Florence Comite

Cyclical ovarian function resistant to treatment with an analogue of luteinizing hormone releasing hormone in McCune-Albright syndrome.

THE McCune–Albright syndrome was originally described in the 1930s as the triad of polyostotic fibrous dysplasia, cafe-au-lait pigmentation, and precocious puberty.1 , 2 The mechanism of the precoc...

Ovarian Function in Girls with McCune-Albright Syndrome

ABSTRACT. We measured plasma estradiol levels and ovarian volumes in eight girls with precocious puberty due to McCune-Albright syndrome. Six girls had gonadotropin-independent ovarian estrogen secretion and two girls had pubertal gonadotropin levels. Mean ovarian volume in all patients was significantly greater than in normal prepubertal girls. Mean ovarian volumes of the girls with McCune-Albright syndrome overlapped the range found in girls with idiopathic central precocious puberty or central precocious puberty associated with central nervous system lesions. However, the degree of asymmetry between the right and left ovaries was significantly greater in girls with McCune-Albright syndrome. Asymmetry was due, for the most part, to the presence of large solitary cysts in the larger of the two ovaries. In the six girls with McCune-Albright syndrome and gonadotropin-independent precocious puberty, both mean ovarian volume and the degree of asymmetry between the right and left ovaries were significantly correlated with plasma estradiol. Serum follicle-stimulating hormone bioactivity was increased in two patients but did not vary with ovarian cyst size. Thyroid-stimulating hormone levels were normal but serum prolactin was slightly elevated in one of the six girls with gonadotropin-independent precocious puberty. Fluctuation in the size of unilateral ovarian cysts appears to result in changes in the plasma estradiol level, leading to advancement and spontaneous regression of secondary sexual characteristics and menses in girls with McCune-Albright syndrome. The cause of the cyst formation is unknown but may be related to periodic elevation of as yet undefined serum factors such as follicle-stimulating hormone bioactive substances.

Ultrasound evaluation of female isosexual precocious puberty.

Fifty‐six female children with signs of precocious puberty were examined. Adult‐sized ovaries and an intermediate‐sized uterus were characteristic of true sexual precocity, either idiopathic or due to a CNS lesion. Premature thelarche and premature adrenarche showed normal infantile pelvic organs, while in cases of precocious pseudopuberty, the appearances of the ovaries and uterus varied depending upon the underlying process. Large ovarian cysts and large ovaries were found in six patients with McCune‐Albright syndrome. An ultrasound study is of benefit in the evaluation of female children with precocious sexual development because it can demonstrate the adult‐sized ovaries of true precocious puberty, thereby distinguishing this condition from premature thelarche and premature adrenarche, and it can demonstrate specific causes of precocious sexual development, such as adrenal and ovarian tumors and ovarian cysts.

Dental Development in Precocious Puberty

One hundred and one children with precocious puberty were given an oral examination. Dental root development was assessed using panoramic radiographs. All mandibular canines, pre-molars, and molars which could be visualized without apparent distortion were included. The patients were grouped for analysis according to the etiology of their precocity, e.g., McCune-Albright syndrome, familial male, congenital adrenal hyperplasia, central nervous system lesions, and idiopathic precocious puberty. Dental development was significantly retarded relative to their chronological age in patients with idiopathic precocious puberty. However, no significant abnormal dental development was detected in any of the other groups. Individual oral-facial growth and development remain the primary considerations for timing orthodontic treatment.

LHRH Analog Treatment of Central Precocious Puberty Complicating Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) has long been recognized as a major cause of peripheral precocious puberty (premature sexual development without activation of pubertal LH and FSH secretion).’4 Elevated adrenal androgen production in this disorder causes pubic and axillary hair development, penile or clitoral enlargement, and rapid growth and advanced bone age. Treatment with hydrocortisone and fludrocortisone usually halts the progression of these findings in children with CAH. Gonadotropin levels are within the normal prepubertal range. Breasts do not develop in the girls and the testes do not enlarge generally in the boys. This is as would be predicted for peripheral precocious puberty due to increased serum concentrations of adrenal androgens. Some young children with CAH continue to grow rapidly and advance in bone age. However, despite adequate suppression of adrenal androgen overproduction, such children have been found to have elevated gonadotropin levels both basally and in response to LHRH, suggesting that the CAH led to an early activation of pubertal gonadotropin secretion (central precocious p ~ b e r t y ) . * * ~ ~ ” ~ ~ Recent studies have shown that a long-acting analog of LHRH (D-Trp6-Pro9NEt-LHRI-I) can suppress pituitary gonadotropins and gonadal sex steroids in children with central precocious This study evaluated the addition of the LHRH analog D-Trp6-Pro9-NEt-LHRH to a treatment regimen of hydrocortisone and fludrocortisone in four children with central precocious puberty secondary to congenital adrenal hyperplasia.”

Mechanism of precocious puberty in McCune-Albright syndrome (MAS)

The hypotheses to explain precocious puberty in the MAS include premature pubertal gonadotropin secretion, and autonomous ovarian estradiol (E2) secretion without gonadotropin (LH and FSH) activation. We have used the observation that luteinizing hormone releasing hormone (LHRH) analogs suppress LH and FSH to prepubertal levels (Clin Res 29:504A,1981) to test the hypothesis of autonomous ovarian E2 secretion in MAS. A 5 y/o female presented with classic MAS (café-au-lait spots, polyostotic fibrous dysplasia, and precocious puberty). She was treated with D-Trp6-Pro9-NEt-LHRH (LHRHa), 4 μg/kg/s.c. daily, a regimen which decreases LH, FSH and E2 to prepubertal levels in all females with idiopathic precocious puberty (IPP). Results (mean±SE) are shown below.LHRH-stimulated gonadotropins remained <3mIU/ml throughout therapy. In contrast to IPP, this patient with MAS had marked cyclic E2 elevations during LHRHa therapy with no change of gonadotropins. E2 appeared to correlate with ovarian cyst size by ultrasound. We conclude that in MAS changes in ovarian estradiol secretion appear to be independent of changes in plasma gonadotropin concentration.

EEG and evoked potentials in precocious puberty

We recorded brain stem auditory evoked potentials, pattern reversal visual evoked potentials and electroencephalograms in 19 children, 2-8 years old. Sixteen had precocious puberty and three had precocious adrenarche. Two of the children with precocious puberty had hypothalamic hamartomas, one had an optic glioma, and one had a history of hydrocephalus. The EEG was abnormal in 7 patients: three had diffuse slowing, and four showed possible paroxysmal features. BAEPs and VEPs were normal in all patients. This study showed no abnormalities in two conduction pathways of the central nervous system and no evidence of a deleterious effect of hormonal aberrations in patients with precocious puberty. Abnormal EEG in these patients is more likely to reflect occult diencephalic disease than widespread neurophysiological dysfunction.

Luteinizing hormone releasing hormone analogue therapy for central precocious puberty: Long-term effect on somatic growth, bone maturation, and predicted height

The long-acting analogue of luteinizing hormone releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), is effective in the short-term treatment of central precocious puberty. We report the results of two to four years of LHRHa therapy in 27 children with this disorder. Secondary sex characteristics regressed in most patients. Sex steroid levels and basal and LHRH-stimulated gonadotropin levels remained suppressed compared with pretreatment values. Linear growth rates decreased from 11.0 +/- 0.8 (SEM) cm/yr before treatment to 5.7 +/- 0.4 cm/yr at two years of treatment and 3.7 +/- 0.7 cm/yr at four years of treatment. Predicted heights by the Bayley-Pinneau method increased from 156.4 +/- 2.0 cm before treatment to 162.3 +/- 2.3 cm at two years and 163.4 +/- 2.4 cm at three years. Five patients treated for four years had a mean increase in predicted height of 5.5 cm. To date no adverse effects have been observed. However, the ultimate safety of this analogue is not known. We conclude that LHRHa appears to be an effective long-term therapy for central precocious puberty.

Pituitary Desensitization with a Long-Acting Luteinizing-Hormone-Releasing Hormone Analog

Normal puberty appears to be initiated by the pulsatile secretion of luteinizing-hormone-releasing hormone (LHRH) from the hypothalamus at a frequency of about 1 pulse/hr (see Figure 1) (Boyar, Finkelstein, Roffwarg, Kapen, Weitzman, and Hellman, 1972; Knobil, 1980). The pulsatile secretion of LHRH stimulates secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn stimulate gonadal sex steroid secretion. The rise in the gonadal sex steroids estradiol and testosterone induces the secondary sexual changes at puberty.