The Clinical Effects of GnRHa in Treating Idiopathic Central Precocious Puberty in Girls
Purpose: This study will explore the clinical effects of the gonadotropin-releasing hormone analogue (GnRHa) to treat girls with idiopathic central precocious puberty (ICPP). Methods: Fifty-four ICPP girls were treated with triptorelin acetate. To evaluate the clinical effects of GnRHa, measurements were taken of the girls' height, weight, ovaries, and uterus before treatment and at 6 and 12 months after treatment. Findings: During the one-year treatment period, the height growth rate slowed in the second half of the year, and the secondary sexual characteristics retracted to varying degrees. Intracavitary ultrasound showed a decrease in the ovary and uterus volumes and in the ovaries' longitudinal diameter, transverse diameter, and anteroposterior diameter and the uterus's transverse diameter. Conclusions: GnRHa can inhibit the development of the gonads and secondary sexual characteristics and induce significant changes in the volume of the ovaries and uterus, longitudinal ovarian diameter, transverse ovarian diameter, anteroposterior ovarian diameter, and transverse uterine diameter.
Keyword : BMI; GnRHa; Idiopathic central precocious puberty in girls; Pelvic ultrasound; Secondary sexual characteristics
Developing secondary sexual characteristics before the age of eight or menarche before the age of ten is defined as precocious puberty.1 In recent years, with increasing social and economic growth, the rate of central precocious puberty among girls has increased every year. Idiopathic central precocious puberty (ICPP) refers to precocious puberty without organic lesions. ICPP is caused by the release of the gonadotropin-releasing hormone (GnRH) after early activation of the hypothalamic-pituitary-gonadal axis (HPGA) function. The pituitary gland secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to an increase in ovarian and uterine volumes.
Girls with precocious puberty have higher levels of criminal activity, substance abuse, social isolation, early sexual behaviour, and mental health problems.2 Precocious girls with a history of adolescent behaviour disorder have more depressive tendencies compared to their peers.2
The gonadotropin-releasing hormone analogue (GnRHa), including triptorelin, is the first choice for treating ICPP.3 GnRHa can act as a hypothalamic analogue to competitively inhibit the GnRH secreted by the hypothalamus and reduce the secretion of pituitary gonadotropin, inhibiting or delaying gonadal development and delaying puberty.1 GnRHa treatment can effectively delay the development of gonads and sexual characteristics and improve adult height, with few side effects.4
To develop a therapeutic model and evaluate the clinical effects of triptorelin in ICPP treatment, this study analyzed and compared the changes in height and weight, uterus and ovaries, and other key parameters.
Fifty-four girls diagnosed with ICPP were enrolled in this study. The age range was six to ten years old, with an average age of 8.62±1.15 years old. The study was approved by the hospital's ethics committee. The study protocol was outlined to the girls' guardians, and they signed informed consent.
Inclusion criteria: (1) secondary sexual characteristics developed before the age of eight and menarche or breast development before the age of 10, (2) linear growth acceleration with an annual growth rate higher than that of normal children, (3) bone age at least one year older than the actual age, (4) a pelvic ultrasound showing an increased volume of the uterus and ovaries and multiple ovarian follicles with diameters greater than 4 mm, and (5) activated HPGA with serum gonadotropins and sex hormones at puberty levels. The immunochemiluminometric assay (ICMA) showed that the LH peak value was ≥5 U/l; the GnRHa stimulation test showed that the LH peak FSH peak was >0.6.1
Treatment of GnRHa
All the girls were treated with triptorelin acetate intramuscularly every 4 weeks, the starting dose was 60-160 mG/kg. We adjust the dose of triptorelin according to the gonadal suppression and the weight changes of the children. The maximum single dose was 3.75 mg.
Detection of height, weight, and body mass index (BMI)
The girls' height and weight were measured and recorded before treatment and at 6 and 12 months after treatment. Height growth rate = height after treatment - the height before treatment; BMI = weight (kg)/square of height (m).
The girls were examined by transrectal ultrasonography before treatment and at 6 and 12 months after treatment, and the parameters of the uterus and ovaries were recorded. No girl had significant differences between the parameters of the left and right ovaries. The ovaries' longitudinal diameter, anteroposterior diameter, and transverse diameter were defined as the mean values of the parameters of the right and left ovaries. Ovarian volume (ml) = (longitudinal diameter x anteroposterior diameter x transverse diameter) x 0.523. The volumes of the two ovaries and the mean volume were calculated. The uterus volume (ml) = (longitudinal diameter x anteroposterior diameter x transverse diameter) x 0.523. The fundal-cervical ratio (FCR) of the (uterus = anteroposterior diameter of the uterus/anteroposterior diameter of the cervix).
After the data had been collected, they were statistically analyzed using the software SPSS 16.0. The measurement data were expressed as mean ± standard deviation (x ± SD). In the present study, single-factor, least significant difference analysis was used to compare normally distributed data with homogeneous variance. Non-normally distributed data, such as volumes of the uterus and ovaries, were compared using a nonparametric U-test. P<0.05 was considered statistically significant.
Secondary Sexual Characteristics
After treatment, the secondary sexual characteristics retracted by varying degrees: the breast glands became softer and smaller in 37 of 54 girls; menstruation disappeared in 24 of 33 girls; and vaginal secretion decreased or disappeared after treatment in 21 girls.
Changes in Height and BMI
In the first six months of treatment, the height growth rate was greater compared to the rate at 6 to 12 months after treatment, and the difference was statistically significant (P<0.05) (Table 1).
There was no significant change in BMI before and after treatment, and the difference was not statistically significant (P>0.05).
To facilitate the statistical analysis, the data before treatment and at 6 and 12 months after treatment began, respectively, were designated as group 1, group 2, and group 3.
Changes in the Ovaries
The longitudinal ovarian diameter, transverse ovarian diameter, and anteroposterior ovarian diameter decreased after treatment began (P<0.05) (Tables 2 and 3), when compared to the measurements before treatment; the reduction in the first six months of treatment was significant (P<0.05) (Table 4 and Figure 1). The volume of the ovaries shrank during treatment, and this was most obvious in the first six months of treatment (P<0.05).
Changes in the Uterus
The transverse diameter of the uterus decreased during treatment (P<0.05), and the reduction was most pronounced during the first six months (P<0.05) (Tables 3 and 5). The results showed no significant changes in the longitudinal uterine diameter, anteroposterior uterine diameter, and uterine FCR before and after treatment (P>0.05). The results showed that the volume of the uterus decreased during treatment, and this was most obvious during the first six months (P<0.05) (Table 4 and Figure 2).
The results showed that there was no significant difference in the anteroposterior diameter and transverse diameter of the cervix before and after treatment (P>0.05) (Table 1).
Vaginal Wall Thickness
There was no significant change in the thickness of the vaginal wall before and after treatment (P>0.05) (Table 6).
The incidence of ICPP is correlated to race, heredity, environment, and other factors. For example, Jayasena et al reported that the overactivation of the kisspeptin (KISS) gene, which produces a hypothalamic neuropeptide, can lead to precocious puberty in children.5 Therefore, KISS gene polymorphism was associated with ICPP.6 A scholar also reported that ICPP is correlated with the mutation of the mkrn3 gene.6 In addition, genetic factors, obesity, and environmental factors may be involved in the occurrence and development of ICPP. The widespread presence of endocrine disorder chemicals is suspected of contributing to the trend of the pathogenesis of early puberty.7
Kim et al8 examined 118 ICPP girls and 91 age-matched healthy girls, and the results showed that the plasma levels of daidzein (P=0.0202), genistein (P0.0021), and total isoflavones (P0.0009) were higher in ICPP girls than in healthy girls. This result suggests that the increase in serum isoflavones may be correlated to the risk of ICPP in Korean girls.7 Zhang et al9 reported that concentrations of environmental endocrine disruptors (such as diethylhexyl phthalate, octylphenol, and bisphenol A) were important pathogenic factors of precocious puberty.10 Tassinari et al11 detected the serum concentration of polybrominated diphenyl ether (PBDEs) in 31 girls with ICPP, and the results showed that the levels were higher than the levels in healthy girls. Girls with higher BMIs had higher serum levels of PBDEs.8
GnRHa is the first choice for treating ICPP globally.1 For patients with typical central precocious puberty, GnRHa treatment can effectively improve adult height and does not cause adverse effects on the body and reproductive functions.9,11 In addition, Li et al12 reported that GnRHa could delay the development of secondary sexual characteristics and ovarian maturity with almost no side effects.13 Therefore, this study evaluated the clinical effect of GnRHa triptorelin on ICPP. Fifty-four girls accurately diagnosed with ICPP were treated with GnRHa triptorelin. After treatment began in this study, the secondary sexual characteristics were retracted to varying degrees in 54 girls. The height growth rate was significantly greater in the first six months than in the second six months.
In 2011, Tacilar et al14 reported that treating ICPP with triptorelin could increase the BMI, puberty growth hormone secretion, and insulin-like growth factor in the blood.
Transient insulin resistance in early and middle adolescence can also increase the adipose tissue content and BMI. Jaruratanasirikul et al15 reported that the sexual development of girls was correlated to BMI. The BMI of girls affects the endocrine metabolism regulated by the KISS-1/GPR54 system.16 In the present study, there was no significant change in BMI before and after treatment, and no increase in BMI was found in ICPP girls treated with GnRHa.
Razzaghy-Azar et al17-19 reported that uterine and ovarian parameters are significantly correlated with age, height, weight, puberty stage, and puberty development. The parameters of the uterus and ovaries detected by pelvic ultrasound are important for the diagnosis and evaluation of precocious puberty. Ultrasound can directly reflect the development of the gonads by dynamically monitoring the volume change of the uterus and ovaries after treatment.20-22
The present study showed that the longitudinal ovarian diameter, transverse ovarian diameter, anteroposterior ovarian diameter, ovarian volume, transverse uterine diameter, and uterine volume decreased after treatment, and this reduction was most significant during the first six months. However, there was no significant difference between the reduction six months after treatment and 12 months after treatment. The inhibition effect was most obvious when the drugs were used for six months. However, there were no significant changes in longitudinal uterine diameter, anteroposterior uterine diameter, uterine FCR, cervix transverse diameter, and thickness of the vaginal walls before and after treatment. Hence, these changes cannot be used as sensitive indexes to evaluate the effect of treatment.
GnRHa triptorelin treatment for girls with ICPP can retract the secondary sexual characteristics and inhibit gonad development. There was no significant change in BMI. The reduction in the volume of the ovaries and uterus, longitudinal ovarian diameter, transverse ovarian diameter, anteroposterior ovarian diameter, and transverse uterine diameter can be an effective and sensitive index for observation.
Conflicts of Interest
The authors declare that they have no competing interests.
1. Endocrinology, genetics and metabolism, pediatrics society of Chinese medical association; Editorial board of the Chinese Journal of Pediatrics. [Consensus on diagnosis and treatment of central precocious puberty (2015)]. Chin J Pediatr 2015;53:412-8. [Article in Chinese]
2. Copeland W, Shanahan L, Miller S, Costello EJ, Angold A, Maughan B. Outcomes of early pubertal timing in young women: a prospective population-based study. Am J Psychiatry 2010;167:1218-25.
3. Kletter GB, Klein KO, Wong YY. A pediatrician's guide to central precocious puberty. Clin Pediatr (Phila) 2015;54:414-24.
4. Willemsen RH, Elleri D, Williams RM, Ong KK, Dunger DB. Pros and cons of GnRHa treatment for early puberty in girls. Nat Rev Endocrinol 2014;10:352-63.
5. Jayasena CN, Nijher GMK, Narayanaswamy S, et al. Age-dependent elevations in plasma kisspeptin are observed in boys and girls when compared with adults. Ann Clin Biochem 2014;51:89-96.
6. Mazaheri A, Hashemipour M, Salehi M, Behnam M, Hovsepian S, Hassanzadeh A. Mutation of kisspeptin 1 gene in children with precocious puberty in isfahan city. Int J Prev Med 2015;6:41.
7. Simon D, Ba I, Mekhail N, et al. Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. Eur J Endocrinol 2016;174:1-8.
8. Kim J, Kim S, Huh K, Kim Y, Joung H, Park M. High serum isoflavone concentrations are associated with the risk of precocious puberty in Korean girls. Clin Endocrinol (Oxf) 2011;75:831-5.
9. Zhang SL, Wei HY, Gu QR, Chen YX, Liu XJ. [Analysis on the correlation between environmental endocrine disrupter chemicals and childhood precocious puberty]. Matern Child Health Care China
2015;30:736-8. [Article in Chinese]
10. Mouritsen A, Aksglaede L, Sørensen K, et al. Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty. Int J Androl 2010;33:346-59.
11. Tassinari R, Mancini FR, Mantovani A, Busani L, Maranghi F. Pilot study on the dietary habits and lifestyles of girls with idiopathic precocious puberty from the city of Rome: potential impact of exposure to flame retardant polybrominated diphenyl ethers. J Pediatr Endocrinol Metab 2015;28:1369-72.
12. Li WJ, Gong CX, Guo MJ, et al. Efficacy and safety of domestic leuprorelin in girls with idiopathic central precocious puberty: a multicenter, randomized, parallel, controlled trial. Chin Med J (Engl) 2015;128:1314-20.
13. Spielmann S, Partsch CJ, Gosch A, Pankau R. Treatment of central precocious puberty and early puberty with GnRH analog in girls with Williams-Beuren syndrome. J Pediatr Endocrinol Metab 2015;28:1363-7.
14. Taşcilar ME, Bilir P, Akinci A, et al. The effect of gonadotropin-releasing hormone analog treatment (leuprolide) on body fat distribution in idiopathic central precocious puberty. Turk J Pediatr 2011;53:27-33.
15. Jaruratanasirikul S, Thongkum K, Krisaneepaiboon S, Sriplung H. Girls with early puberty attain a near-final height similar to their target height. J Pediatr Endocrinol Metab 2011;24:339-45.
16. Pita J, Barrios V, Gavela-Pérez T, et al. Circulating kisspeptin levels exhibit sexual dimorphism in adults, are increased in obese prepubertal girls and do not suffer modifications in girls with idiopathic central precocious puberty. Peptides 2011;32:1781-6.
17. Razzaghy-Azar M, Ghasemi F, Hallaji F, Ghasemi A, Ghasemi M. Sonographic measurement of uterus and ovaries in premenarcheal healthy girls between 6 and 13 years old: correlation with age and pubertal status. J Clin Ultrasound 2011;39:64-73.
18. Badouraki M, Christoforidis A, Economou I, Dimitriadis AS, Katzos G. Evaluation of pelvic ultrasonography in the diagnosis and differentiation of various forms of sexual precocity in girls. Ultrasound Obstet Gynecol 2008;32:819-27.
19. Wen XD, Zhang H, Zhang HF, Zhang MW, Cai WJ, Yang Y. [Value of color Doppler ultrasonography in the diagnosis of precocious puberty in girls]. Chin J Ultrason 2014;23:798-803. [Article in Chinese]
20. Sathasivam A, Rosenberg HK, Shapiro S, Wang H, Rapaport R. Pelvic ultrasonography in the evaluation of central precocious puberty: comparison with leuprolide stimulation test. J Pediatr 2011;159:490-5.
21. de Vries L, Phillip M. Pelvic ultrasound examination in girls with precocious puberty is a useful adjunct in gonadotrophin-releasing hormone analogue therapy monitoring. Clin Endocrinol (Oxf) 2011;75:372-7.
22. Wang HR, Chen YQ, Xu YF, Jiang J, Hu HY. [Ultrasound evaluation of leuprorelin therapeutic efficacy in girls with central precocious puberty]. Chin J Ultrason 2018;27:714-9. [Article in Chinese]
This web site is sponsored by Johnson & Johnson (HK) Ltd.