Rivka Kauli

Cyproterone acetate in treatment of precocious puberty.

Twenty-nine children (23 girls, 6 boys) with precocious puberty were treated with cyproterone acetate for various periods of time ranging from 6 months to 3 years 4 months. They received an oral dose ranging from 70-150 mg/m2 per day, or an intramuscular depot injection once a fortnight or once a month at a dose ranging from 107-230 mg/m2. Both forms of therapy were found to suppress the signs of sexual maturation, but the oral form proved to be superior. Only the younger patients with a bone age under 11 years showed a beneficial effect upon linear growth and bone maturation. No side effects were noted, but additional advantageous effects upon behaviour and sociability were. It is concluded that at present cyproterone acetate by mouth is the drug of choice in the treatment of precocious puberty. The treatment should be initiated as early as possible to attain maximum benefit.

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.

A vasopressin analogue in treatment of diabetes insipidus

Six children, 3 adolescents, and 3 adults with vasopressin-sensitive diabetes insipidus were treated with a vasopressin analogue, DDAVP (1-deamino-8-D-arginine vasopressin), at a daily dose ranging from 5 to 20 μg administered twice a day intranasally. The period of follow-up of these patients has been from 3 months to 1 year. DDAVP was effective in maintaining normal diuresis and normal urine concentration during both day and night. No local or vasopressor side effects were observed. Compared to other antidiuretic drugs, such as nasal pitressin powder, lysine-vasopressin nasal spray, or pitressin tannate injections, used previously by the patients, DDAVP proved to be superior in the control of the diabetes insipidus and in the subjective feeling of the patients. It is concluded that DDAVP is the drug of choice in the treatment of vasopressinsensitive diabetes insipidus.

Hepatitis Associated with Propylthiouracil Treatment

A 12-year-old girl with hyperthyroidism who had started treatment with propylthiouracil (PTU) 100 mg tid developed hepatitis. The drug was stopped, and the clinical and laboratory findings of hepatitis disappeared within a week. She was not receiving other drugs that could cause hepatic damage, and investigations for various viral agents were negative. This is the ninth report of PTU-induced hepatitis. The clinical picture is similar to that of viral hepatitis. Recovery usually occurs after withdrawal of the drug, but there have been two fatal cases of PTU-induced hepatitis.

The LH and FSH responses to LH-releasing hormone (LH-RH) in girls with true precocious puberty treated with cyproterone acetate

Ten girls with precocious puberty ranging in age from 7 to 10 7/12 years who were treated with oral cyproterone acetate on a long term basis, were subjected to LH-RH tests, prior to and 3 to 16 months after the institution of therapy. Cyproterone acetate was given in doses from 60 to 153 mg/m2, which proved to be clinically effective, as evidenced by the slowing down of sexual maturation.The basal levels of LH were found to be unaffected by therapy and corresponded to the pubertal stages of the individual girls. The peak increment of LH after LH-RH stimulation was markedly suppressed by the therapy. FSH secretion and its responsiveness to LH-RH was not affected by cyproterone acetate. The basal levels of FSH were higher during therapy than before, but the peak FSH increment remained the same. An escape phenomenon in the LH peak response was evident in 2 patients upon retesting after prolonged therapy. It is possible that the antigonadotrophic action of cyproterone acetate is due to its progestational nature.

IGF-I deficiency, longevity and cancer protection of patients with Laron syndrome

Laron syndrome (LS) is a unique model of congenital IGF-I deficiency. It is characterized by dwarfism and obesity, and is caused by deletion or mutations of the growth hormone receptor (GH-R) gene. It is hypothesized that LS is an old disease originating in Indonesia and that the mutated gene spread to South Asia, the Middle East, the Mediterranean region and South America.

Differential effects of hGH and IGF-I on body proportions.

UNLABELLED The differential growth effects of hGH and IGF-I on the upper/lower (U/L) body segment in relation to height (Ht) were analyzed in 15 patients with isolated Growth hormone deficiency (IGHD,:7M, 8F) mean age 5.0 +/- 3.2 (SD) years treated with hGH; 21 patients with multiple pituitary hormone deficiency including growth hormone (MPHD: 14M, 7F) aged 10.0 +/- 3.8, treated with hGH; 9 patients with Laron Syndrome (LS) (4M,5F) aged 6.9 +/- 5.6 years treated with IGF-I; 9 boys with intrauterine growth retardation (IUGR) aged 6.3 +/- 1.25 years treated by hGH; and 22 boys with idiopathic short stature (ISS) aged 8.0 +/- 1.55 years treated by hGH. The dose of hGH was 33 microg/kg/day, that of IGF-I 180-200 microg/kg/day. RESULTS the U/L body segment ratio in IGHD patients decreased from 2.3 +/- 0.7 to 1.1 +/- 0.7 (p <0.001), and the Ht SDS increased from -4.9 +/- 1.3 to 2.3 +/- 1 (p < 0.001) following treatment. In MPHD patients the U/L body segment decreased from 1.1 +/- 1.1 to -0.6 +/- 1.0 (p < 0.001), and the Ht SDS increased from -3.3 +/- 1.4 to -2.5 +/- 1.0 (p < 0.009). In the LS group the U/L body segment ratio did not change with IGF-I treatment but Ht improved from -6.1 +/- 1.3 to -4.6 +/- 1.2 (p < 0.001), The differential growth response of the children with IUGR and with ISS resembled that of the children with LS. CONCLUSIONS hGH and IGF-I act differentially on the spine and limbs.

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.