Clin Pediatr Endocrinol 2002; 11(2), 77-86 Copyright© 2002 by The Japanese Society for Pediatric Endocrinology Original A 9-Year-Old Girl Presenting Central Precocious Puberty with Polycystic Ovary Syndrome Kanshi Minamitani1), Hiromichi Nakajima1), Akira Hoshioka1), Kazuto Tamai1), Tomomichi Kurosaki1), Reiko Matsumoto2), Masanori Minagawa3) and Yoichi Kohno3) 1)Department of Pediatrics, 2)Department of Obstetrics and Gynecology, Chiba Municipal Kaihin Hospital, Chiba, 3)Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan Abstract. A 9-year-old girl presented central precocious puberty (CPP) with polycystic ovary syndrome (PCOS) simultaneously. She had obesity, hirsutism and acanthosis nigricans. Laboratory examination revealed high levels of serum LH, FSH (LH > FSH), testosterone and insulin. The response of dehydroepiandrosterone sulfate after administration of ACTH was normal for a female. She has been treated with GnRH analog and weight reduction. Excessive androgen production results from ovarian defect and therefore, functional ovarian hyperandrogenism and hyperinsulinemia might be major factor in the pathogenesis. This case is the first report of a PCOS woman demonstrating CPP simultaneously. Key words: central precocious puberty, polycystic ovary syndrome, hyperinsulinemia, hyperandro- genism, GnRH analog Introduction relationships between these diseases, which involve abnormal regulation of gonadotropin Polycystic ovary syndrome (PCOS) was secretion (5–10). The mechanism in a PCOS girl described by Stein and Leventhal in 1935 (1) and presenting CPP remains unknown. characterized by chronic anovulation and hyperandrogenism. Possible causes are Case Report dysregulation of LH secretion by the hypothalamus or abnormalities of ovaries or adrenal glands or A 9-year 7 month-old girl was referred because hyperinsulinemia, but its etiology remains of vaginal bleeding. She was born uneventfully unknown (2–4). after a full-term gestation. Birth weight was 3422 g We report the first case of a PCOS patient and length was 49.5 cm. She showed signs of demonstrating central precocious puberty (CPP) obesity from the age of 4 (23.3% above the ideal simultaneously. Some reports show patients with weight for height). She was first noted to have CPP followed by PCOS and suggest some bilateral breast development at the age of 7, followed by pubic hair growth at the age of 8. Her Received: May 2, 2002 height velocity was increased and obesity and Accepted: June 14, 2002 hirsutism had progressed since seven years of age. Correspondence: Dr. Kanshi Minamitani, Department of Pediatrics, Chiba Municipal Kaihin Hospital, 3–31–1 On the first visit to our hospital, her height and Isobe, Mihama-ku, Chiba 261–0012, Japan. weight were 147.7 cm (2.35 SD) and 66.3 kg (body 78 Minamitani et al. Vol.11 / No.2 Table 1 Laboratory findings at diagnosis GH 0.8 ng/ml UA 6.8 mg/dl IGF-I 837 ng/ml GOT 19 U/l TSH 1.45 µIU/ml GPT 11 U/l T3 206 ng/dl ALP 1089 U/l T4 8.6 µg/dl T-cho 152 mg/dl LH 6.1 mIU/ml TG 159 mg/dl FSH 3.6 mIU/ml glucose 88 mg/dl HCG <1.0 mIU/ml insulin 19 µU/ml PRL 17.2 ng/ml (insulin/glucose=0.22) E1 49.0 pg/ml CPR 3.4 ng/ml E2 98 pg/ml HbA1c4.8% testosterone 100 ng/dl urinary DHEAS 1210 ng/ml glucose (–) 17-OHP 3.6 ng/ml ketone body (–) Table 2 Endocrinological data at diagnosis 0 min 30 min 60 min 90 min 120 min LH-RH test LH (mIU/ml) 6.1 52.8 63.2 75.6 95.7 FSH (mIU/ml) 3.6 10.3 13.3 17.6 21.7 E2 (pg/ml) 98 129 TRH test TSH (µIU/ml) 1.45 8.64 6.27 4.39 3.65 PRL (ng/ml) 17.2 23.5 15.4 12.8 14.7 Arginine tolerance test GH (ng/ml) 27.4 28.6 39.9 30.6 18.0 Insulin tolerance test GH (ng/ml) 4.1 1.3 6.3 15.3 27.4 cortisol (µg/dl) 10.8 17.6 14.0 18.2 24.9 mass index: 30.4), respectively. The breast and (Table 2). The ratio of serum insulin to plasma pubic hair were at Tanner stage lV and lll, glucose was slightly elevated (19/88 = 0.22) (Table respectively. She had hirsutism and acanthosis 1). Ultrasonography and magnetic resonance nigricans. Her bone age assessed by the Greulich- imaging (MRI) of the abdomen revealed bilateral Pyle method was 12 yrs old. polycystic ovaries (Fig. 1A, B). MRI of the pituitary Laboratory examination revealed high levels gland showed no central nervous system of serum LH, FSH (LH > FSH) and testosterone abnormalities including hypothalamic-pituitary (Table 1). The basal and maximal concentrations tumors (Fig. 2A, B). After eight months' treatment of LH after administration of LH-releasing with GnRH analog, the basal levels and maximal hormone (LHRH) were high, although the levels of responsiveness of dehydroepiandrosterone sulfate FSH remained in the normal range (Table 2). The (DHEAS), androstenedione, testosterone and 17α- basal concentration of TSH was normal and the hydroxyprogesterone (17-OHP) in response to peak level after TRH administration was also administration of ACTH were normal for pubertal normal (Table 2). Although the basal females (Table 4). On the basis of these concentration of PRL was slightly increased, the investigations, PCOS with CPP was diagnosed. peak level after TRH administration was normal She has been treated with GnRH analog and December 2002 PCOS Girl Presenting CPP Simultaneously 79 AB Fig. 1 Unenhanced sonogram (A) and axial unenhanced T2-weighted MR image (B) of ovary at diagnosis. AB Fig. 2 Sagittal (A) and coronal (B) unenhanced T1-weighted MR image of pituitary gland at diagnosis. 80 Minamitani et al. Vol.11 / No.2 Table 3 Serum hormone concentrations after 4 months of GnRH analog treatment IGF-I 707 ng/ml, DHEAS 1170 ng/ml Fasting plasma glucose, 79 mg/dl, insulin 13 µU/ml Postprandial plasma glucose, 94 mg/dl, insulin 30 µU/ml LH-RH test before 30 min 60 min 90 min 120 min LH (mIU/ml) 0.6 1.7 1.2 0.9 0.8 FSH (mIU/ml) 3.3 4.9 4.3 4.2 4.1 E2 (pg/ml) <10 <10 testosterone (ng/dl) 30 30 Table 4 Responses to rapid ACTH test after 8 months of GnRH analog treatment 0 min 30 min 60 min cortisol (µg/dl) 23.8 25.7 31.8 progesterone (ng/ml) 1.1 1.5 1.5 17-OHP (ng/ml) 3.0 3.7 3.6 androstenedione(ng/ml) 2.3 2.4 2.3 DHEAS (ng/ml) 2120 1850 1690 testosterone (ng/dl) 20 30 20 weight reduction induced by a standardized regression of polycystic ovaries. hypocaloric diet consisting of 1500 kcal daily based on the food exchange list of the Japan Diabetes Discussion Society and an exercise program. Treatment with GnRH analog resulted in prompt cessation of breast The endocrinological features of PCOS are development and vaginal bleeding and arrested hyperandrogenism, increased concentration of LH progression of hirsutism along with a deceleration or an increase in the ratio of LH to FSH, and of growth velocity and bone maturation. Adequate increased levels of estrone and insulin. The suppression was biologically documented by pathogenesis of PCOS has been variously ascribed reductions in the concentrations of basal LH, to primary abnormalities of LH regulation, ovaries, estradiol, PRL, and testosterone and prepubertal adrenal glands or recently hyperinsulinemia. But response to LHRH testing (Fig. 3, Table 3). the etiology of this disorder including the source of Likewise, the ratios of LH to FSH at baseline were androgen remains elusive. normalized after treatment. The DHEAS levels If a girl develops secondary sexual were within the normal range and did not change characteristics before the age of seven years, she is after GnRH analog treatment. Basal serum insulin considered to have sexual precocity. Our patient levels were decreased after dietary weight was diagnosed as CPP on the basis of the early reduction. As noted in Fig. 4, the MR image after 4 onset of thelarche, pubarche, menarche, increased months of GnRH analog treatment showed height velocity and advanced bone maturation. December 2002 PCOS Girl Presenting CPP Simultaneously 81 Fig. 3 Clinical course. Obesity, hirsutism and enlarged polycystic ovaries associated with high concentrations of LH, androgen and insulin were consistent with PCOS. On the other hand, late onset congenital adrenal hyperplasia (nonclassical CAH) also causes adrenal hyperandrogenism and precocious puberty. Our patient had typical clinical features of PCOS-obesity, hirsutism, enlarged polycystic ovaries, hypersecretion of LH and insulin. The rapid ACTH stimulation produced normal responses of serum 17-OHP, DHEAS, androstenedione and testosterone after gonadal suppression therapy. Therefore her adrenal gland function might be normal, and nonclassical CAH was excluded. Petrus et al. (5), Root et al. (6), Ibanez et al. (7), Pienkowski et al. (8), Lazar et al. (9) and Kumazaki et al. (10) independently reported cases of patients who presented with precocious puberty and later developed PCOS, and there are some Fig. 4 Axial unenhanced T2-weighted MR image of relationships between these diseases, having the ovary three months after GnRH analog abnormal regulation of gonadotropin secretion. treatment. This case is the first report of a PCOS woman demonstrating CPP. Progesterone, 17-OHP and testosterone 82 Minamitani et al. Vol.11 / No.2 Fig. 5 Mechanism of ovarian steroidogenesis. production per cell were more noticeably androstane-3,17-dione produced from increased in propagated theca cell cultures from androstenedione, in polycystic ovaries are capable PCOS than in controls (11, 12). 17α-hydroxylase/ of greatly inhibiting human granulosa cell 17,20-desmolase (CYP17), 3β-hydroxysteroid aromatase activities by functioning as a dehydrogenase (3β-HSD), steroidogenic acute competitive inhibitor and suppress estradiol regulatory protein (StAR) and cholesterol side production by 75% (13, 14).