Reproductive axis after discontinuation of gonadotropin-releasing hormone analog treatment of girls with precocious puberty: Long term follow-up comparing girls with hypothalamic hamartoma to those with idiopathic precociouspuberty

Although the GnRH agonist analogs have become an established treatment for precocious puberty, there have been few long term studies of reproductive f unction and general health after discontinuation of therapy. To this end, w e compared peak LH and FSH after 100 mu g sc GnRH, estradiol, mean ovarian volume (MOV), age of onset and frequency of menses, body mass (BMT), and in cidence of neurological and psychiatric problems in 2 groups of girls: thos e with precocious puberty due to hypothalamic hamartoma (HH; n = 18) and th ose with idiopathic precocious puberty (IPP; n = 32) who had been treated w ith deslorelin (4-8 mu g/kg.day, sc) or histrelin (10 mu g/kg.day, SC) for 3.1-10.3 yr and were observed at 1, 2, 3, and 4-5 yr after discontinuation of treatment. The endocrine findings were also compared to those in 14 norm al perimenarcheal girls. There were no differences between the HH and IPP g roups in age or bone age at the start of treatment, at the end of treatment , or during GnRH analog therapy. We found that whereas the peak LH level wa s higher in HH than in IPP girls before (165.5 +/- 129 os. 97.5 +/- 55.7; P < 0.02) and at the end (6.8 +/- 6.0 vs. 3.9 +/- 1.8 mIU/mL; P < 0.05) of t herapy, this difference did not persist at any of the posttherapy time poin ts. LH, FSH, and estradiol rose into the pubertal range by 1 yr posttherapy in both HH and IPP. However, the mean posttherapy peak LH levels in both H H and IPP groups tended to be lower than normal, whereas the peak FSH level s were not different from normal, so that the overall posttherapy LH/FSH ra tio was decreased compared to that in the normal girls (HH, 2.1 +/- 0.3; TP P, 2.6 +/- 0.1; normal, 5.2 +/- 4.8; P < 0.05). The MOV was larger in HH th an IPP at the end of treatment (3.7 +/- 3.5 vs. 2.0 +/- 1.2 mL; P < 0.05) a nd tended to increase in both groups over time to become larger than that i n normal girls by 4-5 yr posttherapy(HH, 14.9 +/- 12.9: IPP 7.6 +/- 2.2; no rmal, 5.4 +/- 2.5 mL; P < 0.05). Whereas the onset of spontaneous menses varied widely in both groups, once menses had started, the HH group had a higher incidence of oligomenorrhea. Pelvic ultrasonography revealed more than 10-mm hypoechoic regions in 4 HH patients, 15 IPP patients, and 3 normal girls, all of whom were reporting r egular menses. Live births of normal infants were reported by 2 HH and 2 IP P patients, and elective terminations of pregnancy were reported by 1 HH an d 2 IPP patients. BMI was greater than normal in HH and IPP both before tre atment and at all posttherapy time points and tended to be higher in the HH patients. Marked obesity (BMT, +2 to +5.2 SD score) was observed in 5 HH a nd 6 IPP patients, 1 of whom had a BMI of +2.5 so score and developed acant hosis nigricans, insulin resistance, and hyperglycemia. Seizure disorders d eveloped during GnRH analog therapy in 5 HH and 1 IPP patient, and 2 additi onal HH girls developed severe depression and emotional lability posttherap y. Although the mean anterior-posterior dimension of the hamartoma was larg er in the KH patients with seizure than in those who were seizure free (1.7 +/- 1.2 vs. 0.9 +/- 0.4 cm; P < 0.05), no change in hamartoma size was obs erved either during or after therapy, and no patient has reported the onset of a seizure disorder posttherapy. Other than a tendency toward a larger M OV, a higher incidence of oligomenorrhea, obesity, and frequency of neurolo gical disorders, recovery of the reproductive iuds after GnRH analog therap y was not markedly different in HH compared to IPP. Continued follow-up of these patients may determine whether the decreased LH responses and increas ed BMI in both groups compared to those in normal girls remain clinically s ignificant problems.