Zvi Laron

D-TRP6-ANALOGUE OF LUTEINISING HORMONE RELEASING HORMONE IN COMBINATION WITH CYPROTERONE ACETATE TO TREAT PRECOCIOUS PUBERTY

A 6-year-old girl with central (true) precocious puberty was successfully treated with a combination of the luteinising hormone releasing hormone analogue (D-Trp6)-LH-RH and cyproterone acetate. This treatment led to an almost complete arrest of gonadotrophin and oestrogen secretion, induced regression of pubertal signs, and markedly slowed bone maturation. It is suggested that the paradoxical refractoriness of the gonadotrophic and gonadal cells induced by long-term treatment with LH-RH agonists can be exploited in the treatment of precocious puberty.

TREATMENT OF PRECOCIOUS PUBERTY WITH LHRH ANALOGUE IN COMBINATION WITH CYPROTERONE ACETATE—FURTHER EXPERIENCE

Six girls and one boy with precocious puberty were treated with a superactive LHRH analogue (D‐TRP6‐LHRH) for periods ranging from 1 year to 2 years and 3 months. In the first phase of the treatment it was administered in combination with cyproterone acetate (CyA) to counteract an early stimulatory effect until inhibition of gonadotrophin secretion was achieved. The gonadotrophin‐dependent signs i.e. gonadarche, showed sustained arrest and even regression. Gonadal sex steroids decreased but the adrenal androgens were unaffected. In four patients who showed progression of the angrogen‐dependent signs (adrenarche), despite suppression of gonadotrophins, increasing the dosage of the LHRH analogue was ineffective and combined therapy with CyA was reinstituted in three of them because of accelerated growth and bone maturation. It is concluded that at present the treatment of choice for precocious puberty is the daily administration of a superactive LHRH analogue such as D‐TRP6‐LHRH, together with CyA in the initial stage, and at a later state if adrenarche progresses too rapidly.

GONADAL FUNCTION IN BLOOM'S SYNDROME

Five patients with Blooms syndrome aged from 2 8/12 to 27 years, all of whom had hypogonadism, were subjected to an i.v. LHRH test and two of them to an i.m. HCG test. There was increased responsiveness of plasma LH and FSH, indicating that the hypogonadism is primary in nature and of early development. The tubular element of the testis seems to be mainly affected, as indicated by the particularly high FSH response to LHRH stimulation, a history of sterility in the two adult patients and documented azoospermia in one of them. The Leydig cells seem to be less affected and secrete sufficient androgens to enable puberty within acceptable normal limits. Hypogonadism seems to be a major characteristic of Blooms syndrome.

DIFFERENTIAL DIAGNOSIS BETWEEN HYPOTHALAMIC AND PITUITARY hGH DEFICIENCY WITH THE AID OF SYNTHETIC GH‐RH 1–44

Synthetic GH‐RH 1–44 administered as an intravenous bolus (1 μg/kg) evoked a marked hGH rise (>20 ng/ml) in three children with constitutional short stature and in two of eight children diagnosed as having hGH deficiency by insulin hypoglycaemia and/or clonidine tests. As judged by the intensity of the hGH response to the dose employed and the peak time, GH‐RH 1–44 may be as potent as GH‐RH 1–40 in children. It is concluded that GH‐RH is an important addition to the endocrine armamentarium, providing the means for differentiation between hypothalamic and pituiary hGH deficiency in a simple test which is devoid of side effects.

Long-Term Effect of d-Trp6-Luteinizing Hormone-Releasing Hormone on Testicular Size and Luteinizing Hormone, Follicle-Stimulating Hormone, and Testosterone Levels in Hypothalamic Hypogonadotropic Males *

Six men, ages 18 to 34 years, with hypothalamic hypogonadotropism were treated with D-Trp6-luteinizing hormone-releasing hormone (10 micrograms intramuscularly on alternate days) for a period of 6 months. They underwent an intravenous luteinizing hormone-releasing hormone (LH-RH) test (50 micrograms/sq m) before and after 1, 3, and 6 months of treatment. During the first 3 months of therapy, the mean (+/- standard deviation) testicular volume increased from 3.5 +/- 1.0 ml to 6.0 +/- 2.0 ml, but decreased to 5.0 +/- 1.0 ml after 6 months. A significant increase in the plasma LH response to LH-RH over pretreatment levels was noted after 1 month (10.2 +/- 4.2 mIU/ml versus 1.6 +/- 1.0 mIU/ml, P less than 0.001) and 3 months (3.0 +/- 1.6 mIU/ml, P less than 0.01) with a subsequent decline to pretreatment levels after 6 months of treatment. The follicle-stimulating hormone response to LH-RH was not significant. It is concluded that D-Trp6-LH-RH induced an initial stimulation in these patients but, probably because of the excessively high dose used, a paradoxical inhibitory response was obtained after 3 months of therapy.

Plasma Growth Hormone Response to Synthetic GH-RH1-44 in 52 Children and Adults with Growth Hormone Deficiency of Various Etiologies

52 patients (42 children and 10 adults) with growth hormone deficiency (GHD), grouped into four diagnostic categories, and 6 children with constitutional short stature who served as controls were tested for plasma GH response to synthetic GH-RH1-44 given in an intravenous bolus. The response was classified into three degrees according to the magnitude of the maximal rise: Good, greater than 9 ng/ml; Partial, 3.1-9.0 ng/ml; None, less than or equal to 3 ng/ml. Among the GHD patients the highest response was observed in patients with partial growth hormone deficiency (PGHD), and 60% of the children with isolated GH deficiency (IGHD) showed an increase in plasma GH levels. Nevertheless, the response of the GHD patients was lower than that in the control group. In the children and adolescents with PGHD and IGHD the response was not age related. Among those with multiple pituitary hormone deficiencies-idiopathic (MPHD-ID) there was no response in the adolescents although a hypothalamic disorder had been documented by other tests. Among those with MPHD-organic (MPHD-ORG) the GH-RH stimulated GH secretion in the patients with glioma, who had received only irradiation treatment, and in the youngest of the patients with craniopharyngioma. Of the 10 young adults tested none showed a good response. It is concluded that GH-RH is useful in differentiating between GH deficiency of hypothalamic origin and that of pituitary origin, and in selecting those patients who might benefit from long-term treatment with GH-RH in the future.

Sexual Development in Patients with Laron Syndrome

The sequence of sexual development in boys and girls is described and illustrated. Despite delayed puberty mainly in boys, both genders reach full sexual development and reproductive potential.

Linear Growth Pattern of Untreated Laron Syndrome Patients

Description with examples of the disproportional linear growth retardation of untreated boys and girls with Laron syndrome.

GROWTH HORMONE (GH) IS NORMAL IN GIRLS WITH PRECOCIOUS PUBERTY DURING SUPPRESSIVE THERAPY WITH LH-RH ANALOGUE (D-TRP-6-LH-RH)

The inhibition of gonadotropin secretion in children with central precocious puberty treated with LH-RH analogues results in suppression of the pubertal development, including growth velocity. In some patients, a marked slowing of growth is observed. To test whether this is related to inhibition of GH secretion, we performed a clonidine test (150 mcg/m2 p.o.) in 9 girls with central precocious puberty (age range: 4 4/12 to 11 8/12 yrs) treated with D-TRP-6-LH-RH, a superactive LH-RH analogue, 6 by daily s.c. injections of an acqueous preparation, and 3 by monthly i.m. injections of a depot preparation (Decapeptyl - Ferring). The daily dose ranged from 1.5 to 3 mcg/kg/day and the treatment periods were from 10 to 60 months. In all patients a normal GH response was found, by a peak value of 18 ng/ml or higher. In all, gonadotropin suppression was confirmed by a concomitant i.v. LH-RH test. These data show that GH reserve is not affected by the LH-RH analogue therapy and cannot be implicated in the slowing of growth, which is probably due to lack of sex hormones.

87 EFFECT OF CRF 1–41 AS COMPARED TO INSULIN HYPOGLYCEMIA (ITT) ON PLASMA CORTISOL AND ACTH IN SUBJECTS WITH INTACT OR DEFECTIVE HYPOTHALAMIC-PITUITARY FUNCTIONS

Synthetic CRF 1-41 in a dose of 1 mcg/kg was administered i.v. Plasma cortisol (CO) and ACTH were determined before and at 30, 60, 90 & 120 min. Fourteen children (12M, 2F 12±4.8 yrs) were investigated including 2 normal controls, 6 with IGHD and 6 with MPHD. According to the peak plasma CO during ITT the subjects were classified into 2 groups: Gr. A - intact hypothalamic-pituitary-adrenal (HPA) axis (peak CO > 16 ug/dl; Gr. B - subnormal responders.The CRF test made it possible to distinguish between a pituitary lesion (ACTH def.) and a hypothalamic defect (CRF def.). There was also a good correlation between the CRF, GH-RH and TRH tests in the same patients. It is concluded that the CRF test is a useful addition to the diagnostic endocrine armamentarium.