation of age related centiles. Ann Hum BioI 1988;15: Healy MJR. Statistics of growth standards. In: Faulkner F, Tanner JM, editors. Human growth. Vol. 1. Principles and prenatal growth. New York: Plenum Press, 1986: Milner RDG, Russell Frazer T, Brook CGD, Cotes PM, Farquar JW, Parkin JM, et al. Experience with human growth hormone in Great Britain; the report of the MRC Working Party. Clin Endocrinol (Oxf) 1979;11: Darendelier F, Hindmarsh PC, Preece MA, Cox L, Brook CGD. Growth hormone increases rate of pubertal maturation. Acta Endocrinol (Copenh) 1990;122: Homburg R, Eshel A, Abdalla HI, Jacobs HS. GH facilitates ovulation induction by gonadotrophins. Clin Endocrinol (Oxf) 1988;9: Fowler PA, Templeton A. Ovarian response to gonadotrophins: effects of GH. Clin Endocrinol (Oxf) 1991;35: Adashi EY, Resnick CE, D'Ercole AJ, Svoboda ME, Van Wyk JJ. Insulin like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev 1985;6: Adashi EY, Resnick CE, Ricciarelli E, Hurwitz A, Kokia E, Tedeschi C, et al. Granulosa cell derived insulin like growth factor (IGF) binding proteins are inhibitory to IGF-1 hormonal action. J Clin Invest 1992;90: Stanhope R, Adams J, Pringle JP, Jacobs HS, Brook CDG. The evolution of polycystic ovaries in a girl with hypogonadotropic hypogonadism before puberty and during puberty induced with pulsatile gonadotropin releasing hormone. Fertil Steril1987;47: Kazer RR, Unterman TG, Glick RP. An abnormality ofthe GH/IGF 1 axis in women with PCO syndrome. J Clin Endocrinol Metab 1990;71: Eden JA, Jones J, Carter GD, Alaghband-Zadeh J. Follicular fluid concentrations of insulin like growth factor, transforming growth factor alpha and sex steroids in volume matched normal and polycystic human follicles. Clin Endocrinol (Oxf) 1990;32: San Roman G, Magoffin DA. Insulin like growth factor binding proteins in ovarian follicles from women with polycystic ovarian disease: cellular source and levels in follicular fluid. J Clin Endocrinol Metab 1992;75: Bridges et al. Ovarian volume in childlwod Fertility and Sterility

Imaging in Pediatric and Adolescent Gynecology

Background and Tools Sultan C (ed): Pediatric and Adolescent Gynecology. Evidence-Based Clinical Practice. Endocr Dev. Basel, Karger, 2004, vol 7, pp 9 22 Imaging in Pediatric and Adolescent Gynecology