Abstract
Objective : Due to non-affordability of GnRH analogues we have treated 10 patients (8 girls and 2 boys) with sexual precocity (9 central and one peripheral) over period 7 months to 7 years with medroxyprogesterone acetate (MPA). The progression of growth and sexual and bone maturation has been studied.
Design : Retrospective study

Methods : MPA either oral (10 to 30 mg/day) or injectable (100 to 150 mg every two to three weeks) was given to children presenting with sexual precocity after thorough clinical examination, hormonal investigations (FSH, LH, oestradiol or testosterone), brain imaging where needed and pelvic USG in girls. All these children were followed up at 6 months to one year interval to reassess anthropometry, SMR staging and repeat hormonal evaluation and USG pelvis. The growth data was expressed as SDS for bone age, chronological age and growth velocity.

Results : Girls presented with breast stage 3 (7 girls) and 4 (one girl) and pubic hair stage 2 (6 girls) and 1 (2 girls). Boys presented with Tanners 3 of SMR. On treatment, breast size decreased in 3 girls, was same in 2, showed an initial decrease followed by increase in 2 and increased in one girl. Pubic hair decreased in one girl, increased in 2 and showed no progress in 5 girls. Boys did not show progression in puberty. Menstrual bleeding was controlled in all girls presenting with menses. Gonadotropins showed a decrease in 5 out 6 patients retested. However there was no significant change in bone age and increased growth in these patients.

Conclusion : MPA helps in arresting secondary sexual characters in most patients and in controlling menstrual bleeding and is a suitable alternative to GnRH analogues where cost matters.

Introduction
Precocious puberty is one of the important reasons for referral to our paediatric endocrine services. It constitutes 5.5% of total referrals annually. GnRH analogues are current treatment for central precocious puberty. Due to non-affordability of this form of therapy we have treated children presenting with precocious puberty by using medroxyprogesterone acetate (MPA). It has been used as therapy for both central and peripheral precocious puberty. We present here our experience in 10 patients treated over 7 months to 7 years with MPA in children with sexual precocity (9 central and 1 peripheral precocious puberty). The progression of growth and sexual and bone maturation has been studied.

Material and Methods

The records of 10 cases (2 males and 8 females) presenting to our clinic with appearance of secondary sexual characters prior to age of 8 years in girls and 9 years in boys were retrospectively studied. Detailed history, thorough clinical examination, anthropometry, sexual maturity rating (SMR) staging by Tanner’s method was done in all cases. Laboratory evaluation in form of basal FSH, LH, oestradiol or testosterone by radioimmunoassay was estimated. Bone age estimates were determined from hand and wrist x-rays using the standards of Greulich and Pyles atlas method. All girls had pelvic USG for evaluation of uterine dimensions, ovarian size and presence of follicles/cysts at presentation. MRI/CT scan of the brain was done wherever indicated.

MPA either oral (10 to 30 mg/day) or injectable (100 to 150 mg every two to three weeks) was given. The effective dose was established so as to control the symptoms. All these children were followed up 6 months to one year interval. On follow up detailed assessment regarding anthropometry, SMR staging, bleeding per vaginum, bone age, FSH, LH, oestradiol or testosterone levels, USG pelvis was done. The growth data was expressed as SDS for bone age, chronological age and growth velocity.

Results
The data accumulated from this study is listed in Tables. There were 8 girls and 2 boys who presented with precocious puberty. The mean age of presentation was 52.1 ± 21.7 months while the mean age of onset was 43 ± 23.4 months. The breast stage before initiation of therapy was B3 in 7 patients and B4 in one patient. Pubic hair stage was P2 in 6 girls while 2 girls did not show pubic hair. Four girls had menses at presentation. Both the boys had genital stage 3 with testicular volumes of 10 and 12 ml measured by orchidometer and stretched penile lengths of 8 and 10 cm respectively. Bone age was done in all patients of CPP, out of which six patients had advanced bone ages at onset of therapy. Bone age was greater than height age (HA) in all patients and greater than chronological age (CA) in 8 patients. Two patients had symptoms of hyperactivity and one had café-au-lait spots on the body. Two patients had delayed milestones.

Pubertal range of FSH and LH are between 1-10 mIU/ml and 2-8 mIU/ml respectively while the serum oestradiol and testosterone levels are usually more than 10 pg/ml and 30 ng/dl respectively with LH to FSH ratio usually more than one.1,2 FSH was increased in 9 patients and LH in 8 patients with LH/FSH > 1 in 5 patients. 7 out of 8 girls had oestradiol levels more than 10 pg/ml. USG pelvis showed increased uterine dimensions in all girls and increased ovarian volumes in 6 girls. 4 girls had bilateral small ovarian follicles. Nine patients had CPP due to various causes like hypothalamic hamartoma (3 patients), brain injury due to perinatal asphyxia (2 patients) and in remaining 4 patients no cause could be found out. One patient had peripheral precocious puberty due to McCune Albright syndrome.

Nine patients received inj. MPA out of which one opted for oral MPA 6 mo after injections and the remaining received oral MPA. Five patients required change in dose of MPA. The follow up is over period of 7 months to 7 years.

Three patients showed a decrease in breast size, 2 patients did not show any change, 2 patients showed an initial decrease followed by increase in breast size and in one patient breast size increased. Pubic hair decreased in one girl, did not show a change in 5 girls and increased in 2 girls. Four girls had menstrual bleeding at initiation of therapy which got controlled after increasing the dose of MPA. Testicular volumes, penile lengths and pubic hair stages did not change in boys on treatment. One boy had erections at start of therapy which decreased on treatment. Repeat FSH, LH was possible in 6 patients of CPP out of which 5 showed a decrease in levels. The patient with Mc-Cune Albright did not progress to CPP as evident by normal FSH and LH on follow up.

In 7 patients bone age could be done on follow up. Bone age increased significantly in 6 patients. BA/CA ratio increased in 4 patients while HA/BA ratio increased in 3 patients, however in all patients bone age was more than height age even on follow up. Height SDS score for CA showed deterioration in one patient. SDS score for growth velocity showed improvement in five, deterioration in three, initial improvement and then deterioration in two and no change in one. Ht SDS score for BA showed deterioration in six patients and no change in three patients. Paired t-test was applied to compare height SDS before treatment with MPA and one year after treatment. It showed a significant change (p, 0.05, t = 3.48). However growth velocity SDS and height SDS for BA did not show a statistical difference in the same period. Fisher Z-transformation test was used to test the equality of correlation coefficient between ht. SDS BA, ht. SDS CA before and after one year of treatment. There was no significant difference in the correlation coefficients.

Discussion
Precocious puberty (PP) is classified as central/GnRH dependent (CPP) or peripheral/GnRH independent (PPP) precocious puberty. Varying causes of PP requires different types of therapy.^1,3 GnRH analogues are the current treatment modalities of CPP.⁴ However due to the prohibitive cost, and ineffectiveness in PPP, medroxyprogesterone acetate becomes the choice of treatment in our country.

MPA is a progestational agent that can suppress gonadotropins.^5,6 It has been used for both CPP and PPP.³ Our patients received MPA over 7 months to 7 years. At the end of last follow up 3 girls showed a decrease in breast size while 2 did not show a change. Similar effects were found in other studies.^6,7,8 Two patients showed an initial decrease followed by increase in breast size and in one breast size increased. The result was comparable with Lee et al⁵ who found that change in development of breasts varied depending on the degree of development at the onset of treatment. Our study showed no change in sexual hair in all his patients and similar results were found by Richman et al.⁹ Menstrual bleeding got controlled in all patients with MPA at time of presentation. Similar results were found by other authors.^6-9 Lee et al in his study found that MPA had effect only on stopping menses.⁵ The boys did not show any advancement in precocious puberty. However in one boy erections decreased. Similar effect was seen in other studies.^6,9 Five out of 6 patients in whom FSH, LH was repeated showed a decrease. Similar results were seen by Pasquino et al.⁸ However Warren et al¹⁰ found a decrease only in LH. One girl who showed an increase in gonadotropins and breast size already had advanced bone age at presentation.

Bone age could be done at follow up in 7 patients. MPA did not show any effect on bone maturation or increased growth. This was consistent with the findings of other authros.^3,5,9 MPA can be used in our patients of PP for its effects on controlling menses and progression of secondary sexual characters. In cases of PPP it probably has local anti-oestrogen effect.¹¹

Key messages

• MPA is a suitable alternative in treating patients with PP due to prohibitive cost of GnRH analogues.
• MPA helps in arresting secondary sexual characters in most patients and in controlling menstrual bleeding.

Acknowledgement
The authors gratefully acknowledge Dr. Dod, Chief Senior Executive of BJ Wadia Hospital for Children for giving us permission to publish this article and Dr. Meena Desai for her guidance in managing the patients and critical analysis of the manuscript.

References

1. Menon PSN. Precocious puberty. In : Pediatric Endocrine disorders. Eds. Meena PD, Vijayalaxmi B, Menon PSN. Orient Longman Ltd., 2001; 138-53.
2. Appendix. Hormone reference values. In Pediatric Endocrine disorders. Eds. Meena PD, Vijayalaxmi B, Menon PSN. Orient Longman Ltd, 2001; 422.
3. Wheeler MD, Styne DM. The treatment of precocious puberty. Endocrinol Metab Clin North Am 1991; 20 (10 : 183-90.
4. Wheeler MD, Styne DM. Drug treatment in precocious puberty. Drugs 1991; 41 (5) : 717-28.
5. Lee PA. Medroxyprogesterone therapy for sexual precocity in girls. Am J Dis Child 1981; 135 (5) : 443-5.
6. Sadeghi-Nejad A, Kaplan SL, Grumbach MM. The effect of MPA on adrenocortical function in children with precocious puberty. J Pediatr 1971; 78 (4) : 616-24.
7. Nanbu A, Kumamato Y, Takagi Y, Maruta H. Study on cases of precocious puberty. Hinyokika Kiyo 1989; 35 (10) : 1715-20.
8. Pasquino AM, Fraioli F, Lannetti P, et al. Longterm treatment with MPA in 4 children with true precocious puberty. Minerva Pediatr 1976; 28 (8) : 517-25.
9. Richman RA, Underwood LE, French FS, Vanwyk JJ. Adverse effects of large doses of MPA in idiopathic isosexual precocity. J Pediatr 1971; 79 (6) : 963-71.
10. Warren MP, Mathews JH, Morishima A, Vanderwiele R. The effect of MPA on gonadotropin secretion in girls with precocious puberty. Am J Med Sci 1975; 269 (3) : 375-81.
11. Rao S, Colaco MP. McCune Albright syndrome (MCAS) : A case series. Indian Pediatr 2003; 40 (1) : 29-35.