Indian Pediatrics 2005;42:57-60 

Growth Hormone and GnRHa Combination Therapy in the Management of Precocious Puberty

From the Growth and Pediatric Endocrine Research Unit, Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, 32, Sassoon Road, Pune-411001.

Correspondence to: Dr. Vaman Khadilkar, Consultant Pediatric Endocrinologist, Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, 32, Sassoon Road,
Pune-4110001. E-mail: [email protected], [email protected]

Manuscript received: December 15, 2003; Initial review completed: March 1, 2004; Revision accepted: June 15, 2004.

Abstract:

Growth hormone when used in precocious puberty in combination with Gonadotropin releasing hormone analogue (GnRHa) instead of using GnRHa alone has been shown to improve final height prognosis. We report here a two-year follow-up of three cases of precocious puberty, two of whom were treated with a combination of GH and GnRHa and the third treated with GnRHa alone.

Key words: GH, GnRHa, Precocious puberty.

 

Precocious puberty may lead to short stature due to the premature fusion of epiphyseal growth plates(1). In Central precocious puberty (CPP) Gonadotropin releasing hormone analogue (GnRHa) has been used to halt the progress of puberty and postpone premature fusion of the epiphysis(2). With this treatment the growth velocity (GV) often becomes subnormal. To combat this situation Growth hormone (GH) has been used simultaneously with GnRHa to improve final height prognosis(3). Reports of the combined use of GnRHa and GH in patients with CPP are scarce in Indian literature. We report a two-year follow-up of three cases of CPP, two treated with GH and GnRHa and the third treated with GnRHa alone.

Case Reports

The clinical spectrum of the three patients with precocious puberty is depicted in Table I.

Table I Patient characteristics

Case 1: A 7½-year-old girl, operated for hydrocephalus at 3.8 years, presented with history of breast development of 8 months duration. Her mid-parental height (MPH) was 157 cm, height was 115 cm (just below 25th centile, Agarwal charts(4)) and weight was 17 kg (10th centile). Her sexual maturity rating (Tanner staging) was axillary hair 1, pubic hair 2, breast stage 3 and no menses. Her bone age was 9.8 yr and her GV was 8.3 cm/year (Normal GV 5 cm/yr). The presence of a previous CNS pathology and clinical findings on presentation lead to the clinical suspicion of the diagnosis of central form of isosexual precocity. Leutinising hormone (LH) was 6.2 miu/mL (normal <1 miu/mL), follicle stimulating hormone (FSH) was 3.0 miu/mL (<1 miu/mL) and LH/FSH ratio was 2.1 (normal prepubertal <1), prolactin was 7.5 ng/mL (2-15 ngm/mL), estradiol was 80 pg/mL (normal prepubertal < 10 pg/mL) and she was euthyroid. Pelvic ultrasound showed adult-type uterus. Both ovaries showed 3-4 follicles and were 1.2 mL in volume. Neuroimaging showed the shunt in place and a normal pituitary gland. She was treated with GnRHa (Tryptorelin 100 Microgm/Kg) intra- muscularly, as a monthly injection for a period of 2 years and GH in the dose of 20 iu/m2/week. Final height prediction done by the Tanner Whitehouse 3 method(5) was 132 cm. After 3 months of therapy there was regression of all signs of puberty, and hormones showed prepubertal values. GV dropped to 6 cm per year. After 2 years of treatment, puberty was still suppressed and her height was 127 cm, weight was 23 Kg, bone age was 10.4 years, height SDS was –0.74 and final height prediction improved to 138 cm.

Case 2: A 9-year-old girl presented with history of regular menses for 6 months, height was 136 cm, and weight was 30 Kg, both above 75th centile for age. Her MPH was 158 cm, her GV was 13.5 cm /year (Normal GV 4-5 cm/year) and bone age was 13.2 years. Other clinical findings and treatment were similar to case 1. Final height prediction was 139 cm. Three months after therapy puberty was suppressed and GV dropped to 6 cm/year. After two years of treatment her height was148 cm, weight was 34 Kg, bone age was 14.2 years, height SDS was 0.93 and final height prediction improved to 149 cm.

Case 3: A 4-year-old girl presented with bilateral breast development for 3 months. Her MPH was 146 cm, height was 100.3 cm (50th centile), weight was 13 Kg (just above 3rd centile), GV was 8.6 cm/year (Normal GV 5 cm/year) and bone age was 9.2 years. Other findings were similar to case 1. Her final height prediction was 155 cm. She was treated with GnRHa as above. Economic constraints did not allow GH therapy. Her GV declined to 3.6 cm/year. At the end of 2 years of treatment her height was 109.5 cm, weight was 15 Kg, bone age was 10.4 years, height SDS was –0.64 and final height prediction was 158 cm.

Discussion

Precocious puberty is of concern as it may result in short adult stature due to rapid skeletal maturation attributable to early secretion of sex hormones, and the psychosocial difficulties that the sexually precocious child encounters(6). Effective management depends on identification and treatment of the cause and also the arrest of progression of puberty. In CPP, the pubertal hypothalamo-pituitary-gonadal axis can be inhibited by the administration of a long acting analogue of GnRH. While on therapy with GnRHa bone age progression is slowed and thus there is a potential to extend the time available for pre-pubertal growth(1).

Kaplowitz has reasoned that while on treatment with GnRHa, improvement in adult height has been disappointing because the benefit of slower bone age advancement is offset by slower than normal linear growth once sex steroids are suppressed(7). Pucarelli, et al. have treated 35 girls (who have now reached adult height) with CPP with GnRHa for 2-3 years whose GV fell below the 25th percentile for age, 17 of these received GH in addition. It was concluded that patients treated with combination therapy showed an adult height significantly higher than pretreatment predicted adult height, while adult height of patients on therapy with GnRHa alone was not significantly higher than pretreatment predicted adult height(8). They have also commented in an earlier paper that GnRHa decreases GV so markedly as to impair predicted adult height to below the third percentile(9).

GV during GnRHa therapy given alone may often decline to subnormal levels thus reducing the advantage of treatment in terms of final height achievement. A combination of GH and GnRHa is hence suggested which may lead to a better adult height. Exogenous GH replaces the secretion of endogenous GH, which gets suppressed with GnRHa treatment(3).

A major consideration in India is the cost of therapy as GnRHa given alone costs about Rs. 4000/month, when GH is added to therapy it costs an extra Rs. 20,000 - 25,000/month.

In our 3 patients, we have demonstrated that GnRHa, is effective in arresting the progress of puberty but as our case 3 shows, when GnRHa used alone, the GV reduces to less than normal pre-pubertal levels, thus compromising final height prognosis (Table II). We demonstrated in our first two cases that the decline in GV following GnRHa therapy to levels below normal was prevented with the use of GH, thus improving final height potential.

TABLE II

Comparison of Height Velocity

Case No.	Pre-treatment	Post-treatment
1. GH + GnRHa	8.3	6.0
2. GH + GnRHa	13.0	6.0
3. GnRHa alone	8.6	3.6

Contributors: VVK and AVK carried out the clinical workup. AVK and GBM collected the data and drafted the manuscript. VVK will act as guarantor of the study.

Funding: HCJMRI, Jehangir Hospital, Pune.

Competing interests: None.

 References