Ovarian Ultrasound Assessment in Normal Children, Idiopathic

Arch Dis Child: first published as 10.1136/adc.60.2.116 on 1 February 1985. Downloaded from

Archives of Disease in Childhood, 1985, 60, 116-119 Ovarian ultrasound assessment in normal children, idiopathic precocious puberty, and during low dose pulsatile gonadotrophin releasing hormone treatment of hypogonadotrophic hypogonadism

R STANHOPE, J ADAMS, H S JACOBS, AND C G D BROOK Endocrine Unit, Middlesex Hospital, London

SUMMARY Ultrasound assessment of ovarian volume, follicular size, and uterine growth was undertaken in 40 normal premenarcheal girls aged 6 months to 14 years. Ovarian follicles were detected from 6 months of age and increased in size and number, so that after the age of 8-5 years there was a progressive increase in the incidence of 'megalocystic' appearance. Eight girls with idiopathic precocious puberty had large megalocystic ovaries which regressed on treatment with gonadotrophin releasing hormone analogue. These findings contrasted with those seen in two prepubertal patients with hypogonadotrophic hypogonadism in whom the natural sequence of ovarian development was greatly accelerated by pulsatile administration of native gonadotrophin releasing hormone. copyright.

The initiation and maintenance of human sexual method of assessing ovarian size and structure as development requires the pulsatile release of gona- well as uterine changes in normal children. We have dotrophins from the pituitary in response to pulsa- compared the ovarian morphological changes of tile gonadotrophin releasing hormone.' Treatment normal childhood with those seen during the sup- of hypogonadotrophic hypogonadism with pulsatile pression of idiopathic precocious puberty and during gonadotrophin releasing hormone can restore repro- induction of puberty in patients with hypogonado- ductive function in both males2 and females.3 The trophic hypogonadism. http://adc.bmj.com/ use of analogues that desensitise the pituitary response to endogenous gonadotrophin releasing Patients and methods hormone has been established as an effective treatment of idiopathic precocious puberty.4 We studied 40 normal premenarcheal girls, eight Buserelin (6-D-Ser-(TBu)-GnRH-(1-9) ethylamide) with idiopathic precocious puberty, four of whom is a superactive analogue that desensitises the were treated with analogue, and two with delayed pituitary by down regulation of the gonadotrope puberty treated by pulsatile administration of native and thereby interferes with the secretion of gonadotrophin releasing hormone. All ultrasound on September 28, 2021 by guest. Protected gonadotrophins.5 scans were performed by JA using an Emisonic 4201 Necropsy studies have shown that ovarian size static scanner with a long focussed 3 5 mHz trans- increases gradually during childhood.6 Normal ducer and more recently an Aloka sector scanner adolescent ovaries contain multiple follicular cysts7 with 3-5 mHz long focussed and 5-0 mHz trans- whose development determines the rapid ovarian ducers. Ovarian volume was calculated by measuring enlargement at puberty.8 Both ovarian and follicular length, width, and depth and by assuming the shape size increase progressively from fetal life to puberty to be ellipsoid.12 Uterine size was estimated from and there is histological evidence of a continued measurements of maximum length and depth in turnover of follicles throughout childhood.9 Ovaries sagittal section and expressed as cross sectional containing multiple cysts have been shown by area. ultrasound in normal prepubertal girls"' and single Four of the patients with precocious puberty were or multiple follicular cysts have been reported in treated with Buserelin (gonadotrophin releasing girls with precocious puberty." hormone analogue), given intranasally between 400 We have used ultrasound as a non-invasive and 800 ,ug daily in divided doses. Native gonado- 116 Arch Dis Child: first published as 10.1136/adc.60.2.116 on 1 February 1985. Downloaded from

Ultrasound assessment of ovarian development 117 trophin releasing hormone was administered sub- cutaneously in pulses using a miniature infusion pump:'3 a dose of 15 ,ug was administered at 90 minute intervals throughout 24 hours. Informed parental consent was given for normal control patients. Results Ovarian volume gradually increased during childhood from a mean of 1 cm3 at 2 years of age to a mean of 2 cm3 at 12 years (Fig. 1). A maximum follicular diameter of 7 mm was normal in early childhood (Fig. 2). We define a 'megalocystic' ovary as one containing more than six follicles greater than 4 mm in diameter present in each ovary (Fig. 3). There was a progressive increase in the proportion of normal girls with megalocystic ovaries over the age of 8*5 years (Fig. 1). Uterine size was unchanged from 6 months to 10 years, mean cross sectional area was 2 cm2 (Fig. 4) and there was a rapid increase in Fig. 3 Sagittal ultrasound image ofa megalocystic ovary uterine size after the age of 10 years associated with from a normalprepubertal 8-8 year old girl, seen through the onset of puberty. the bladder (B) which is the dark area at the top ofthe image. 8r The white lines represent 1 cm markers. Arrows outline the margin of one ovary which contained eight 'cysts' greater than 4 mm in diameter. V indicates A the ovarian vessels entering the superior pole of the ovary. copyright. E 6 A C a A At presentation, all eight girls with idiopathic 9 4 A precocious puberty had large megalocystic ovaries, c A greater than 3 cm3 in volume (Fig. 1), which a approached or fell within the normal adult range. 0 2 0 was within the normal 0 Maximum follicular diameter 0 0 0 0

0 http://adc.bmj.com/ 0000 range for age (Fig. 2). All eight had uterine cross 0 oo000 0 0 00 0 0 n sectional areas greater than 4 cm2 (Fig. 4). Four of n-u L 2 4 6 8 10 12 1 the eight patients were treated with intranasal Age (years) gonadotrophin releasing hormone analogue which Fig. 1 Ovarian volume of 40 normal pr-emenarcheal girls resulted in either arrest or regression of the clinical (circles) and eight girls with idiopathic precocious puberty (triangles).

. are . as _:_ . tnose not- - I16r Megalocystic ovaries represented solia symbols, megalocystic VI on September 28, 2021 by guest. Protected as open symbools. .

12- 12

AA A* o 8- .A *0 u A E *. 4A *AA * 0 0 0 . i; E . AAA A E 4 4 0 .0 .00 0 00' 00 0 000 0.0 0 0 000 0 100 0 0 0 x 000 0 * .- * i_ 0 c 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Age (years) Age (years) Fig. 2 Diameter ofthe largest ovarian follicle in either Fig. 4 Uterine cross sectional area of40 normal ovary of 40 normal premenarcheal girls (circles) and eight premenarcheal girls (circles) and eight girls with idiopathic girls with idiopathic precocious puberty (triangles). precocious puberty (triangles). Arch Dis Child: first published as 10.1136/adc.60.2.116 on 1 February 1985. Downloaded from

118 Stanhope, Adams, Jacobs, and Brook

Case 1 Case 2 Case2 Before Before After 2 weeks' treatment treatment = 10 treatment

15- 15

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40 5

a L) 0 20 60 Fig. 5(a) Sagittal ultrasound image of one ovary 0 20 60 0 20 60 Time (minutes) (arrowed) of a 2½ year old girl with idiopathic precocious puberty. The dark area at the top ofthe image is the Fig. 6 Follicle stimulating hormone and luteinising bladder (B). hormone response, at 0, 20, and 60 minutes, to a diagnostic Horizontal lines represent I cm markers. The ovary was large (3-2x2)2 cm) test of an intravenous injection of 100 ,ug native and megalocystic. Breast development was lanner stage 111. gonadotrophin releasing hormone. the same girl (b) Sagittal ovarian ultrasound image from In case 2 the test was repeated after two weeks of pulsatile gonadotrophin after one year ofgonadotrophin releasing hormone releasing hormone treatment. analogue treatment.

of cm markers is along the bottom of the image. The ovary The scale I copyright. (arrowed) was reduced in size (2-5xl-7 cm) and intra-ovarian cysts' were mality except in the gonadotrophin responses to a suppressed both in size and number. Breast development hid regressed to test gonadotrophin Tanner stage 11. diagnostic of 100 ,ug intravenous releasing hormone (Fig. 6). Ovarian ultrasound showed very small ovaries containing no follicles. Two weeks after beginning pulsatile treatment, signs of their pubertal development. The change in there was a pronounced increase in the gonado- pubertal status correlated with a decrease in ovarian trophin response to a diagnostic test of intravenous size and regression of the megalocystic ovarian releasing hormone (Fig. 6). The

gonadotrophin http://adc.bmj.com/ appearance (Fig. 5). pattern of growth of the ovary and uterus in response to treatment is shown in Fig. 7. After 8 Case reports weeks of treatment the ovaries became megalocystic. During a 10 day period of mechanical pump Case 1. An 18 year old girl who presented with short failure both ovaries and uterine size decreased, stature and primary amenorrhoea, had been treated resection of at the age of 17 years by transethmoidal Pulsatile GnRH a craniopharyngioma. After the operation she had on September 28, 2021 by guest. Protected mild diabetes insipidus and adrenocorticotrophic 6- c and growth hormone deficiencies, for which she 5 -1 received hormone replacement treatment. Gona- E 4 410 dotrophin responses to an intravenous diagnostic

4 injection of gonadotrophin releasing hormone are E in 6. Ovarian ultrasound showed small Weecklocystic. shown Fig. ro 2 2 ~~~~~~~~ovaries 4 9 a few small follicles, and a ovaries containing only I0 very small uterus. There was a gradual ovarian enlargement and increase in follicle numbers and 0~ size in response to pulsatile gonadotrophin releasing 0 2 4 6 8 1 hormone treatment, so that by day 220 both ovaries Weeks af treatment were megalocystic. Fig. 7 Serial ultrasound data from a 17year old girl with hypogonadotrophic hypogonadism (case 2) during hormone. Case 2. A 17 year old girl presented with no signs of treatment with pulsatile gonadotrophin releasing puberty. Endocrine assessment showed no abnor- A megalocystic ovariani appearance was established at 8 weeks of treatment. Arch Dis Child: first published as 10.1136/adc.60.2.116 on 1 February 1985. Downloaded from

Ultrasound assessment of ovarian development 119 although follicular size continued to increase. She changes with the more familiar clinical markers of had developed stage II breast development'4 after sexual maturation. three months of treatment. We thank Dr Patrick Magill, (Senior Medical Advisor, Hoescht UK) for supplies of native gonadotrophin releasing hormone and Discussion analogue (Buserelin). Although ultrasound imaging provides a non- References invasive method of assessing ovarian and uterine Boyar RM, Finkelstein J, Roffwarg H. Kapen S, Weitzman E, changes, there have been few gynaecological ultra- Kellman L. Synchronisation of LH secretion with sleep during sound studies in normal childhood. Difficulty has puberty. N Engl J Med 1972;287:582-6. 2 Hoffman AR, Crowley WF. Induction of puberty in men by been experienced in ovarian ultrasonic definition in long-term pulsatile administration of low dose gonadotrophin infants and young children,'5 16 even up to the age releasing hormone. N Engl J Med 1982;307:1237-41. of 7 years.'7 Our data on uterine and ovarian Crowley WF, McCarthur JW. Simulation of the normal ultrasound assessment of normal girls is in agree- menstrual cycle in Kallman's syndrome by pulsatile administration of luteinising hormone releasing hormone (LHRH). J Clin ment with more recent work.'8 19 In addition to Endocrinol Metab 1980;51:173-5. measuring ovarian size we have been able to assess 4 Kauli R, Pertzelan A, Ben-Zeev Z, et al. Treatment of intra-ovarian morphology using ultrasound in nor- precocious puberty with LHRH analogue in combination with cyproterone acetate-further experience. Clin Endocrinol mal girls as young as 6 months of age. 1984;20:377-87. We have found that pelvic ultrasound assessment 5 Donaldson MDC, Stanhope R, Lee TJ, Price DA, Brook CGD, is helpful in the diagnosis and classification of Savage DCL. Gonadotrophin responses to GnRH in precocious precocious puberty. The presence of a large uterus puberty treated with GnRH analogue. Clin Endocrinol 1984; with a cross sectional area greater than 4 cm2 21:499-503. 6 Simbkins CS. Development of the human ovary from birth to confirms this diagnosis. In addition to the uterine sexual maturity. Am J Anat 1932;51:465-505. changes, the ovaries in idiopathic precocious pu- 7 Polhemus DW. Ovarian maturation and cyst formation in berty are large, approach adult size, and are always children. Pediatrics 1953;11:588-94. 8 megalocystic. An ovarian volume of than 3 Krantz KE, Atkinson JP. Paediatric and adolescent gynae- copyright. greater cology: gross anatomy. Ann N Y Acad Sci 1967;142:551-75. cm3 is outside the normal range and confirms a 9 Peters H, Byskov AG, Grinster J. The development of the diagnosis of idiopathic precocious puberty. Treat- ovary during childhood in health and disease. In: Coutts JRT, ment with gonadotrophin releasing hormone ana- ed. Functional morphology of the human ovary. Lancaster: logue is associated with regression of the MTP Press, 1981:26-34. megalocys- 1' Cabrol S, Haseltine FP, Taylor KJJ, Viscomi G, Genel M. tic ovarian appearance. Ultrasound examination of pubertal girls and of patients with In our experience of inducing puberty in patients gonadal dysgenesis. J Adolesc Health Care 1981;1:185-92. with hypogonadotrophic hypogonadism, changes Haller JO, Friedman AP, Schaffer R, Lebensart DP. The occur in ovarian normal and abnormal ovary in childhood and adolescence. http://adc.bmj.com/ morphology and uterine size which Seminars in Ultrasound 1983;4:206-25. closely resemble those seen in normal puberty. The 12 Campbell S, Goessens L, Goswamy R, Whitehead M. Real-time megalocystic appearance is an ovarian response to ultrasonography for determination of ovarian morphology and pulsatile gonadotrophin secretion. We hypothesise volume. Lancet 1982;i:425-6. that pulsatile secretion of gonadotrophin 13 Sutherland IA, White S, Chambers GR, et al. A miniature releasing infuser for the pulsatile administration of LHRH. J Biomed Eng hormone in low amplitude and long periodicity leads 1984;6:129-33. to the beginning of ovarian maturation early in 14 Tanner JM. Growth at adolescence. Oxford: Blackwell Publica- childhood, before there are any clinical signs of tions, 1962. puberty. A phase of megalocystic ovarian appear- '5 Haller JO, Schneidner M, Kassner EG, et al. Ultrasonography on September 28, 2021 by guest. Protected in paediatric gynaecology and obstetrics. Am J Radiol ance occurs before the development of a dominant 1977;128:423-39. follicle. These changes can be reproduced in 16 Sample WF, Lippe BM, Gyepas MT. Gray scale ultrasono- patients with hypogonadotrophic hypogonadism graphy of the normal female pelvis. Radiology 1977;125:477-83. treated with pulsatile gonadotrophin hor- 7 Ivarsson SA, Nilsson KO, Persson P-H. Ultrasonography of the releasing pelvic organs in prepubertal and postpubertal girls. Arch Dis mone by varying pulse frequency and amplitude. Child 1983;58:352-4. The megalocystic ovarian appearance is dependent 18 Colle M, Calabet A, Sanciaume C, Battin J. Contribution of on pulsatile gonadotrophin releasing hormone pelvic ultrasonography (PUS) to endocrine investigations in secretion and can be suppressed with girls. Pediatr Res 1984;18:113. analogue. 19 Tassoni P, Salardi S, Orsini LF, et al. Ultrasound biometry of Ultrasound imaging has a key role in the diagnosis pediatric female internal genital structures. Pediatr Res and management of disorders of sexual maturation, 1984;18:1 14. reducing the requirement for more complex bio- chemical measurements. The information afforded Correspondence to Dr C G D Brook, Middlesex Hospital, by this non-invasive technique offers a new way of Mortimer Street, London WIN 8AA. establishing the relation of the neuroendocrine Received 28 August 1984