1. GnRH agonist various uses in children
Abdulmoein E Al-Agha MBBS,DCH,CABP,FRCPCH(UK)
Consultant, Pediatric Endocrinologist

2. GnRH agonists
Are synthetically modelled after the natural GnRH decapeptide with specific amino acid substitutions typically in position 6 and 10
These substitutions inhibit rapid degradation
Agonists with 2 substitutions include:
leuprolide (Lupron)
buserelin (Suprefact)
nafarelin (Synarel)
histrelin (Supprelin )
goserelin (Zoladex)
deslorelin (Suprelorin)

3. GnRH agonists
Leuprolide acts as an agonist at pituitary GnRH receptors
By interrupting the normal pulsatile stimulation and the desensitization of the GnRH receptors
It indirectly down regulates the secretion of gonadotropin (LH) and (FSH) leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels in both sexes

4. Therapeutic Uses of Synthetic GnRH Agonists
Pulsatile intravenous administration of gonadorelin every 1–4 hours stimulates FSH and LH secretion
Continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response
The first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females
The continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids

5. Therapeutic Uses of Synthetic GnRH Agonists in Adults & Children
Female and male infertility
Diagnosis of LH responsiveness
Endometriosis
Uterine Fibroids
Prostate Cancer
Central Precocious Puberty

6. New research indication
Use of GnRH agonists in children with short stature and early puberty or in children with idiopathic short stature

7. GnRH agonist side effects in children & adults
Headache, light-headedness, nausea, and flushing.
Local swelling at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration.
Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur.
Ovarian cysts may develop within the first 2 months of therapy and generally resolve after an additional 6 weeks
Reduced bone density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses.
In men treated with continuous GnRH agonist administration, adverse effects include hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia.
GnRH analog treatment of children is generally well tolerated

8. PRECOCIOUS PUBERTY

9. PRECOCIOUS PUBERTY
Appearance of secondary sexual characteristics before the age of 8 years in girls and before the age of 9 years in boys
The overall incidence has been estimated to be 1:5,000 to 1:10,000 children
The female to male ratio is approximately 10:1
It occurs prior to age 6 for African American girls or age 7 for Caucasian girls

10. PRECOCIOUS PUBERTY Results from increased sex steroid production
True precocious puberty, also known as complete precocious puberty, refers to puberty that appears early and either progresses through each of the pubertal landmarks
A GnRH challenge test that demonstrates the pubertal response of gonadotropin (i.e., LH response > FSH response) is the hallmark of this diagnosis as is the usual ability to suppress pubertal development with GnRH agonists

11. Central Precocious Puberty (CPP)
This results from early maturation of the hypothalamic- pituitary- gonadal axis
Idiopathic precocious puberty seems to be the most common cause of CPP
CNS lesions identified include neoplasm, trauma, hydrocephalus, post infectious encephalitis, congenital brain defects, and such genetic disorders as neurofibromatosis type 1 and tuberous sclerosis
The most commonly identified neurogenic neoplasms found in CPP include hamartomas, astrocytomas, and pituitary microadenomas
Hamartomas are congenital hypothalamic malformations that histological contain GnRH- secreting neurons

12. Axiology at the diagnosis of precocious puberty
At diagnosis of precocious puberty, height and height velocity are increased and bone age is advanced
The mean growth velocity ranges from 8 to 10 cm/year, roughly +2 to +4 SD for chronological age, and results in increased heights, between +1.5 and +2.5 SD for age on average
The mean bone age is advanced over chronological age by ∼3 years and results in decreased predicted adult height (5 to –11 cm compared to target height)
This pattern of growth is not only due to the direct effects of estrogens but also to the sex steroid‐dependent increase in growth hormone (GH) and insulin‐like growth factor (IGF)‐I production

13. GnRH agonists in precocious puberty: effects on stature growth
GnRH agonists have been used for more than 30 years in the treatment of central precocious puberty (Crowley et al., 1981; Laron et al., 1981).
The most widely used GnRH agonists are triptorelin and leuprorelin Depot (or slow release formulations) of both have been studied in children treated for precocious puberty (Roger et al., 1986; Carel et al., 1995, 2002b)

14. GnRH agonists in precocious puberty: effects on stature growth
Predicted height has been shown to improve with long-term GnRH agonist therapy and the absence of treatment is associated with reductions of these height predications
Studies consistently demonstrate that girls presenting under age six are able to subsequently achieve normal adult height because of the GnRH agonist therapy

15. Adult height in girls treated with GnRH agonists for precocious puberty: results of selected studies.
Figure 1. Adult height in girls treated with GnRH agonists for precocious puberty: results of selected studies. For each study, the mean ± SD of target height (—), predicted height before treatment (—) and achieved adult height (—) is presented; the study reference and the number of patients are shown on the x‐axis.
Carel J et al. Hum. Reprod. Update 2004;10:
European Society of Human Reproduction and Embryology

16. Three situations should be individualized:
Use of GnRH agonists in children with short stature and early puberty or in children with idiopathic short stature
The results observed in precocious puberty and the hope that interrupting puberty might increase adult height has led to several attempts to use GnRH agonists in patients other than those with strict criteria for precocious puberty
Three situations should be individualized:
Children with ‘Early normal variant’ puberty
Those with normal puberty and poor growth prognosis due to idiopathic short stature
Those who are treated with GH for idiopathic GH deficiency and their growth percentiles are below target height with pubertal development are advancing

17. Growth chart
Classical finding in females who were growing normally then their growth affected by fusal of epiphysis due to menses
dad
mom
Session agenda 17

18. Endocrine Care
The Efficacy and Safety of Gonadotropin-Releasing Hormone Analog Treatment in Childhood and Adolescence: Long-Term Follow-Up Study
|2010 Archive, |January 2010, |Magiakou et al. 95 (1): 109
Division of Endocrinology, Metabolism, and Diabetes (M.A.M., D.M., N.L., C.K.-G., G.P.C., C.D.-V.), First Department of Pediatrics, Athens University Medical School

19. Objective: The objective of the study was to evaluate the long-term effect of GnRH analog (GnRHa) treatment on final height (FH), body mass index (BMI), body composition, bone mineral density (BMD), and ovarian function.
Subjects/Methods: Ninety-two females, evaluated in adulthood, were categorized as follows:
group A, 47 girls with idiopathic central precocious puberty (33 GnRHa treated and 14 non-treated);
group B, 24 girls with isolated GH deficiency (15 GnRHa and GH treated and nine GH treated);
group C, 21 girls with idiopathic short stature (seven GnRHa and GH treated, seven GnRHa treated, and seven non-treated)

20. Results
Girls treated in childhood with GnRHa have normal BMI, BMD, body composition, and ovarian function in early adulthood
There is no evidence that GnRHa treatment predisposes to polycystic ovary syndrome or menstrual irregularities later after discontinuation of therapy

21. CONCLUSION
For almost 30 yr GnRH analogs (GnRHa) have been used in the management of central precocious puberty (CPP)
GnRH as have also been used to increase the final height (FH) of children with early puberty, and patients with GH deficiency (GHD) or idiopathic short stature (ISS) and normally timed puberty, who have short stature at puberty onset
Whether FH improves with GnRHa treatment has not been definitively answered yet!! (still indicated as clinical trials)
whereas the long-term consequences of GnRHa treatment on body mass index (BMI), bone mineral density (BMD), body composition, and reproductive function are still under investigation