Giovanna Municchi

Progression of premature thelarche to central precocious puberty

To evaluate whether girls with premature thelarche progress to central precocious puberty (CPP) and to analyze their clinical and hormonal characteristics, we retrospectively examined 100 girls with premature thelarche who were followed for several years. Fourteen of the patients with characteristics diagnostic of premature thelarche (isolated breast development before age 8 years, bone age advancement within 2 SD of normal, normal growth velocity, follicle-stimulating hormone-predominant response to luteinizing hormone-releasing hormone) progressed during follow-up to precocious or early central puberty (progressive breast size increase, bone age acceleration, and significant decrease in predicted adult height). The chronologic age of this group of 14 girls was 5.1 +/- 2.0 years at the onset of premature thelarche and 7.8 +/- 0.6 years (mean +/- SD) after progression to central early or precocious puberty. Pelvic ultrasonography showed significant differences in measurements between the time of diagnosis of premature thelarche and progression to CPP. Nine of these patients required treatment, three with cyproterone acetate and six with luteinizing hormone-releasing hormone analogs, and all responded as expected for classic CPP. At baseline evaluation, no clinical or hormonal characteristics could be established that separated the 14 children who progressed to precocious or early puberty from the 86 girls who did not. We conclude that premature thelarche is not always a self-limited condition and may sometimes accelerate the timing of puberty.

Maternal and environmental factors influence the hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone infusion in offspring of mothers with or without mood disorders.

Individuals with melancholic major depression exhibit basal hypercortisolism and an attenuated ACTH response to exogenous corticotropin-releasing hormone (CRH) infusion. Given the greater incidence of depression in children of depressed parents, we examined the ACTH and cortisol responses to ovine CRH (oCRH) infusion in 63 adolescent offspring of mothers with major depression, bipolar illness, or no psychiatric illness. Psychiatric and observational assessments of these families had been conducted over the course of 10 years preceding this study. We examined the childrens responses to CRH in relation to maternal characteristics and family environment and found the following: (a) cortisol responses were negatively related to chronic family stress and (b) offspring of depressed mothers with an avoidant personality disorder showed an exaggerated ACTH response. In addition, adolescents in late puberty (Tanner 4 and 5) had lower ACTH and cortisol responses to oCRH infusion than those in early puberty. Further, offspring with early histories of mood problems, and those who developed major depressive disorder as young adults, did not exhibit basal hypercortisolism but did show an attenuated ACTH response to CRH. Our results add to the growing body of literature showing the influence of maternal characteristics and environmental factors on hypothalamic-pituitary-adrenal axis patterns in children.

Nocturnal thyrotropin surge in growth hormone-deficient children

Because some patients with growth hormone (GH) deficiency are found to be hypothyroid after initiation of treatment with GH, we assessed the predictive value of the nocturnal thyrotropin surge (a sensitive test for central hypothyroidism) in 56 untreated GH-deficient children and adolescents. Eighteen patients had a subnormal thyrotropin surge (mean 18% (range -30% to 46%)), significantly less than that of 96 normal control subjects (mean 124%; 95% confidence limits, 47% to 300%; p less than 0.01); 13 of the 18 had a subnormal total thyroxine (T4) level or a subnormal free T4 level, or both. These 18 patients were given thyroid hormone replacement therapy; GH deficiency was confirmed during treatment with thyroxine. Of the remaining 38 patients, who had no initial evidence of dysfunction of the hypothalamic-pituitary-thyroid axis, 23 were re-examined while they were receiving GH treatment. Hypothyroidism developed in none of those 23 children during GH therapy. The nocturnal thyrotropin surge test and determination of iodothyronine levels were repeated in 14 of these euthyroid patients. There was no significant change in mean thyrotropin surge (129% (range +49% to +300) vs 125% (range +51% to +222%)), mean serum level of total T4 (111 +/- 4 vs 103 +/- 3 nmol/L), mean serum level of free T4 (19 +/- 0.7 vs 18 +/- 0.8 pmol/L), mean serum level of triiodothyronine (2.5 +/- 0.1 vs 2.5 +/- 0.1 nmol/L), or mean serum level of thyrotropin (2.9 +/- 0.3 vs 2.9 +/- 0.5 mU/L (mean +/- SEM)). We conclude that GH treatment does not appreciably alter thyroid function in GH-deficient patients who have no evidence of thyroid axis dysfunction before GH treatment.

Effect of hCG or hCG + treatments in young thalassemic patients with hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism (HH) is common (40%) in beta-thalassemic patients. Taking into consideration that in HH non-thalassemic patients we obtained good results in pubertal development using hCG treatment (1500 IU every 6 days), 10 HH thalassemic subjects (14 5/12 -17 yr, all with bone age greater than 13 6/12) were treated with the same regimen. In 5 of these patients purified FSH (75 IU every 3 days) was added to hCG in order to evaluate the FSH effect on testosterone (T) response (Group 1 was given hCG alone, Group 2 hCG + FSH: Profasi HP and Metrodin Serono). To evaluate the kinetics of testosterone response, plasma level of T was determined basally and 1, 2, 4 and 6 days after hCG injection. This dynamic study and a clinical examination were carried out at the beginning of treatment and at the 4th and 12th month after. Results obtained in the first group confirmed our previous data from non-thalassemic HH patients: in fact, after 12 months of therapy a stage G2-G3 was reached. In the second group, however, testis size and testosterone secretion were significantly higher than in the first group. At the 4th month, in Group 1 and in Group 2 testis size and the area under the T response curve were 3.18 ± 0.18ml and 13,364 ± 1047 ng/dl vs 4.62 ± 0.25 ml (p < 0.02) and 18,045 ±1110 ng/dl (p < 0.016), respectively. At the 12th month testis size and area under T response curve were increased to 6.12 ± 0.25 ml and 24,017 + 1176 ng/dl in Group 1 and 8.12 ± 0.6 ml (p < 0.01) and 33,924 ± 2181 ng/dl (p < 0.01) in Group 2. After 12 months, a significant comparable increase in growth velocity, without bone age acceleration, was observed in both groups. Our results demonstrate that hCG or hCG + FSH treatments are able to induce a satisfactory sexual development in thalassemic HH patients; moreover FSH in addition to hCG seems to improve not only testis size as expected, but also testosterone production.

X-LINKED CONGENITAL ADRENAL HYPOPLASIA, GONADOTROPIN DECICIENCY AND HIGH FREQUENCIES SENSORINEURAL HEARING LOSS

X-linked congenital adrenal hypoplaeia (CAH) may occur alone or in association with hypogonadotropic hypogonadism (HH), glycerol kinase deficiency (GKD) and myopathy. The relationship between these conditions is genetic since the loci for CAH, HH and GKH are located in the same region of X chromosome. A progressive high frequency hearing loss (HL) has been recently described only by Zachmann. We report two male cousins (aged 24.2 and 21.7 yrs at last observation) with CAH, HH and an unusual tall stature. GKD was excluded by determination of plasma and urine glycerol levels. A mild bilateral HL for high frequencies was diagnosed in the younger patient at 15 yrs of age. At this time the audiogram of the older patient was normal. The hearing evaluation performed in the following years showed a progression of the HL most evident at 4KHr in the younger patient and a cochlear site of lesion was revealed by brainstem response audiometry. In the older patient, the last audiogram showed just a slight asymmetric sensorineural HL for the high frequencies (2-8 KHr}. In agreement with Zachmanns report, our data show that HL may be associated with CAH and HH even if the degree of HL is unpredictable. Therefore the hearing funciton of these patients must be monitored. The hypothesis of a genetic basis of the relationship between CAH, HH and HL (vicinity of the locus of X-linked deafness with the loci of CAH and HH) is fashinating and requires further support.