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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 Precocious Puberty

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Penelope P. Feuillan, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N 262, Bethesda, Maryland 20892.

Although the GnRH agonist analogs have become an established treatment for precocious puberty, there have been few long term studies of reproductive function and general health after discontinuation of therapy. To this end, we compared peak LH and FSH after 100 µg sc GnRH, estradiol, mean ovarian volume (MOV), age of onset and frequency of menses, body mass (BMI), and incidence of neurological and psychiatric problems in 2 groups of girls: those with precocious puberty due to hypothalamic hamartoma (HH; n = 18) and those with idiopathic precocious puberty (IPP; n = 32) who had been treated with deslorelin (4–8 µg/kg·day, sc) or histrelin (10 µg/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 normal perimenarcheal girls. There were no differences between the HH and IPP groups 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 was higher in HH than in IPP girls before (165.5 ± 129 vs. 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 therapy, this difference did not persist at any of the posttherapy time points. 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 HH and IPP groups tended to be lower than normal, whereas the peak FSH levels were not different from normal, so that the overall posttherapy LH/FSH ratio was decreased compared to that in the normal girls (HH, 2.7 ± 0.3; IPP, 2.6 ± 0.1; normal, 5.2 ± 4.8; P < 0.05). The MOV was larger in HH than IPP at the end of treatment (3.7 ± 3.5 vs. 2.0 ± 1.2 mL; P < 0.05) and tended to increase in both groups over time to become larger than that in normal girls by 4–5 yr posttherapy (HH, 14.9 ± 12.9; IPP, 7.6 ± 2.2; normal, 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 regular menses. Live births of normal infants were reported by 2 HH and 2 IPP patients, and elective terminations of pregnancy were reported by 1 HH and 2 IPP patients. BMI was greater than normal in HH and IPP both before treatment and at all posttherapy time points and tended to be higher in the HH patients. Marked obesity (BMI, +2 to +5.2 SD score) was observed in 5 HH and 6 IPP patients, 1 of whom had a BMI of +2.5 SD score and developed acanthosis nigricans, insulin resistance, and hyperglycemia. Seizure disorders developed during GnRH analog therapy in 5 HH and 1 IPP patient, and 2 additional HH girls developed severe depression and emotional lability posttherapy. Although the mean anterior-posterior dimension of the hamartoma was larger in the HH 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 observed either during or after therapy, and no patient has reported the onset of a seizure disorder posttherapy. Other than a tendency toward a larger MOV, a higher incidence of oligomenorrhea, obesity, and frequency of neurological disorders, recovery of the reproductive axis after GnRH analog therapy was not markedly different in HH compared to IPP. Continued follow-up of these patients may determine whether the decreased LH responses and increased BMI in both groups compared to those in normal girls remain clinically significant problems.

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