M. Joan Mansfield

Puberty without gonadotropins: a unique mechanism of sexual development

Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.

Anorexia Nervosa, Athletics, and Amenorrhea

Menstrual dysfunction is common in adolescents who are involved in intensive athletic activity or who are limiting their nutritional intake excessively. The mechanism for hypothalamic amenorrhea in athletes and dieters is not yet fully understood. Other causes of menstrual dysfunction due to pregnancy, central lesions, hormone imbalance, or ovarian failure should be excluded in the athlete with amenorrhea. Amenorrheic patients who have sufficient estrogen effect on their endometrium to have withdrawal bleeding following exposure to progestins should be cycled with progestins on a regular basis to prevent endometrial hyperplasia. Estrogen replacement with cyclic progestin should be considered in the hypoestrogenic adolescent with prolonged amenorrhea. The long-term consequences of hypothalamic amenorrhea in adolescents remain to be determined.

Sleep Modulation of Neuroendocrine Function: Developmental Changes in Gonadotropin-Releasing Hormone Secretion during Sexual Maturation

ABSTRACT: To assess sleep-associated changes in gonadotropin-releasing hormone secretion during sexual maturation, we studied nighttime and daytime patterns of LH and FSH secretion in two groups with qualitatively similar sex steroid levels: girls with central precocious puberty and young adult women in the early follicular phase of an ovulatory menstrual cycle. In the girls with central precocious puberty, all indices of LH secretion were significantly higher at night than during the day (mean LH levels, 12 ± 2 versus 5 ± 1 IU/L, p ≤ 0.01; LH pulse amplitude 16 ± 2 versus 7 ± 1 IU/L, p ≤ 0.01; and LH pulse frequency 0.70 ± 0.05 versus 0.35 ± 0.08 pulse/patient-h, p ≤ 0.01). Girls with a history of menses, who were presumably the most mature, lacked this diurnal variability. Mean nocturnal FSH levels were only slightly higher than daytime levels (7.6 ± 0.5 versus 7.2 ± 0.5 IU/L, p ≤ 0.05) resulting in alternating periods of LH (nighttime) and FSH (daytime) predominance in this pubertal population. In contrast, the adult women had lower mean gonadotropin levels and LH pulse frequencies at night than during the day (mean LH 7 ± 1 versus 10 + 1 IU/L, p ≤ 0.05; mean FSH 9 ± 1 versus 10 ± 1 IU/L, p ≤ 0.05; LH pulse frequency 0.40 ± 0.08 versus 0.70 ± 0.10 pulse/patient-h, p ≤ 0.05) and often (six of eight) demonstrated striking suspension of gonadotropin-releasing hormone secretion during sleep. The smaller changes in FSH again resulted in periods of relative LH (daytime) and FSH (nighttime) predominance. When between-group comparisons were made, the girls with central precocious puberty differed significantly from the women in the early follicular phase with respect to each index of gonadotropin secretion except for daytime LH pulse amplitude. Thus, neuroendocrine maturation in the human female appears to be characterized by changes in both the pattern of gonadotropin-releasing hormone secretion and the daily alternating periods of relative LH and FSH predominance in response to sleep.

Diagnosing dysglycemia in adolescents with polycystic ovary syndrome.

PURPOSE Screening for impaired glucose tolerance (IGT) is recommended for adolescents with polycystic ovary syndrome (PCOS) with oral glucose tolerance test (OGTT). Whether glycated hemoglobin (HbA1c) can be used for screening in this patient population is unknown. We sought to determine the utility of HbA1c and 2-hour OGTT for diagnosing dysglycemia in adolescents with PCOS. METHODS This was a retrospective cohort study of 68 adolescents with PCOS seen in the Boston Childrens Hospital Division of Adolescent Medicine between 2008 and 2011 and not known to have diabetes. Prevalence of dysglycemia (impaired fasting glucose, IGT, increased risk for diabetes, or diabetes mellitus as diagnosed by fasting plasma glucose, 2-hour OGTT, and/or HbA1c) and sensitivity and specificity of HbA1c for diagnosing dysglycemia compared with OGTT were assessed. RESULTS Twenty-four participants had abnormal glucose testing, including one participant (1.5%) who met criteria for diabetes mellitus and 23 participants (34%) who met criteria for impaired fasting glucose/IGT/prediabetes. More patients were identified as having dysglycemia by HbA1c than OGTT. Compared with OGTT, HbA1c had a sensitivity of 60% and a specificity of 69% for diagnosing dysglycemia. CONCLUSIONS In adolescents with PCOS, HbA1c had moderate sensitivity and specificity for detecting dysglycemia compared with OGTT. Clinicians should be aware that both tests have benefits and limitations, and the optimal test for follow-up requires further study.

177 DECREASE IN GROWTH HORMONE (GH) AND SOMATOMEDIN C (SOMC) DURING LHRH AGONIST (LHRHa) TREATMENT OF CENTRAL PRECOCIOUS PUBERTY (CPP)

LHRHa suppresses both gonadotropin pulsations and sex steroids and slows height velocity (HV) in patients with CPP. To evaluate GHs role in this slowing of growth, sleep induced GH secretion (20 min. samples, 10 PM-2 AM) and SOMC (10 PM) were measured in 9 pre-adrenarchal girls with CPP (ages at onset 1.6-6.3 yrs, M=3.8; bone ages advanced a mean of 3.7 years). Therapy suppressed gonadotropin pulsations, response to LHRH, estradiol and maturation indices in all patients. Growth velocity fell from 14.4 ± 1.7 cm/yr (Mean ± SEM, all measurements) pretherapy to 8.7 ± 1.4 after 6 mos of therapy (p=0.0005). SOMC levels decreased from 3.1 ± 0.7 IU/ml pretherapy to 1.3 ± 0.2 at 3 mos (p=0.009) and 1.4 ± 0.2 at 6 mos (p=0.007). Nocturnal peak levels fell from 25.4 ± 6.8 ng/ml pretreatment to 9.1 ± 1.7 at 3 mos (p < 0.01) and 7.5 ± 1.1 at 6 mos of therapy (p < 0.01). Total GH secreted during the 4 hr interval decreased a mean of 58% at 3 mos and 48% at 6 mos compared to pretreatment. The accelerated HV in CPP patients under 6 years is associated with increased GH and SOMC production. With LHRHa induced suppression of gonadal steroids, both HV and GH and SOMC production are decreased.

Growth Patterns and Skeletal Maturation During Sex Steroid Suppression and Reactivation in Central Precocious Puberty

Children with centrally-mediated precocious puberty (CPP) undergo a sequence of hypothalamic-pituitary-gonadal activation which appears to be normal except for the age of its occurrence. Premature exposure to gonadal steroids in children with precocity is associated with an acceleration of linear growth identical to the adolescent growth spurt save for the age of its occurrence. Skeletal maturation is even more markedly advanced by this early exposure to gonadal steroids in these patients, often leading to early epiphyseal fusion and compromised adult stature [1–3]

Impact of Sex Steroids and Their Suppression on Skeletal Growth and Maturation

Forty girls with central precocious puberty (CPP) were studied before and during 1-3 yr of luteinizing hormone-releasing factor (LHRH) agonist (LHRHa) administration to examine the impact of gonadal steroid secretion and its suppression on skeletal growth and maturation. Pubertal growth velocity (GV) was 10.1 +/- 0.7 (SE) cm/yr and, when normalized for chronological age (CA) and bone age (BA), demonstrated that the effects of sex steroids were most profound in patients with the youngest CA and BA. GV decreased significantly to 5.8 +/- 0.3 (n = 40), 4.6 +/- 0.3 (n = 30), and 3.2 +/- 0.6 cm/yr (n = 12) during 3 yr of gonadal suppression and correlated negatively with starting BA. Skeletal maturation was markedly accelerated by premature sex steroid secretion (BA/CA = 1.8 +/- 0.1), was slowed significantly with gonadal suppression (mean delta BA/delta CA less than 1), and also was negatively correlated with the starting BA. Cumulative increases in predicted adult height were observed regardless of starting BA and averaged +2.0 +/- 0.4, +5.2 +/- 0.5, and +6.7 +/- 1.2 cm after 1, 2, and 3 yr of gonadal suppression. The comparable changes in height predictions across all BAs despite highly variable GVs underscore the need for use of developmental (i.e., BA-based) rather than CA-based standards in the analysis of growth during gonadal steroid exposure and suppression in childhood.

Long-Term Treatment of Central Precocious Puberty with a Long-Acting Analogue of Luteinizing Hormone-Releasing Hormone. Effects on Somatic Growth and Skeletal Maturation

The gonadotropin-releasing hormone-like agonist D-Trp6-Pro9-NEt-LHRH (LHRHa) has been shown to induce a reversible short-term suppression of gonadotropins and gonadal steroids in patients with central precocious puberty. Since accelerated statural growth and bone maturation are clinical features of precocity not well controlled by conventional therapies, we examined the effects of prolonged LHRHa therapy for 18 consecutive months on growth and skeletal maturation in nine girls with neurogenic or idiopathic precocious puberty. Suppression of gonadotropin pulsations and gonadal steroids was maintained in all subjects. Growth velocity fell from a mean rate (+/- S.E.M.) of 9.35 +/- 0.64 cm per year during the 19 months before treatment to 4.58 +/- 0.60 cm per year during treatment (P less than 0.001). Bone age advanced a mean of 9.4 +/- 2.3 months during treatment. These changes resulted in a mean increase of 3.3 cm in predicted height (P less than 0.01). Complete suppression of the pituitary-gonadal axis can be maintained by LHRHa therapy, resulting in slowing of excessively rapid growth and skeletal maturation and in increased predicted adult height in girls with precocious puberty.