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:
akhadilkar@vsnl.net,
vkhadilk@vsnl.com
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.
