Arch Dis Child 1998;79:323–327 323

EYcacy of Zoladex LA () in the Arch Dis Child: first published as 10.1136/adc.79.4.323 on 1 October 1998. Downloaded from treatment of girls with central precocious or early puberty

W F Paterson, E McNeill, S Reid, A S Hollman, M D C Donaldson

Abstract ples include (Hoechst), Objective—To assess the eYcacyofa (Searle; Syntex), (Ortho), and longer acting preparation of the gonado- deslorelin (Roberts). It has been reported that trophin releasing hormone (GnRH) ana- intranasal preparations give incomplete gona- logue goserelin (Zoladex LA, 10.8 mg) in dotrophin suppression4 and because they need 12 girls with central precocious or early to be given four times a day compliance is dif- puberty. ficult to achieve. These preparations have Methods—Two girls started treatment de largely been superseded by long acting depot novo; the remainder had been on suppres- preparations, given by intramuscular or sub- sive treatment for a median duration of 1.5 cutaneous injection, usually on a monthly (range, 0.2–5.6) years. Assessment com- basis—for example, leuprolide (Wyeth, Berks, prising auxology, pubertal staging, and UK; TAP), (Speywood; Ferring), pelvic ultrasound examination was carried and goserelin (Zeneca). out at weeks 0, 4, 8, 10, and 12 (first cycle) Goserelin, in the form of a 3.6 mg depot and weeks 8, 10, and 12 (second cycle) to preparation (Zoladex), has been particularly 5–7 evaluate the required injection frequency. successful. This preparation is administered Thereafter, assessment was performed on by subcutaneous injection into the anterior the day of injection. Zoladex LA was given abdominal wall, and is generally eYcacious every 12 weeks unless pubertal progression when given at intervals of three or four weeks. occurred. A longer acting formulation of goserelin (Zola- Results—Satisfactory control was dex LA; 10.8 mg biodegradable depot; Zeneca, achieved in eight patients using this Cheshire, UK) has become available recently. regimen, and three patients required Because this product is three times the dose of more frequent injections. One girl was the standard preparation, a reduced injection removed from the study because of clini- frequency can be anticipated. Our study was cal progression and extreme mood swings. undertaken to assess the eYcacy of Zoladex LA No serious adverse eVects occurred. Mean in girls with early or , and http://adc.bmj.com/ height velocity during the study period the optimum injection frequency required to was 4.5 cm/year (range, 3.1–6.6) com- achieve pubertal suppression. pared with 6.5 cm/year (range, 3.8–9.6) before treatment in nine patients for Patients and methods whom data were available. PATIENTS Conclusions—Zoladex LA was eVective in Our study group comprised girls with central

controlling precocious puberty in girls precocious or early puberty, defined as “preco- on September 29, 2021 by guest. Protected copyright. when given at intervals of 9–12 weeks and cious” if onset of symptoms was before age 8 it is recommended that an initial assess- years and “early” if between the ages of 8 and ment is made eight weeks after beginning 10 years. The diagnosis was based on the treatment. history of pubertal symptoms and signs, (Arch Dis Child 1998;79:323–327) increased height velocity, and bone age ad- Keywords: central precocious puberty; gonadotrophin vance, and was confirmed by pelvic ultrasono- Department of Child releasing hormone analogue treatment; height velocity graphy and luteinising hormone releasing hor- Health, Royal Hospital mone (LHRH) stimulation test (100 µg HRF; for Sick Children, Monmouth Pharmaceuticals, Surrey, UK). Yorkhill, Glasgow Synthetic gonadotrophin releasing hormone Pelvic ultrasound findings were compared with G3 8SJ, UK the standards described by GriYn ,8 (table W F Paterson (GnRH) analogues have been used in the et al E McNeill treatment of central precocious puberty since 1) while a pubertal response to LHRH was M D C Donaldson 1981.1 Substitution of two amino acids in the defined as peak LH > 5.0 U/l. Girls with native GnRH peptide results in the production specific pathology aVecting the hypothalamo– Department of of a “superactive” agonist with greater potency pituitary axis—for example, intracranial neo- Diagnostic Imaging, and duration of action than endogenous plasm or previous cranial irradiation, were Royal Hospital for Sick excluded. Children GnRH. Continued administration of the S Reid synthetic agonist eVectively desensitises the A S Hollman pituitary response to GnRH, resulting in TREATMENT reduced secretion of gonadotrophins and sex Treatment was with GnRH analogue only. The Correspondence to: steroids.23 The first GnRH analogues avail- anti-, , which can Dr Donaldson. able needed to be given either by daily be given to counteract the initial stimulatory Accepted 12 May 1998 subcutaneous injection or intranasally. Exam- eVect of GnRH analogue treatment,9 was not 324 Paterson, McNeill, Reid, Hollman, Donaldson

Table 1 Normal values for uterine length and ovarian volumes during childhood indicated in 10 of the 12 girls who were already Arch Dis Child: first published as 10.1136/adc.79.4.323 on 1 October 1998. Downloaded from being treated with an analogue. In the remain- Age (years) Uterine length (cm) Right ovary volume (cm3) Left ovary volume (cm3) ing two girls, we decided not to use cyproter- 5.0 2.6 (1.55–3.65) 0.75 (0.2–2.55) 0.6 (0.2–2.4) one acetate in case it resulted in the known 6.0 2.7 (1.55–3.85) 0.85 (0.25–3.0) 0.7 (0.2–2.9) adverse eVects of fatigue and depression. 7.0 2.85 (1.6–4.15) 1.0 (0.2–3.4) 0.8 (0.25–3.35) 8.0 3.1 (1.7–4.5) 1.15 (0.35–4.0) 1.0 (0.3–3.95) Long acting goserelin (Zoladex LA, 10.8 mg 9.0 3.4 (1.8–4.9) 1.35 (0.4–4.6) 1.15 (0.35–4.6) biodegradable depot; Zeneca) was given ini- 10.0 3.75 (2.1–5.4) 1.55 (0.5–5.3) 1.35 (0.4–5.4) tially at 12 week intervals, by subcutaneous 11.0 4.15 (2.3–6.0) 1.8 (0.5–6.2) 1.6 (0.45–6.4) 12.0 4.65 (2.7–6.6) 2.1 (0.6–7.2) 1.8 (0.5–7.5) injection into the anterior abdominal wall. In 13.0 5.2 (3.1–7.3) 2.4 (0.7–8.3) 2.2 (0.6–8.9) most cases, the injection was given by the endocrine nurse specialist in hospital, after the Values are mean (range 3rd–97th centiles), transcribed from the centile charts of GriYn et al.8 application of a local anaesthetic cream (ligno- caine 25 mg/prilocaine 25 mg/g; EMLA; Table 2 Pelvic ultrasound results and breast stages for patient 1 Astra). In a few cases, the child’s family practitioner gave the treatment. A play leader Cycle of Zoladex LA treatment was used to provide distraction in the few 0123*456 instances where the girls became distressed at the time of injection. Age (years) 8.4 9.1 9.6 Breast stage 1 1 – 1111 Uterineshape CCCP I CC Uterine length (cm) 4.2 4.0 3.3 5.6 4.4 3.1 2.8 MONITORING Endometrial echo (mm) –––1.0––– Evaluation was carried out at zero, four, eight, Right ovary volume (cm3) 4.4 2.9 2.7 6.5 3.9 0.6 1.1 10, and 12 weeks (first treatment cycle) and Left ovary volume (cm3) 2.0 2.2 2.7 3.8 1.0 0.4 2.1 eight, 10, and 12 weeks (second treatment Zoladex LA injections were given every 12 weeks. cycle) to determine the required injection *Changed to injections every nine weeks. frequency. Thereafter, each girl was assessed I, infantile (cervix larger than fundus); C, cylindrical (mid-childhood shape with cervix and fun- on the day of injection. Assessment comprised: dus approximately the same); P, pear shaped (adult shape with fundus larger than cervix). + Auxology: height and weight each time, bone age annually according to the TW2 Table 3 Pelvic ultrasound results and breast stages for patient 2 (RUS) method10

Cycle of Zoladex LA treatment + Pubertal staging: breast, axillary hair, and pubic hair (according to the system of 012345 Tanner11) Age (years) 8.2 9.3 + Pelvic ultrasound: uterine length and con- Breast stage 1+ 1 1 1+ 1+ 1+ figuration, fundo–cervical ratio, ovarian vol- Uterineshape CCCCCC umes and number, size of follicles, and Uterine length (cm) 3.2 2.7 3.6 3.4 2.6 2.9 812 Endometrial echo (mm) –––––– endometrial echo. Right ovary volume (cm3) 4.2 4.2 1.2 2.9 1.0 1.9 Uterine shape was designated as follows: I, Left ovary volume (cm3) 3.0 1.9 1.1 1.5 1.1 1.7 infantile (cervix larger than fundus); C, cylin- drical (mid-childhood shape with cervix and http://adc.bmj.com/ Zoladex LA injections were given every 12 weeks. C, cylindrical (mid-childhood shape with cervix and fundus approximately the same). fundus approximately the same); P, pear shaped (adult shape with fundus larger than cervix). Table 4 Pelvic ultrasound results and breast stages for patient 3 Measurement of gonadotrophin and oestra- Cycle of Zoladex LA treatment diol levels was not carried out because this was considered to be unnecessarily invasive. Also, 0123456

we have previously found gonadotrophin sup- on September 29, 2021 by guest. Protected copyright. Age (years) 9.7 11.1 pression in some girls on GnRH analogue Breast stage 2222222 treatment despite ultrasonic evidence of inad- Uterineshape CCCP CCC Uterine length (cm) 3.2 3.3 3.7 3.9 2.8 3.3 3.3 equate control (Donaldson MDC, unpub- Endometrial echo (mm) – 1.2 1.1 –––– lished data 1993). Right ovary volume (cm3) 0.7 2.5 1.3 2.9 0.8 2.4 2.4 Left ovary volume (cm3) 1.0 1.8 1.3 1.6 0.7 1.4 1.4 CRITERIA FOR ADEQUACY OF SUPPRESSIVE Zoladex LA injections were given every 12 weeks. TREATMENT C, cylindrical (mid-childhood shape with cervix and fundus approximately the same); P, pear shaped (adult shape with fundus larger than cervix). EYcacy of treatment was determined primarily by growth rate, breast stage, and uterine and ovarian morphology. In addition, the following Table 5 Pelvic ultrasound results and breast stages for patient 4 signs and symptoms were also noted and taken Cycle of Zoladex LA treatment into consideration: + Deterioration in behaviour (for example, 0123456 irritability and mood swings), especially if Age (years) 5.5 6.9 related to the one to two weeks preceding Breast stage 2222223 the next injection Uterineshape CCPIIII + Cyclical abdominal pain Uterine length (cm) 2.6 3.4 3.0 3.4 3.0 3.4 3.3 Endometrial echo (mm) ––––––– + Vaginal discharge Right ovary volume (cm3) 1.6 1.9 1.7 1.2 2.1 1.9 1.8 + Adult body odours. Left ovary volume (cm3) 1.8 1.4 1.3 3.0 1.3 1.3 2.1 Control was considered inadequate if the following criteria were met: Zoladex LA injections were given every 12 weeks. I, infantile (cervix larger than fundus); C, cylindrical (mid-childhood shape with cervix and fun- + Vaginal bleeding and/or more than one of dus approximately the same); P, pear shaped (adult shape with fundus larger than cervix). the following adverse ultrasound features: Zoladex LA in girls with central precocious or early puberty 325

Table 6 Pelvic ultrasound results and breast stages for patient 5 Table 9 Pelvic ultrasound results and breast stages for Arch Dis Child: first published as 10.1136/adc.79.4.323 on 1 October 1998. Downloaded from patient 8 Cycle of Zoladex LA treatment Cycle of Zoladex LA treatment 012 34567 0 123 Age (years) 5.1 6.3 Breast stage 2 2+ 2+ 22222+ Age (years) 10.4 11.0 Uterineshape CP C CCCCP Breast stage 2+ 3+ 3+ 3+ Uterine length (cm) 3.0 4.7 4.6 3.0 2.4 3.6 3.0 3.5 Uterine shape P P C P Endometrial echo (mm) – 2.6 – ––––– Uterine length (cm) 5.5 6.7 5.2 4.5 Right ovary volume (cm3) 1.1 2.7 15.5 1.4 1.1 1.6 2.3 3.4 Endometrial echo (mm) 1.0 – – – Left ovary volume (cm3) 1.8 1.3 3.8 2.6 2.0 2.0 1.6 1.0 Right ovary volume (cm3) 8.8 5.5 1.9 – Left ovary volume (cm3) 3.2 5.1 3.1 5.6 Zoladex LA injections were given every 10 weeks for the first cycle only, then every nine weeks. C, cylindrical (mid-childhood shape with cervix and fundus approximately the same); P, pear Zoladex LA injections were given every 12 weeks. shaped (adult shape with fundus larger than cervix). C, cylindrical (mid-childhood shape with cervix and fundus approximately the same); P, pear shaped (adult shape with fun- Table 7 Pelvic ultrasound results and breast stages for patient 6 dus larger than cervix).

Cycle of Zoladex LA treatment Suppressive treatment was instituted in the 0123456 five girls with early puberty in view of Age (years) 8.3 9.7 compounding factors of familial short stature Breast stage 2+ 2+ 2222+2+ (n = 2) or rapid progression of puberty Uterineshape P CCCCCC (n = 2), which would compromise final height Uterine length (cm) 4.2 5.3 4.2 4.8 4.5 4.2 3.2 Endometrial echo (mm) 3.1 –––––– and emotional immaturity (n = 1). Ten girls Right ovary volume (cm3) 2.9 3.8 2.1 9.7 0.3 2.6 0.8 had been on suppressive treatment before Left ovary volume (cm3) 3.6 2.0 2.1 5.6 0.3 1.7 1.0 commencing Zoladex LA (Zoladex 3.6 mg Zoladex LA injections were given every 12 weeks. (n = 8) or 3.75 mg (Prostap SR; C, cylindrical (mid-childhood shape with cervix and fundus approximately the same); P, pear Wyeth n = 2)). The injection frequency was shaped (adult shape with fundus larger than cervix). every three to four weeks and the median dura- Table 8 Pelvic ultrasound results and breast stages for patient 7 tion of treatment was 1.5 (range, 0.2–5.6) years in these girls. Two girls (patients 6 and 11) Cycle of Zoladex LA treatment were starting treatment de novo. The median ages at clinical diagnosis, start of treatment 012345 with GnRH analogue, and start of treatment Age (years) 9.3 10.5 with Zoladex LA were 7.3 (range, 1.8–9.9) Breast stage 2+ 2+ 3+ 3 3 3 years, 7.5 (range, 1.8–10.5) years, and 8.8 Uterineshape CCCCCC Uterine length (cm) 4.1 3.9 3.8 4.6 4.5 4.3 (range, 5.1–10.8) years, respectively. At the Endometrial echo (mm) –––––– time of writing, the median duration of Right ovary volume (cm3) 1.1 0.8 1.4 1.3 0.8 1.2 treatment with Zoladex LA was 1.2 (range, Left ovary volume (cm3) 0.8 2.2 2.1 0.7 0.7 1.7 0.6–1.4) years in 11 of the 12 girls.

Zoladex LA injections were given every 12 weeks. A reduction in growth rate was noted in nine http://adc.bmj.com/ C, cylindrical (mid-childhood shape with cervix and fundus approximately the same). girls after treatment with Zoladex LA (pretreat- + increased uterine length/maturation, in- ment heights were unavailable for the two girls creased ovarian volume, presence of treated de novo). Mean annual height velocities endometrial echo with or without any of were as follows: pretreatment 6.5 (range, the following: 3.8–9.6) cm/year; post-treatment 4.5 (range, + persistent progression of breast develop- 3.1–6.6) cm/year. The mean rate of skeletal ment maturation was normalised in 10 girls for on September 29, 2021 by guest. Protected copyright. + increased height velocity whom data were available (change in bone age/ + any of the minor signs and symptoms change in chronological age (ÄBA/ÄCA) = 1.1 listed above. years), although the range was relatively wide at 0–3.1 years. Tables 2–12 show pelvic ultra- Results sound and pubertal staging results for 11 Twelve girls were studied, five with early patients. puberty and seven with precocious puberty. Breast development remained the same Initial diagnosis was confirmed by the LHRH throughout the study in two girls, waxed and test in 11 of the 12 girls, with a mean peak LH waned in five girls, and progressed in four girls. of 35.6 (range, 8.0–87.7) U/l. One girl (patient No regression of breast stage occurred. Uterine 1) had a peak LH of 4.5 U/l on presentation, length was consistently greater than the mean but was considered to be in the early stages of for age in four girls, while in two others true precocious puberty in view of her rapidly (patients 5 and 6) it was above average in five progressing clinical signs, advanced uterine out of six and six out of seven cycles of and ovarian development, and response to treatment, respectively. There was poor corre- treatment with GnRH analogue. Uterine de- lation between breast and uterine develop- velopment was advanced for age in 11 girls (10 ment. An age appropriate cylindrical uterine of whom had a midline endometrial echo), and configuration was either attained or maintained ovarian development was advanced in eight in eight of the 11 girls during the course of our girls. Mean bone age advancement was 2.4 study. Interestingly, three girls regressed to the (range, 0.9–4.4) years. The condition was idio- infantile uterine configuration during the pathic in nine girls and associated with learning course of our study, but only the youngest diYculties in three girls (one autism, one Wil- (patient 4) has maintained this stage over liam’s syndrome, and one unclassified). several cycles of treatment. 326 Paterson, McNeill, Reid, Hollman, Donaldson

Table 10 Pelvic ultrasound results and breast stages for patient 9 pain (n = 1), and body odour (n = 1), reinforc- Arch Dis Child: first published as 10.1136/adc.79.4.323 on 1 October 1998. Downloaded from ing their pelvic ultrasound data. Cycle of Zoladex LA treatment One girl with autism experienced extreme 0123*456 mood swings, abdominal pain, and clinical progression of puberty eight weeks after her Age (years) 10.7 11.4 12.0 first injection, and was removed from the study Breast stage 3+ 3+ 3+ 4+ 5 5 5 Uterine shape C C – C C – C at parental request. Treatment was changed to Uterine length (cm) 3.4 3.7 – 3.6 3.9 – 3.9 Zoladex 3.6 mg, given at 3 week intervals by Endometrial echo (mm) – – – 1.0 – – – Right ovary volume (cm3) 3.0 1.8 – 3.9 3.2 – 3.3 her general practitioner. After seven months, Left ovary volume (cm3) 3.7 3.3 – 4.6 1.5 – 3.5 she experienced vaginal bleeding, and pubertal progression was confirmed by pelvic ultra- Zoladex LA injections were given every 12 weeks. *Changed to injections every 10 weeks. sound. Continuation of this treatment regimen C, cylindrical (mid-childhood shape with cervix and fundus approximately the same). for a further six weeks, with injections given in hospital, resulted in improvement of clinical Table 11 Pelvic ultrasound results and breast stages for patient 10 symptoms with no further menstruation. Cycle of Zoladex LA treatment Thereafter, Zoladex LA treatment, given at 10 week intervals, was reinstated with no deterio- 0 123456 ration in ultrasonic appearances or clinical Age (years) 10.8 12.2 signs of puberty. Administration of the depot Breast stage 3+ 3+ 4+ 3333 preparation is extremely diYcult in this patient Uterine shape C P C C I I C as she does not keep still. We postulate that loss Uterine length (cm) 3.3 4.0 4.0 3.9 3.4 3.4 3.2 Endometrial echo (mm) – –––––– of pubertal suppression was a result of the Right ovary volume (cm3) 1.6 0.9 2.6 1.2 0.9 1.2 2.5 depot not having been inserted deeply enough Left ovary volume (cm3) 1.5 1.6 3.0 1.4 1.8 0.9 3.0 and slipping out. Zoladex LA injections were given every 12 weeks. No serious adverse eVects occurred during I, infantile (cervix larger than fundus); C, cylindrical (mid-childhood shape with cervix and fun- our study. Possible associated events reported dus approximately the same); P, pear shaped (adult shape with fundus larger than cervix). were: headache (n = 1), transient rash (n = 1), Table 12 Pelvic ultrasound results and breast stages for fatigue (n = 1), and “flu-like” symptoms patient 11 (n = 1).

Cycle of Zoladex LA treatment Discussion 0 123 Precocious puberty is a distressing condition for patients and their families and provision of Age (years) 10.5 11.2 a simple and eVective form of treatment is Breast stage 4 3+ 3+ 4 Uterine shape P C C C beneficial. Depot preparations of GnRH ana- Uterine length (cm) 5.2 4.0 4.7 4.9 logue are simple to administer, and should be Endometrial echo (mm) 1.0 – – – painless if given after the application of a local Right ovary volume (cm3) 4.4 4.0 3.1 5.0 Left ovary volume (cm3) 3.4 2.4 3.2 7.2 anaesthetic cream. We have found that the fear

of receiving such a large injection can be greatly http://adc.bmj.com/ Zoladex LA injections were given every 12 weeks. C, cylindrical (mid-childhood shape with cervix and fundus alleviated by distraction techniques. approximately the same); P, pear shaped (adult shape with fun- Zoladex LA oVers the advantage of less fre- dus larger than cervix). quent injections. Most of our study group remained controlled on injections given at 12 week intervals, with only three requiring more Uterine length and shape proved reliable frequent treatment every nine to 10 weeks. In indicators of pubertal status, with obvious pro- keeping with previous work,14 we have found gression in two of three girls who required that some girls with precocious puberty are on September 29, 2021 by guest. Protected copyright. injections every nine or 10 weeks. All three of diYcult to suppress and that the completely these girls also showed ovarian enlargement. prepubertal state is seldom achieved. Partial However, there was great variation in ovarian suppression of puberty rather than complete volume in the study group as a whole, both regression appears to be a more realistic aim of between individuals and within individuals, treatment. and only one (patient 5) showed evidence of Maximisation of growth potential is an multicystic morphology (defined as at least six important factor influencing the decision of follicles of > 4 mm diameter in each ovary13). whether to treat girls with central precocious A midline endometrial echo was present in puberty, particularly those with below average three patients at the beginning of the study, in target heights. Recent studies following girls the three patients who were insuYciently sup- treated with GnRH analogues to final height pressed and required more frequent injections, have shown promising results. For example, and in another patient who remained otherwise Brauner and colleagues15 found a direct corre- adequately suppressed throughout the study. lation between final height and target height in Overall, eight of the 12 girls were considered 18 of 19 girls treated previously with triptorelin to be suppressed adequately on injections given for a minimum of two years, while Oostdijk and at 12 week intervals. Of these, two (patients 8 colleagues16 reported that 62% of girls treated and 11) stopped treatment after three cycles, at with the same GnRH analogue for 3.4 years ages 11.0 (BA 13.3) and 11.2 (BA 13.2) years, attained final heights within their target range. respectively, at parental request. The three girls It is our intention to follow our study group to who needed more frequent injections reported final height, and it is encouraging to note the clinical signs and symptoms of mood swings normalisation of growth rate and bone age (n = 3), vaginal discharge (n = 1), abdominal advance during treatment with Zoladex LA. Zoladex LA in girls with central precocious or early puberty 327

Clinical symptoms such as mood swings, 1 Crowley WF Jr, Comite F, Vale W, et al. Therapeutic use of Arch Dis Child: first published as 10.1136/adc.79.4.323 on 1 October 1998. Downloaded from pituitary desensitisation with a long-acting LHRH agonist: abdominal pain, and vaginal discharge corre- a potential new treatment for idiopathic precocious lated with uterine morphology and were puberty. J Clin Endocrinol Metab 1981;52:370–2. reliable indicators of pubertal progression. In 2 Wheeler MD, Styne DM. Drug treatment in precocious puberty. Drugs 1991;41:717–28. contrast, breast development and ovarian mor- 3 Breyer P, Haider A, Pescovitz OH. -releasing phology were less helpful signs. We were hormone agonists in the treatment of girls with central pre- cocious puberty. Clin Obstet Gynecol 1993;36:764–72. impressed by the accuracy of parents’ ability to 4 Merke DP, Cutler GB. Evaluation and management of pre- detect incomplete suppression in their daugh- cocious puberty. Arch Dis Child 1996;75:269–71. ters, merely by their behaviour, with “moodi- 5 Bassi F, Serio M. Trattamento con agonista LH-RH (Zola- dex depot) in soggetti aVetti da puberta precoce. Drugs Exp ness” being the most frequently quoted symp- Clin Res 1990;XVI(suppl):33–7. tom. 6 Rangasami JJ, Grant DB. Familial precocious puberty in Of the three girls who required more girls. JRSocMed1992;85:497–8. 7 Thomas BC, Stanhope R, Leiper AD. Gonadotrophin frequent injections, two completed three cycles releasing hormone analogue and growth hormone therapy of treatment before pubertal advance occurred. in precocious and premature puberty following cranial irradiation for acute lymphoblastic leukaemia. Horm Res The third (patient 5) had very early onset pre- 1993;39:25–9. cocious puberty (age 1.8 years) and has proved 8GriYn IJ, Cole TJ, Duncan KA, Hollman AS, Donaldson extremely diYcult to suppress adequately. MDC. Pelvic ultrasound measurements in normal girls. Acta Paediatr 1995;84:536–43. Injections at 10 week intervals were com- 9 Kauli R, Pertzelan A, Ben-Zeer Z, et al. Treatment of preco- menced but, subsequently, she required injec- cious puberty with LHRH analogue in combination with cyproterone acetate—further experience. Clin Endocrinol tions every nine weeks to achieve satisfactory 1984;20:377–87. control. Currently, no patient has needed 10 Tanner JM, Whitehouse RH, Cameron N, Marshall WA, injections at an interval of less than nine weeks. Healy MJR, Goldstein H. Assessment of skeletal maturity and prediction of adult height (TW2 method). 2nd ed. London: We conclude that Zoladex LA is an eVective Academic Press, 1983. treatment for girls with precocious or early 11 Tanner JM. Growth at adolescence. 2nd ed. Oxford: Blackwell Scientific Publications, 1962. puberty and recommend the following proto- 12 GriYn IJ, Cole TJ, Duncan KA, Hollman AS, Donaldson col: MDC. Pelvic ultrasound findings in diVerent forms of + Careful clinical history and pelvic ultra- sexual precocity. Acta Paediatr 1995;84:544–9. 13 Stanhope R, Adams J, Jacobs HS, Brook CJD. Ovarian sound scans at eight, 10, and 12 weeks for at ultrasound assessment in normal children, idiopathic least two “cycles” of treatment to establish precocious puberty, and during low dose pulsatile gonado- trophin releasing hormone treatment of hypogonado- the optimum frequency of injections for trophic hypogonadism. Arch Dis Child 1985;60:116–19. individual patients 14 Donaldson MDC, Stanhope R, Lee TJ, Price DA, Brook Thereafter, pelvic ultrasound scanning CGD, Savage DCL. Clin Endocrinol 1984;21:499. + 15 Brauner R, Adan L, Malandry F, Zantleifer D. Adult height should be performed at the time of injection in girls with idiopathic true precocious puberty. J Clin to monitor eYcacy of treatment. Endocrinol Metab 1994;79:415–20. 16 Oostdijk W, Rikken B, Schreuder S, et al. Final height in central precocious puberty after long term treatment with This study was carried out independently, with the approval of, a slow release GnRH agonist. Arch Dis Child 1996;75: but no financial assistance from, Zeneca Pharma. 292–7. http://adc.bmj.com/ on September 29, 2021 by guest. Protected copyright.