Suppression of Idiopathic Central Precocious Puberty in Girls with Goserline (Zolidex)

Bushra J. Al-Rubayae
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Keywords : Idiopathic Central,Goserline,serum Luteinizing Hormone
Medical Journal of Babylon  10:4 , 2014 doi:1812-156X-10-4
Published :03 June 2014

Abstract

Background: The precise neuro-endocrine mechanisms underlying activation of hypothalamic-pituitary-gonad axis maturation are elusive. The wide age range of pubertal onset among normal individuals throughout the world may suggest that both genetic and environmental factors modulate the timing of puberty. Early activation of the hypothalamic-pituitary-gonad axis, termed central precocious puberty (CPP), causes psychosocial difficulties and may lead to compromised final height, especially if medical intervention is delayed Objective: Depot Gonadotrophin releasing hormone analogues are widely used in the treatment of precocious puberty or suppression of relatively early puberty where growth or psychosocial well-being may be compromised. One example is Zolidex (goserelin 3.6 mg), which can be given every 4 weeks to stop hypothalamic –pituitary ovarian axis until suitable age to start normal activation. Patients and Method: The study conducted in Babylon Maternity and Paediatrics Teaching Hospital during the period from September 2006 till September 2011. Ten girls with clinical evidence of central precocious puberty were started on Zolidex. Their ages at diagnosis ranged from eight months to 60months (mean 30.3 months).Treatment every four weeks with Zolidex and follow up the response regarding symptoms and signs, ultrasound findings and hormonal assay until the end of the study. Results : At diagnosis their ages ranged between (8 – 60) months, their weight between (7.5-16) kg mean 12.1± 2.22, height (70 -105)cm mean 75.7±2.54, body mass index 14.51- 21.33 mean 12.15±2.01.clincal presentation breast development associated with pubic hair and vaginal bleeding in three cases. Ultrasound findings uterus large for age in all the cases except one and follicular activity in seven cases return to normal after treatment and remain as such for the rest of the study also Serum Follicular Stimulating Hormone (FSH) before treatment 12.8 IU/L, and 0.4 IU/L after treatment P value0.0001, serum Luteinizing Hormone (LH) before treatment was17 IU/L and after treatment 0.5 IU/L P value 0.0001 and remained normal for the rest of the follow up period.. Conclusion: Zolidex-LA induces a significant reduction in symptoms over 12weeks and great reduction in gonadotrophins within six months.

Introduction

Precocious puberty may be defined as the appearance of secondary sexual maturation at an early age, before age of 8 years in girls and 9 years in boys. The Lawson Wilkins Paediatric Endocrine Society guidelines recommend that breast development or pubic hair in white girls before age of 7 and black girls before age of 6 should be evaluated for precocious puberty.[1] The aetiology of this is varied it can be due to ovarian tumour ,adrenal tumour ,Gonadotrophin-secreting tumours, exogenous estrogens, neurological (cerebral tumour), hydrocephalus, post meningitis or McCune-Albright Syndrome or idiopathic which constitutes 95% of all cases of precocious puberty. It’s likely that is solely due to initiation of the normal process at a premature age.[2]Usually breast growth and the growth spurt occurs first, followed by the appearance of pubic then axillary hair and then menstruation. Stage I the pre-pubertal stage, no development has occurred, Stage II the breast bud begins to grow beneath the nipple Stage III the breast is more rounded, Stage I the nipple and areola project forward, Stage V full adult breast. While pubic hair stages include Stage I pre-pubertal stage no terminal hair is visible Stage II terminal hair on the vulva, Stage III the narrower triangular show darker colour, Stage IV a wider triangular area is covered and greater density, Stage V the adult stage. [3] Gonadotrophin -Dependant precocious puberty occurs ten times in girls than boys. [4] Body Mass Index (BMI) for children is referred to as BMI-for-age because weight classifications are different at every age, a child s BMI, derived from height and weight measurements, can be plotted onto a gender-specific BMI-for-age growth chart and compared to standards for the child s age. Evaluation of BMI-for-age is based on percentile’ The BMI-for-age chart helps differentiate between a normal weight gain during growth and excess weight gain BMI-for-age is not as simple as weight, but it is a more accurate measure of excess body weight. Children can be classified into four different categories based on their BMI. Children who are at a healthy weight have a BMI in the healthy range for children of their age. The BMI of underweight children is below the healthy weight range. Two classifications describe children whose BMI is above the healthy weight range – at risk of being overweight and overweight . At risk of being overweight refers to children whose BMI-for-age is between the 85th and 95th percentiles. Children in this range are comparable to adults with a BMI of 25 to 29.9, a classification of being overweight. In children, overweight corresponds to a BMI-for-age greater than the 95th percentile[1]. This is comparable to adults with a BMI of 30 or more, a classification of obese. [5]. Treatment in cases of idiopathic precocious puberty is to ensure the normal onset of puberty so the treatment of choice is the use of gonadotropin releasing hormone (GnRH) analogues, which are extremely effective in obliterating follicle stimulating hormone (FSH) production by the pituitary by doing this the pre pubertal state is re-established and the child can remain on this when the therapy withdrawn and the onset of puberty will ensue. [2] The advantage of depot preparation which maintain fairly constant serum level of long acting GnRH analogues for weeks. The preparations approved Leuprolide acetate dose 0.25-0.3 mg/kg(maximum 7.5mg) I.M every four weeks, other long acting (D-Trip 6-GnRH Decapeptyl, goserlline acetate (Zolidex) are approved for treatment of precocious puberty [4].

Materials and methods

This prospective clinical study conducted in Babylon Maternity and Paediatrics Teaching Hospital involved ten patients complained of idiopathic precocious puberty during five years period of treatment and follow up from September 2006 till September 2011, their ages ranged between eight months old and five years. All patients underwent detailed history regarding age, age of onset of symptoms, the presenting symptoms; all were having negative family history and drug history.

 Detailed physical examination then all sent for ultrasound, hormonal assay including luteinising hormone (LH), follicle stimulating hormone (FSH), estradiol, 17–hydroxy progesterone, thyroid stimulating hormone (TSH), wrist radiograph, magnetic resonance imaging (MRI). To examine the effects of using long acting GnRH analogue (Zolidex) 3.6 mg, subcutaneous injection monthly, follow up the patients monthly by symptoms and signs, ultrasound findings and hormonal assay after six months from starting treatment. Then continue treatment by monthly injection and follow up for the next twelve months, and repeating hormonal assay then follow up for the rest 3.5 years by symptoms and signs and ultrasound findings.

The results were statistically analysed by the help of SPSS version 15 software statistical package using P value at level of significance equal or less than 0.05.


Results

Our study included ten patients with idiopathic precocious puberty their ages at time of presenting symptoms ranged between eight months old and five years old, their height ranged between(70 cm- 105 cm),and their weight (7.5 kg- 16 kg) , body mass index 14.51- 21.33 mean 12.15±2.01 .as in Table -1. Regarding their symptoms at time of presentation, all the patients had bilateral enlarged breasts stage II, and pubic hair stage I, two patients presented with vaginal bleeding (menstruation) Patient No.1 who was eight months old and Patient No.10 who was five years old while Patient No.4 presented with spotting the rest of the patients had no bleeding as in Table -2. About pelvic ultrasound findings all of them having large uterus for their age mean 4.9 mm before treatment and six of them with follicular activity and only one had small ovarian cyst as in Table No. 3, cranial MRI was negative for all the patients. After treatment mean uterine length been 2.6 mm and no follicular activities and remained not changed for the rest of the study.Regarding hormonal assay as in Table No.5, serum LH before treatment range between (1- 2.2) IU/L with a mean of 1.7200 ± 0.35528 and after treatment serum LH mean 0.5400 ± 0.14298 with P value 0.0001, serum FSH level before treatment range between (0.9 -1.8) IU/L with a mean of 1.2800 IU/L ± 0.33528 and after treatment mean 0.4100 ± 0.14491 with P value of 0.0001, serum estradiol level ranged between (5 -1 5) ng/dl with a mean before treatment 8.200 ±2.85968 and after treatment serum Estradiol mean 2.8000 ± 0.78881 and P value 0.0010 while serum TSH within normal range (1.2 – 2.1) with a mean before treatment 2.2400 ± 0.42216 and after treatment the mean 1.6700 ±0.36833 and P value 0.002. After six months of treatment symptoms and signs had been controlled, ultrasound findings return to normal as well hormonal assay and remained as such for the rest of the study.

Discussions

We have assessed the symptoms and signs associated with idiopathic central precocious puberty (CPP) in ten girls for five years with their treatment and follow up. The breast development was associated with other signs in all of cases at presentation, leading to the immediate exclusion of premature thelarche, The distribution of ages at onset of puberty was (8 -60 months) with a mean of 30 months ± 13.25 SD this is differ from that reported in a multicenter study by Cisternino M, et al [6]. In this study, as in Couto-Silva et al [7], the age at onset of CPP was 7–8 years in 60% of cases. : Taher et al [8] the mean age for girls was 4.1year ± 2.5 SD. Midyett et al [9] reported that signs of puberty at 6–8 years should not be considered normal or benign. The association of CPP with a rapid increase in weight is a difficult confounding factor; it may contribute to the earlier onset of puberty. Researchers around the world develop their conclusions on children and weight using the same Body Mass Index (BMI) formula that is used for adults. In adults, the same BMI chart applies to everyone. Because children grow rapidly, and boys and girls grow at different rates, children s BMI charts are based on age and gender. In our study all BMI for girls within the normal range for age. BMI-for-age is not as simple as weight, but it is a more accurate measure of excess body weight. It corresponds well to levels of body fat and can be used to follow body size from childhood through adolescence and into adulthood. Palmert et al [10] found that those girls with slowly progressing idiopathic CPP had lower BMIs than girls with classical CPP (P < 0.02) In our study breast development was clinically found in all the cases associated with other signs. The differentiation is easy in a girl aged less than two years who presents with isolated breast development. However, breast development associated with light pubic hair development. This is probably due to the neonatal period gonadotropins peak. In this situation, pubic hair development is associated with increases in the plasma concentrations of delta 4 androstenedione, but not that of DHAS, suggesting that it is of ovarian rather than adrenal origin [11]. Pescovitz and al [12] speculated that premature thelarche and CPP may be different positions along a continuum of hypothalamic GnRH neuron activation. The baseline evaluation of girls with premature thelarche who progressed during follow-up to early puberty established no characteristics that separated them from those who did not progress [13]. A comparison of the frequencies of premature thelarche and of precocious or early puberty showed different results. Kaplowitz et al [14] studied children over a 3 year period for signs of early puberty, and found that the two most common diagnoses were premature adrenarche (46%) and thelarche (18%), while only 9% had CPP. This differs from the data published by de Vries et al [15], who reported that more than half of the children they studied had either idiopathic CPP or early puberty. These authors suggested that the difference between the two studies could be due to the fact that all of their patients were followed for a minimum of 2 years, and that the diagnoses were deferred for at least 6 months when the clinical picture was not clear [16]. The development of pubic or axillary hair is the most frequent clinical sign associated with breast development in all of the cases in our study, Couto ,et al [7] pubic hair occurring in 67% of cases. The uterus length was ? 35 mm in 54.6% of the cases evaluated. De Vries et al [17] compared girls with CPP to girls with premature thelarche and showed that, uterine transverse diameter, and uterine volume were the most significant variables predicting CPP. In our study uterine volume large for age and follicular activity found in most of the cases 90%,60% respectively return back to normal for age after treatment. Menstruation found in three cases (30%), in our study been controlled after 12 weeks from starting treatment. Our study showed means FSH before treatment was 1.28 IU/l. By 6 months of gonadotropins treatment were suppressed to 0.41 IU/l (P 0.0001), and mean LH was 1.72 IU/l and after 6 months of treatment mean LH were 0.54IUlL (P 0.0001). A study by Julie A. et al [18] median peak LH was 13.6 IU/l and median peak FSH was 12.0 IU/l. By 12 weeks gonadotropins were suppressed to 0.9 and 0.8 IU/l, respectively. Palmert et al [10] defined a pre-pubertal response as an FSH peak greater than the LH peak and an LH peak of less than 25 IU/L. The recently reported girl with CPP due to a GPR54-activating mutation had an LH peak of 8.5 IU/L and a plasma estradiol concentration of13 pg/mL during her initial evaluation [19]. The gonadotropin concentration also varies according to the assay used. In our study Zolidex induces a significant reduction in symptoms and signs within 8-12 weeks and in gonadotropins level within six months. : Julie A., et al [18] found, median peak LH was 13.6 IU/l and median peak FSH was 12.0 IU/l. By 12 weeks gonadotropins were suppressed to 0.9 and 0.8 IU/l, respectively. In the previously treated group, median peak LH at diagnosis was 12.8 IU/l and median peak FSH was 15.0 IU/l with suppression to 0.8 and 1.1 IU/l, respectively, at 12 weeks. In the latter group peak FSH was higher than peak LH at both 8 and 12 weeks (P < 0.05) and there was a significant rise in peak LH (P < 0.05) and FSH (P = 0.01) between 8 and 12 weeks. There was no correlation between age at diagnosis and peak LH or FSH at 8 or 12 weeks. Nevertheless, individual patients in both groups showed evidence of incomplete gonadotropin suppression at 12 weeks. Most centres are using the analogue leuprolide (aqueous form) at a dose of 20 mcg/kg, up to a maximum of 500 mcg. Some studies suggest that an increase in LH levels to more than 8 IU/L is diagnostic of central precocious puberty, but this depends on the specific LH assay used. A study by Carel et al stated that the peak LH level measured by ICMA that defined CPP was 4.1 IU/L in boys and 3.3 IU/L in girls.[20] Another study suggests that when the baseline LH level is prepubertal, an increase in LH level to 5 IU/L or more after leuprolide correlates well with progression of pubertal signs during a 6-month period of observation[21] In Our study no family history of precocious puberty, Couto ,et al [7] found only 4% of the mothers of patients were aged less than 10 years at menarche, while de Vries et al [15] found familial factors in 36% girls with idiopathic CPP. This is probably due to the fact that they made a wide familial analysis, not limited to the maternal age at menarche. We did not collect data on the pubertal maturation of the fathers.

Conclusions

Zolidex-LA induces a significant reduction in symptoms over 12weeks and great reduction in gonadotrophins within six months.

References

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13- Pasquino AM, Pucarelli I, Passeri F, Segni M, Mancini MA, Municchi G. Progression of premature thelarche to central precocious puberty. J Pediatr. 1995; 126:11–14.

14- Kaplowitz P. Clinical characteristics of 104 children referred for evaluation of precocious puberty. J Clin Endocrinol Metab. 2004; 89:3644–3650.

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16- De Vries L, Phillip M. Children referred for signs of early puberty warrant endocrine evaluation and follow-up. J Clin Endocrinol Metab. 2005; 90:593.

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18- : Julie A,Trueman,Vallo Tillmann,Colin F.,Cusick,Peter Foster Suppresion of puberty with long acting goserline(Zolidex-LA) effect on gonadotrophin response tp GnRH in the first treatment cycle.Clin.Endo.; 2002;57,223.

19- Gurgel Teles M, Bianco SDC, Nahime Brito V, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008; 358:709–15.

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21- Sathasivam A, Garibaldi L, Shapiro S, Godbold J, Rapaport R. Leuprolide Stimulation Testing for the Evaluation of Early Female Sexual Maturation. Clin Endocrinol (Oxf). Feb 23; 2010.


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