We report an epi-analysis of 6-yr growth responses obtained with GH treatment in short children born small for gestational age (SGA). Four randomized, multicenter studies explored the effects of continuous and discontinuous regimens of GH treatment in short, non-GH-deficient SGA children. A total of 49 untreated and 139 treated children were followed over 2 and 6 yr, respectively. At the start of the study, the age of these 188 children averaged 5.2 yr (range, 2-8 yr), height was -3.4 SD score, and height adjusted for parental height was -2.4 SD score. Onset of puberty was observed in 46% of the GH-treated cohort, on the average, at 10.7 yr in girls and 11.7 yr in boys. Two studies essentially investigated the effects of continuous GH treatment at a dose of 33 or 67 microg/kg, day, and two studies focused on the growth characteristics during an initial GH treatment for 2-3 yr (dose range, 33-100 microg/kg x day), followed by a withdrawal phase of 1-2 yr, and then by either no or 1 or more episodes of further GH treatment (33 or 67 microg/kg x day). Continuous GH treatment for 6 yr resulted in height increments of 2.0 +/- 0.2 SD (33 microg/kg x day; n = 35) and 2.7 +/- 0.2 SD (67 microg/kg x day; n = 27). Discontinuous GH treatment was given to 77 children, most of them experiencing only 1 (n = 47) or 2 (n = 26) treatment phases with an average duration of 2.0 yr. All these children received GH during the first 2 yr; the dose was only 32 microg/kg x day when averaged over 6 yr. Some individualization of treatment schedules was allowed, and the majority of investigators seemed to aim for a low normal height level, adjusted for parental height. After 2 yr, the mean adjusted height SD score had increased to -0.4 +/- 0.1 and stabilized thereafter. Bone maturation progressed similarly in all treatment subgroups, and after 6 yr of study, bone age remained slightly delayed compared to chronological age. Multivariate analysis identified the average GH dose over 6 yr, parental-adjusted height SD score, and age at start as prime predictors of the growth response. GH treatment was well tolerated. In conclusion, this epi-analysis of growth responses over 6 yr confirms the administration of GH as an effective approach to normalize the stature of short, non-GH-deficient SGA children, at least during childhood and early puberty. In addition, it is now increasingly apparent that a relatively broad spectrum of GH regimens is effective, and this experience should facilitate the design of more individualized treatment schedules in the future, in particular for young children.

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch‐up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. A previous metanalysis of four trials revealed that GH treatment over a period of 2 years induced a dose‐dependent acceleration of linear growth and, to a lesser extent, of the rate of bone maturation in short, prepubertal children born SGA. The rate of bone maturation and the change in height SDS for bone age from the previous 2‐year metanalysis have been re‐analysed according to chronological age (two prepubertal age groups: group A, 3.0–5.9 years old; group B, 6.0–8.9 years old). The rate of bone maturation was slower in younger than in older prepubertal children; this difference was more marked in children receiving high‐dose (0.2 or 0.3 IU/kg/day) GH treatment (p ≤ 0.01). Accordingly, the change in height SDS for bone age was increased by high‐dose GH treatment in both age groups (p ≤ 0.01), and was more pronounced in younger than in older children (1.45 ± 0.28 versus 0.63 ± 0.20; p ≤ 0.01). Height SDS data from 100 short, prepubertal children born SGA have been analysed over 4 years. The change in height SDS appeared to be related to the average dose of GH. A mean GH dose of 0.1 IU/kg/day over 4 years was administered either as 0.1 IU/kg/day for 4 years (continuous) or as 0.2 IU/kg/day for 2 years, followed by 2 years without GH treatment (discontinuous). After 4 years of treatment, the increase in height SDS for the continuous and discontinuous treatment schedules was similar, being 1.42 ± 0.10 SDS and 1.58 ± 0.17 SDS, respectively. In a second regimen, a mean GH dose of 0.2 IU/kg/day over 3 years was administered either as 0.2 IU/kg/day for 3 years (continuous) or as 0.3 IU/kg/day for 2 years, followed by 1 year without GH treatment (discontinuous). After 3 years, the increase in height SDS with the continuous and discontinuous treatment schedules was similar, being 2.01 ± 0.18 SDS and 2.22 ± 0.16 SDS, respectively. GH administration was well tolerated in all treatment groups. In conclusion, the rate of bone maturation in short, prepubertal children born SGA treated with GH appeared to depend not only on the dose of GH, but also on the age of the child. GH treatment resulted in a prolonged increase in height SDS, the magnitude of the rise being dependent on the average GH dose rather than on the continuous or discontinuous mode of GH administration. □ Growth hormone, small for gestational age, catch‐up growth, short stature, rate of bone maturation, height, prepuberty

In the present study, data from 230 short children born small for gestational age, who were participating in four clinical trials, were pooled and analysed. At the start of GH treatment, median age and height SDS were 5.3 years and -3.2 SDS, respectively. A dose-dependent increase in height SDS was observed following 2 years of GH treatment: 1.1, 1.7 and 2.5 SDS for the three GH treatment groups (0.1, 0.2 and 0.3 IU/kg/day, respectively), compared with an increase of 0.14 SDS in the control group. In a multiple regression analysis, four variables were found to correlate independently with the gain in height SDS following 2 years of GH treatment. These are given below in order of importance: gain in height SDS = 7.7 x dose of GH (IU/kg/day) -0.11 x age (years) -0.08 x parental-adjusted height SDS + 0.05 x birth length SDS (SD = 0.5; r2 = 0.64). At the end of the 2-year study period, a total of 48%, 66% and 90% of patients in the groups given GH at 0.1, 0.2 and 0.3 IU/kg/day, respectively, had a parental-adjusted height greater than -1.0 SDS.

Short children born small-for-gestational-age (SGA) appear to be at an increased risk of having a poly-endocrinopathy, including a degree of growth hormone (GH) deficiency and/or insulin-like growth factor 1 (IGF-1) resistance. Among GH-deficient children, those born SGA present a lower growth response to GH therapy than those not born SGA. The growth response of short SGA children to GH treatment does not appear to depend significantly on the secretory status of GH (as judged by provocative testing), indicating that the SGA condition (IGF-1 resistance) predominates over the availability of endogenous GH in determining the short stature of the majority of these children. When a higher than replacement dose of GH is administered, the growth response of short SGA children matches that of GH-deficient non-SGA children, indicating that the IGF-1 resistance towards growth can be overcome, and that a normal stature can be obtained, at least throughout childhood. It is anticipated that, increasingly, the indications and the doses for GH therapy in children will become interlinked with the emerging principles of endocrine programming in early life.

HIV+ human sera contain antibodies against most HIV proteins, including the envelope glycoprotein Gp120. Some of these antibodies may have an epitope that sterically resembles the CD4 region to which the Gp120 molecule binds. Amongst 58 HIV+ sera tested, we found three with the capacity to block the binding of anti-CD4 monoclonal antibodies to CD4+ cells. The serum with the highest blocking capacity was selected for further analysis. The inhibitor was shown to be an antibody that binds to the Gp120 molecule as well as to the anti-CD4 monoclonal T4.2. These CD4-mimicking antibodies were shown not to interfere with CD4-dependent reactions in vitro. Virus neutralizing experiments in vitro could not show any neutralizing effect with these antibodies alone. The HIV+ individual providing this antibody is still healthy, although HIV+ since 1983.

T lymphocyte lines specific for cobalt (CoCl2) were established from one cobalt and nickel sensitive donor. The lines were generated by stimulating peripheral blood mononuclear cells (PBL) with CoCl2 for 7 days. The activated blasts were maintained in interleukin 2 containing media and every 7-10 day restimulated with antigen (CoCl2) and fresh irradiated PBL. The antigen specificity of the lines was attested by their capacity to proliferate and release of IL 2 under restimulation by CoCl2 and not by an antigen like NiSO4, towards which the donor was also sensitized. The cell lines were of the helper phenotype, T3/T4 positive subset, as determined by monoclonal antibodies. Analysis of the HLA class II restriction by using allogeneic PBL as antigen presenting cells and the capacity of anti HLA-D antibodies to effectively inhibit the specific response indicated that the antigen specific T cell response to contact allergens like cobalt chloride is restricted to HLA class II antigens.

The relationship between progesterone (P) and limbic catecholamines (CA) was studied in diestrous (D) and ovariectomized (OVX) female rats using quantitative microfluorimetry and CA turnover estimations after tyrosine hydroxylase inhibition. Plasma P concentrations as determined by radioimmunoassay correlated with dopamine (DA) levels in the olfactory tubercle, the nucleus accumbens (ACC) and "striatal islands" in the caudate nucleus and with noradrenaline (NA) levels in the medial preoptic area (MPOA) in D rats, whereas no dose-effect relationship of external P on limbic CA levels and turnover was found in OVX rats. However, P increased MPOA NA turnover in the lowest dose and dcreased ACC DA turnover in the highest dose. Thus, certain effects of P on CA transmission in the brain may require estrogen-priming, whereas others do not.

The catecholamine (CA) content was measured in nerve terminals of the median eminence (ME) in normal, castrated and adrenalectomized male rats using quantitative microfluorimetry. CA turnover was determined by rates of CA disappearance after tyrosine hydroxylase inhibition. Noradrenaline (NA) levels and turnover in the subependymal layer (SEL) were unchanged 4 weeks after respective surgeries. Dopamine (DA) levels but not turnover in the lateral palisade zone (LPZ) were increased by castration. DA levels and turnover rates were significantly increased in the medial palisade zone (MPZ) by castration, whereas adrenalectomy selectively decreased MPZ CA levels without affecting the turnover rates. These results were discussed in relation to the concept of a medial and a lateral tuberoinfundibular DA pathway innervating different neuroendocrine structures in the rat ME.

(1) The catecholamine (CA) content was determined in nerve terminals of the median eminence in normal, castrated and adrenalectomized male rats using quantitative microfluorimetry. (2) Noradrenaline (NA) concentrations in the subependymal layer (SEL) were unaffected by surgery. (3) Adrenalectomy decreased CA concentrations in the mixed population of NA and dopamine (DA) terminals in the medial palisade zone (MPZ). (4) Castration increased DA concentrations in MPZ and the lateral palisade zone (LPZ). (5) Adrenalectomy and castration had pronounced, but somewhat different, effects on the variations of CA fluorescence intensities in LPZ and MPZ, but no effect in the subependymal layer (SEL). (6) It is postulated that DA terminals in the external layers of the median eminence may interact with tanycytes in the feedback regulation of adrenal and gonadal hormones.

In this review we systematically summarize the effects of progesterone and synthetic progestins on neurogenesis, synaptogenesis, myelination and six neurotransmitter systems. Several parallels between progesterone and older generation progestin actions emerged, suggesting actions via progesterone receptors. However, existing results suggest a general lack of knowledge regarding the effects of currently used progestins in hormonal contraception regarding these cellular and molecular brain parameters. Human neuroimaging studies were reviewed with a focus on randomized placebo-controlled trials and cross-sectional studies controlling for progestin type. The prefrontal cortex, amygdala, salience network and hippocampus were identified as regions of interest for future preclinical studies. This review proposes a series of experiments to elucidate the cellular and molecular actions of contraceptive progestins in these areas and link these actions to behavioral markers of emotional and cognitive functioning. Emotional effects of contraceptive progestins appear to be related to 1) alterations in the serotonergic system, 2) direct/indirect modulations of inhibitory GABA-ergic signalling via effects on the allopregnanolone content of the brain, which differ between androgenic and anti-androgenic progestins. Cognitive effects of combined oral contraceptives appear to depend on the ethinylestradiol dose.

To study whether adolescents with the classical form of polycystic ovary syndrome (PCOS) have alterations in metabolic and vascular structure and function. The effect of metformin was evaluated.Controlled study.University outpatient clinic.Eighteen nonobese adolescents with PCOS were enrolled. Seventeen healthy age-matched adolescents were recruited as control subjects.The metabolic profile and the endothelial structure and function were evaluated.Hormonal and lipid profile, blood pressure (BP) measurement, fasting glucose and insulin levels, C-reactive protein (CRP), homocysteine, tissue-type plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), and plasmin-antiplasmin complexes (PAP) were measured. Flow mediated dilation (FMD), central pulse wave velocity (PWV), radial artery pulse wave, and common carotid intima-media thickness (IMT) were also assessed. Girls with PCOS were also studied 6 months after treatment with metformin (850 mg twice per day).Adolescents with PCOS were insulin resistant and/or hyperinsulinemic and they had higher BP values and levels of CRP and PAI-1 than the control subjects. The levels of tissue-type plasminogen activator and PAP were similar in both groups. FMD, PWV, and IMT were also similar. Metformin significantly (P < .05) reduced insulin, BP, CRP, and PAI-1 levels. The PAP levels significantly (P < .05) increased. Radial artery pulse wave was significantly reduced after metformin treatment. No modifications in FMD, PWV, and IMT were observed.Adolescents with classical PCOS have alterations in some surrogate markers of cardiovascular risk and they are ameliorated by metformin. No deterioration of vascular structure and function has been detected, probably because of the short duration of exposure to the disease.

The effects of estradiol benzoate (E2B) on brain catecholamines (CA) and serum gonadotropins and prolactin were studied in the ovariectomized rat. The levels of noradrenaline (NA) and dopamine (DA) in the median eminence (ME) and the forebrain (F) were studied using quantitative micro-fluorimetry. CA turnover was determined by rates of CA disappearance after tyrosine hydroxylase inhibition. The following areas were studied in the ME: the subependymal layer (SEL), the medial (MPZ) and the lateral palisade zone (LPZ). The following areas were studied in F: the olfactory tubercle (TO), the dorsolateral nucleus accumbens (ACC), the medial part of the medial preoptic area (MPOA), the nucleus interstitialis striae terminalis ventralis (NISTV) and part of the “striatal islands” in the caudate nucleus (CAUD). Serum LH, FSH and prolactin concentrations were determined by radioimmunoassay. In all experiments E2B was given on day O at 0800–0900 h. On the basis of a time course study (day 0–6) the morning of day 3 was selected for an investigation of dose-effect relationships of E2B (0.1–100 μg) on CA levels and turnover and serum LH, FSH and prolactin concentrations. Serum prolactin concentrations and DA turnover in the LPZ and TO were increased and serum LH and FSH concentrations and NA turnover in the SEL and MPOA were decreased in a dose-dependent manner by E2B. LH concentrations correlated with DA turnover in the LPZ. Prolactin concentrations correlated with DA turnover in the ACC. LH and FSH concentrations correlated only after E2B administration. It is concluded that 1) an inhibitory feedback effect of estrogen on LH secretion is exerted via DA terminals in the LPZ, 2) NA terminals in the MPOA may stimulate LH secretion, 3) a non-CA mechanism may regulate FSH secretion, and 4) DA terminals in the ACC may play a role in the control of prolactin secretion.

Using quantitative microfluorimetry in combination with tyrosine hydroxylase inhibition (H44/68) the concentration and turnover of noradrenaline (NA) and dopamine (DA) was studied in the subependymal layer (SEL) and the medial (MPZ) and lateral palisade zone (LPZ) of the rat median eminence during the 4- and 5- day vaginal estrous cycle. Significant cyclic variations were only found in SEL and LPZ. The NA turnover in SEL was high on proestrous and low on all other days of the 4-day estrous cycle, whereas in the 5-day estrous cycle the NA turnover in SEL started to increase already on the second day of diestrous to reach a peak in the afternoon of proestrous. At that time also the NA concentrations in SEL were increased, although significantly only in the 5-day cyclic rats. The DA turnover in LPZ was low on proestrous and high on all other days in both 4-and 5-day cyclic rats. Apart from the median eminence cyclic variations in catecholamine metabolism were only found in the medial preoptic area, where NA turnover was high on proestrous and low on estrous-diestrous. The present findings give further support for the existence of a facilitatory noradrenergic and inhibitory dopaminergic mechanism in the control of gonadotrophin release. Furthermore, it is suggested that an acceleration of reticulo-hypothalamic NA turnover precedes the retardation of tubero-infundibular DA turnover found on proestrous and that the time lag between initial NA activation and subsequent DA inactivation is longer in the 5-than in the 4-day estrous cycle.