A. Pertzelan

Final height of girls with central precocious puberty, untreated versus treated with cyproterone acetate or GnRH analogue. A comparative study with re-evaluation of predictions by the Bayley-Pinneau method.

This study was designed to determine the benefit of therapy on final height (FHt) in girls with central precocious puberty (CPP). A total of 102 patients were evaluated--28 untreated, 26 treated with cyproterone acetate (CyA), and 48 treated with GnRH analogue (GnRHA)-and their achieved FHt was compared to the respective target height (THt). Of the untreated girls, half (14/28) had a slow course of puberty and reached THt +/- 0.5 SD (FHt 160.2 +/- 7.1, THt 159.5 +/- 6.6 cm); the other half (14/28) had an accelerated course of puberty with a FHt well below THt (FHt 150.8 +/- 4.3, THt, 159.2 +/- 5.9 cm) and in most cases (14/28) below the height-SDS of both parents. The treated girls (both regimens) reached THt above (CyA group: FHt 157.8 +/- 5.1, THt 156.8 +/- 5.1 cm; GnRHA group: 159.6 +/- 6.3, THt 157.7 +/- 5.7 cm). We conclude that without treatment the FHt of girls with CPP may be significantly compromised and that therapy is more beneficial if started before bone age exceeds 12 years. Our data also showed that for final height predictions in CPP the Bayley and Pinneau tables for average children should be used, regardless of the advanced bone age of the patients.

Puberty in Laron type dwarfism

The onset and progress of puberty was followed in 18 patients (7 males and 11 females) with Laron-type dwarfism (LTD). The boys had delayed puberty, testicular enlargement occurring between 12–14 years being the first sign. The first conscious ejaculation occurred between 17–21 years and full maturity was reached after the age of 22. In girls menarche occurred between 13–14 years and full maturity was reached between 16–19 years. Two patients—one male and one female—have children.

The comparative effect of 6α-fluoroprednisolone, 6α-methylprednisolone, and hydrocortisone on linear growth of children with congenital adrenal virilism and Addison's disease

Six girls with congenital adrenal virilism and one boy with Addisons diseasewere interchangeably treated with 6α-methylprednisolone (Medrol), 6α-fluoroprednisolone (Alphadrol), and hydrocortisone (Cortef). With the use of such amounts of the drugs as were necessary to suppress excretion of 17-ketosteroids, it was found that Alphadrol markedly suppressed linear growth, Medrol slightly less so, but that Cortef permitted normal growth.

THE IMPACT OF LONG‐TERM THERAPY BY A MULTIDISCIPLINARY TEAM ON THE EDUCATION, OCCUPATION AND MARITAL STATUS OF GROWTH HORMONE DEFICIENT PATIENTS AFTER TERMINATION OF THERAPY

Forty‐two GH deficient patients (14 isolated GH deficiency (IGHD), 28 multiple pituitary hormone deficiencies (MPHD), 23 males and 19 females) were evaluated after termination of hGH therapy and achievement of final height. IGHD patients were found to score higher in intelligence quotients (IQ) than the MPHD patients. The educational and occupational achievements of all patients positively correlated with their IQ level. Three patients achieved only elementary education, 26 completed high school and 13 had higher education. Thirty patients who had completed their education were employed, whereas 12 continued to study. Seventeen of the male patients and five females served in the Army. Eight patients were married and half of the single patients reported having a stable relationship with the opposite sex. The hypopituitary patients did not differ in five out of seven subscales of the human services rehabilitation scale when compared to a normal control group. These results which vary from those previously reported demonstrate the importance of long‐term psychosocial counselling initiated at the time of diagnosis as part of the therapeutic approach in hypopituitary patients.

A novel mutation in PIT-1: phenotypic variability in familial combined pituitary hormone deficiencies.

Mutations in PIT-1 have been described in several cases of familial combined pituitary hormone deficiencies. This study describes a novel PIT-1 mutation that was found in two siblings of a highly consanguineous family of Israeli-Arab origin. The missense mutation (G688A) causes a lysine (K) to glutamic acid (E) substitution at codon 230. This codon resides in the first helix of the POU-homeodomain, which is directly involved in DNA binding. This amino acid is conserved in most homeodomain proteins, suggesting that the substitution disrupts the DNA-binding activity of the mutant protein. Two main observations are described: 1. The clinical presentation of the mutation involves intrauterine growth retardation. 2. One sibling had full deficency of growth hormone and thyroid stimulating hormone, whereas the other had only growth hormone deficiency. This is, to the best of our knowledge, a unique expression of a novel PIT-1 mutation.

PROP-1 Gene Mutation (R120C) Causing Combined Pituitary Hormone Deficiencies with Variable Clinical Course in Eight Siblings of One Jewish Moroccan Family

Background: PROP-1 gene mutations have been described in patients with combined pituitary hormone deficiencies (CPHD). Methods: Clinical follow-up and molecular analysis of the PROP-1 gene were performed in 4 affected sisters of one consanguineous family, in whom 8 members had CPHD. Results: The 4 sisters were homozygous for the same R120C mutation. Growth hormone and thyroid-stimulating hormone deficiencies were diagnosed concomitantly in all subjects, but at different ages (5.5–10.8 years). All 8 subjects exhibited complete gonadotropin deficiency with failure of spontaneous sexual maturation. Adrenocorticotropic hormone deficiency developed in only 2 sisters in the 3rd and 4th decades of life. Conclusions: The CPHD in this family, caused by an R120C mutation, was characterized by clinical phenotypic variability in terms of the severity of hormonal deficiencies and the time of their development. Identifying the mutation does not predict the clinical course. Therefore, continuous follow-up with repeated endocrine evaluations is mandatory to provide proper hormone substitution therapy.

A COMPARATIVE STUDY OF THE EFFECT OF OESTROGEN SUBSTITUTION THERAPY ON BREAST DEVELOPMENT IN GIRLS WITH HYPO—AND HYPERGONADOTROPHIC HYPOGONADISM

During treatment of girls with oestrogen deficiency we observed different patterns of breast development in response to therapy.

THE COMBINED EFFECT OF GROWTH HORMONE AND METHANDROSTENOLONE ON THE LINEAR GROWTH OF PATIENTS WITH MULTIPLE PITUITARY HORMONE DEFICIENCIES

Six patients with multiple pituitary hormone deficiencies (MPHD) were initially treated with separate courses of methandrostenolone and growth hormone and later with the two drugs combined. During the basal period the mean growth velocity was 2.8 cm/year. Methandrostenolone alone, 0.02‐0.05 mg/kg/day given to four of the patients led to an acceleration of the growth velocity to a mean of 5.0 cm/year, while growth hormone 6 mg/week alone accelerated the growth rate to a mean of 6.0 cm/year. Combined therapy led to a striking increase in the mean growth rate to 9.3 cm/year. The shortcoming of the combined growth hormone‐androgen therapy was the fast acceleration in skeletal maturation even after short‐term administration.

Clinical evidence on the role of oestrogens in the development of the breasts

Girls start their puberty including breast development around age 8. Though the best correlation found is that with oestradiol, most girls still have at the onset of breast development oestrogen levels in the normal range for adult males. Therefore, it seems that oestrogen receptor sensitivity plays an important role in breast development. An important insight into the hormonal interplay in breast development was obtained when comparing the effect of exogenous oestrogens in forty-five girls with four different aetiologies of oestrogen deficiency: gonadal dysgenesis (GD). 17-alpha hydroxylase deficiency (17-OHase def), isolated gonadotrophin deficiency (IGnD) and multiple pituitary hormone deficiencies (MPHD). None of the girls had any breast development in the absence of oestrogens. Treatment with oestrogen was given in an identical manner to all. In GD, in whom the hypothalamic-pituitary functions were normal, treatment led to full development of breasts in a relatively short period. In IGnD and MPHD, breast development was incomplete even after years of oestrogen treatment. The conspicuous difference of the hormonal status between GD and IGnD and MPHD is that the latter two groups lack gonadotrophins, while in GD and 17-OHase def. these hormones are pathologically elevated. Thus the gonadotrophins seem to play an important role in mammary gland development. In the girl with 17-OHase def., it was also found that cortisol is necessary for normal breast development. A girl with hyperprolactinaemia due to a microadenoma had delayed puberty including slow breast development. Upon bromocriptine treatment the prolactin fell, the oestrogens rose and puberty including breast development occurred. Patients with Laron-type dwarfism (isolated IGF-I deficiency) have been found to have normal breast development.

INTERMITTENT TREATMENT WITH HUMAN GROWTH HORMONE (GH) IN ISOLATED GH DEFICIENCY AND IN MULTIPLE PITUITARY HORMONE DEFICIENCIES

The results of intermittent GH treatment of 3‐7½ years duration in seven patients with isolated GH deficiency (IGHD) and five patients with multiple pituitary hormone deficiencies (MPHD) are presented.