Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.

Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs. Although several families with MANDP have been reported, homozygous mutations in the matrix metalloproteinase type 9 (MMP9) gene have been described in only one consanguineous family, and thus the pre and postnatal phenotypic spectrum is still obscure. A clinically similar but more severe type is caused by autosomal-dominant inheritance and is caused by mutations in matrix metalloproteinase type 13 gene (MMP13). Here, we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP. We propose that MANDP should be considered in pregnancies with early prenatal shortening of the long bones without associated finding of lethal skeletal dysplasias. In addition, the finding of homozygous mutation in non-consanguineous parents of Jewish-Caucasus ancestry may suggest unawareness of such relation or the occurrence of a founder mutation in this gene.

Extracellular volume measured by whole body CT scans predicts chronic cardiotoxicity in breast cancer patients treated with neoadjuvant therapies based on anthracyclines: A retrospective study.

INTRODUCTION: Neoadjuvant chemotherapies for breast cancer (BC) are effective but potentially cardiotoxic, and expose long survivors at risk of chemotherapy-related cardiac dysfunction (CTRCD). Unfortunately, early screening for CTRCD has actual diagnostic limits. Myocardial extracellular volume (mECV) is a radiological marker used in cardiac CT scans and cardiac magnetic resonance for diagnosis and follow-up of CTRCD. It can be measured in whole-body CT (WB-CT) scan, routinely performed in patients at high risk of relapse, to evaluate CTRCD occurrence during oncological follow-up. METHODS: 82 WB-CT scans were examined at baseline (T0) and during oncological follow-up at first year (T1) and fifth year (T5) after the end of neoadjuvant treatment. mECV was measured at 1 min (PP) and 5 min (DP) after contrast injection. 31 echocardiograms were retrieved in T1 to perform a linear correlation between mECV and left ventricular ejection fraction (LVEF). RESULTS: mECV values in T0 were similar between the two groups both in PP and in DP. Significant results were found for PP values in T1 (37.0 % vs 32 %, p = 0.0005) and in T5 (27.2 % vs 31.2 %, p = 0.025). A cut-off value of 35 % in PP proved significant in T1 (OR = 12.4, p = 0.004), while mECV was inversely correlated with LVEF both in PP (adj-S = -3.54, adj-p = 0.002) and in DP (adj-S = -2.51, adj-p = 0.0002), suggesting a synergistic action with the age at diagnosis (p < 0.0001, respectively). CONCLUSIONS: WB-CT scans performed during oncological reassessment in patients at high-risk of recurrence could be used for CTRCD screening in cardiovascular low-risk patients, especially in aging patients with mECV values above 35 %.

Insulin-like growth factor-I in growth and metabolism.

Deficiency of insulin-like growth factor-I (IGF-I) results in growth failure. A variety of molecular defects have been found to underlie severe primary IGF-I deficiency (IGFD), in which serum IGF-I concentrations are substantially decreased and fail to respond to GH therapy. Identification of more patients with primary or secondary IGFD is likely with investigative and diagnostic progress, particularly in the assessment of children with idiopathic short stature. Diagnosis of IGFD requires accurate and reliable IGF-I assays, adequate normative data for reference, and knowledge of IGF-I physiology for proper interpretation of data. Recombinant human IGF-I (rhIGF-I) treatment improves stature in patients with severe primary IGFD, and has also been shown to improve glycaemic control and insulin sensitivity in patients with severe insulin resistance. Ongoing studies of patients receiving rhIGF-I will allow further evaluation of the clinical utility of this treatment, with concurrent increase in our understanding of IGF-I and conditions of IGFD.

Geographic constraints on women's careers in academia.

Male and female academics have very different residence patterns. Women are more concentrated in our largest urban centers; also, wherever they reside, women are less likely than men to change communities when changing institutions. Much of this sex difference is attributable to the constraints under which married academic women must manage their careers, in particular the requirements of two-career households. The authors argue that the status difference between men and women in academia is attributable, in part, to the geographic limitations on the locations of married women, as these prevent making strategic job changes to advance career prospects.

Activity of delta8- and delta9-tetrahydrocannabinol and related compounds in the mouse.

The 11-hydroxy metabolites of Delta(8).- and Delta(9)-tetrahydrocannabinol are more active than the parent compounds when administered to mice by either the intravenous or intracerebral route. Both Delta(8)- and Delta(9)-tetrahydrocannabinol are rapidly and extensively metabolized by the liver and not by the brain. The hypothesis that the 11-hydroxy metabolites may be the active form of tetrahydrocannabinol is discussed

The insulin-like growth factor-binding protein (IGFBP) superfamily.

Over the last decade, the concept of an IGFBP family has been well accepted, based on structural similarities and on functional abilities to bind IGFs with high affinities. The existence of other potential IGFBPs was left open. The discovery of proteins with N-terminal domains bearing striking structural similarities to the N terminus of the IGFBPs, and with reduced, but demonstrable, affinity for IGFs, raised the question of whether these proteins were "new" IGFBPs (22, 23, 217). The N-terminal domain had been uniquely associated with the IGFBPs and has long been considered to be critical for IGF binding. No other function has been confirmed for this domain to date. Thus, the presence of this important IGFBP domain in the N terminus of other proteins must be considered significant. Although these other proteins appear capable of binding IGF, their relatively low affinity and the fact that their major biological actions are likely to not directly involve the IGF peptides suggest that they probably should not be classified within the IGFBP family as provisionally proposed (22, 23). The conservation of this single domain, so critical to high-affinity binding of IGF by the six IGFBPs, in all of the IGFBP-rPs, as well, speaks to its biological importance. Historically, and perhaps, functionally, this has led to the designation of an "IGFBP superfamily". The classification and nomenclature for the IGFBP superfamily, are, of course, arbitrary; what is ultimately relevant is the underlying biology, much of which still remains to be deciphered. The nomenclature for the IGFBP related proteins was derived from a consensus of researchers working in the IGFBP field (52). Obviously, a more general consensus on nomenclature, involving all groups working on each IGFBP-rP, has yet to be reached. Further understanding of the biological functions of each protein should help resolve the nomenclature dilemma. For the present, redesignating these proteins IGFBP-rPs simplifies the multiple names already associated with each IGFBP related protein, and reinforces the concept of a relationship with the IGFBPs. Beyond the N-terminal domain, there is a lack of structural similarity between the IGFBP-rPs and IGFBPs. The C-terminal domains do share similarities to other internal domains found in numerous other proteins. For example, the similarity of the IGFBP C terminus to the thyroglobulin type-I domain shows that the IGFBPs are also structurally related to numerous other proteins carrying the same domain (87). Interestingly, the functions of the different C-terminal domains in members of the IGFBP superfamily include interactions with the cell surface or ECM, suggesting that, even if they share little sequence similarities, the C-terminal domains may be functionally related. The evolutionary conservation of the N-terminal domain and functional studies support the notion that IGFBPs and IGFBP-rPs together form an IGFBP superfamily. A superfamily delineates between closely related (classified as a family) and distantly related proteins. The IGFBP superfamily is therefore composed of distantly related families. The modular nature of the constituents of the IGFBP superfamily, particularly their preservation of an highly conserved N-terminal domain, seems best explained by the process of exon shuffling of an ancestral gene encoding this domain. Over the course of evolution, some members evolved into high-affinity IGF binders and others into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means (Fig. 10). A final word, from Stephen Jay Gould (218): "But classifications are not passive ordering devices in a world objectively divided into obvious categories. Taxonomies are human decisions imposed upon nature--theories about the causes of nature's order. The chronicle of historical changes in classification provides our finest insight into conceptual revolutions

Growth hormone (GH) insensitivity due to primary GH receptor deficiency.

As demonstrated in Table 2, the differential diagnosis of growth hormone insensitivity (GHI) includes a number of discrete disorders that can be broadly classified as primary or secondary forms. We have selected GHRD (Laron syndrome) as the prototypic disorder of GHI, in part because such dramatic and rapid progress has been made in this clinical condition over the last 6 yr. These advances represent the fortunate convergence of: 1) the cloning of the GHR gene and the identification of deletions and mutations of this gene in GHRD; 2) the development of assay methods for measurement of the GHBP, IGF peptides, and binding proteins; 3) the discovery of a larger number of affected individuals than had been previously suspected, including the recognition and description of a large genetically homogeneous population of GHRD patients in Ecuador; and 4) the production of recombinant IGF-I for therapeutic trials in GHRD. Although we are still in the early phases of clinical trials of recombinant hIGF-I in GHRD, preliminary results have been encouraging. Whether this promise translates into genuine improvements in height and body composition, without significant clinical toxicity, remains to be determined. Similarly, the suitability of IGF-I therapy for other, particularly secondary, forms of GHI is still uncertain, although the responsiveness of GHD-IA patients seems to parallel that seen in GHRD (66, 78). The next few years should provide exciting and potentially important new data on the clinical spectrum, biochemical and molecular characteristics, and responsiveness to therapy of syndromes of GHI.

International consensus (ICON) on management of otitis media with effusion in children.

Otitis media with effusion (OME) is a common childhood disease defined as the presence of liquid in the middle ear without signs or symptoms of acute ear infection. Children can be impacted mainly with hearing impairment and/or co-occurring recurrent acute otitis media (AOM) thus requiring treatment. Although many meta-analyses and national guidelines have been issued, management remains difficult to standardize, and use of surgical and medical treatments continue to vary. We convened an international consensus conference as part of the 2017 International Federation of Oto-rhino-laryngological Societies Congress, to identify best practices in OME management. Overall, regional differences were minor and consensual management was obtained on several important issues. At initial assessment, although a thorough medical examination is necessary to seek reflux, allergy or nasal obstruction symptoms; an age-appropriate auditory test is the only assessment required in children without abnormal history. Non-surgical treatments poorly address the underlying problem of an age-dependent dysfunctional Eustachian tube; auto-inflation seems to be the only beneficial, low-risk and low-cost non-surgical therapy. There was a clear international recommendation against using steroids, antibiotics, decongestants or antihistamines to treat OME, because of side-effects, cost issues and no convincing evidence of long-term effectiveness. Decisions to insert tympanostomy ventilation tubes should be based on an auditory test but also take into account the child's context and overall hearing difficulties. Tubes significantly improve hearing and reduce the number of recurrent AOM with effusion while in place. Adjuvant adenoidectomy should be considered in children over four years of age, and in those with significant nasal obstruction or infection.

Insulin-like growth factor binding proteins from cultured human fibroblasts. Characterization and hormonal regulation.

Specific, high affinity insulin-like growth factor (IGF) binding proteins are secreted by human fibroblasts in culture. By multiple criteria, the species of IGF binding proteins produced by human fibroblasts are distinct from the HepG2/amniotic fluid IGF binding protein, but share many characteristics with the growth hormone-dependent IGF binding protein forms predominant in normal adult human plasma. Treatment of cultured human fibroblasts with growth hormone produced an increase in IGF binding protein activity in the medium, while addition of glucocorticoids markedly diminished IGF binding activity. Insulin, epidermal growth factor, platelet-derived growth factor, and progesterone had no effect on IGF binding activity in fibroblast media. In comparison, HepG2 IGF binding activity was enhanced by progesterone, decreased by insulin, and unaffected by growth hormone or glucocorticoid treatment. Five molecular forms of IGF binding proteins were identified by Western ligand blots in human fibroblast conditioned medium, with Mr = 41,500, 37,000, 32,000, 28,000, and 23,000. In human fibroblast conditioned medium, the Mr = 41,500 and 37,000 IGF binding protein species were abundant, as in normal human plasma, with a major Mr = 23,000 form which was a minor component in plasma.

Decreased serum insulin-like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease.

To determine whether chronic hypoxemia results in alterations in endocrine function that may contribute to growth failure, we measured growth hormone (GH), somatomedins (insulin-like growth factors I and II, IGF-I and IGF-2), hepatic growth hormone receptors, and circulating IGF-binding proteins IGFBP-3 and IGFBP-2 in 12 newborn lambs with surgically created pulmonic stenosis and atrial septal defect, and in 10 controls. During chronic hypoxemia (oxygen saturation of 60-74% for 2 wk), weight gain was 60% of control (hypoxemic, 135 +/- 20 vs. control, 216 +/- 26 g/d, P less than 0.02). IGF-I was decreased by 43% (hypoxemic 253.6 +/- 29.3 SE vs. control 448.0 +/- 75.5 ng/ml, P = 0.01), whereas GH was unchanged (19.9 +/- 5.1 vs. 11.9 +/- 3.0 ng/ml, NS). The increase in IGF-1 was associated with a decrease in IGFBP-3 (hypoxemic, 5.09 +/- 1.25 vs. control, 11.2 +/- 1.08 arbitrary absorbency units per mm (Au.mm), P less than 0.01), and increase in IGFBP-2 (0.47 +/- 0.03 vs. 0.19 +/- 0.13 Au.mm, P less than 0.05), but no significant downregulation of hepatic GH receptors (hypoxemic, 106.1 +/- 20.1 vs. control, 147.3 +/- 25.9 fmol/mg, NS). Thus, chronic hypoxemia in the newborn is associated with a decrease in IGF-I and IGFBP-3 in the face of normal GH. This suggests peripheral GH unresponsiveness, similar to protein-calorie malnutrition or GH receptor deficiency dwarfism, but mediated at a level distal to the hepatic GH receptor.

Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep.

Plasma luteinizing hormone (LH) and testosterone (T) were measured by radioimmunoassay in nine pubertal boys and three sexually mature young men at 20-min intervals for 24 h. Plasma LH and T were also measured in one boy during a delayed sleep onset study. Polygraphic monitoring was carried out to identify precisely sleep onset. Wakefulness, and specific sleep stages. In all nine pubertal boys the plasma T concentration fluctuated and was significantly higher during normal nocturnal sleep as compared to daytime waking. This increased T secretion during sleep was temporally linked to the characteristic pubertal sleep augmentation of LH secretion. To define further the relationship of this increased T secretion to sleep, plasma LH and T were also measured in three of the pubertal boys after acute (1-day) reversal of the sleep-wake cycle. One of these boys was also studied after 3 days of sleep-wake cycle reversal. The results of these studies showed that plasma T was now augmented during the reversed daytime sleep period; the mean T concentrations during this period were significantly higher (P < 0.001) than during nocturnal waking in all four studies. Measurement of plasma LH and T in the three sexually mature young men showed episodic secretion of LH and T during both waking and sleep periods; there was no consistent significant augmentation of LH or T secretion during sleep. This study demonstrates that (a) in normal pubertal boys and sexually mature young men plasma T fluctuates episodically; (b) there is marked augmentation of T secretion during sleep in pubertal boys, which is dependent on increased LH secretion; (c) this pubertal LH-T secretory "program" is dependent on sleep, since it shifts with delayed sleep onset and reversal of the sleep-wake cycle; and (d) this demonstrable tropic effect of LH on T is evident only during puberty, since sexually mature young men fail to show any consistent relationship between LH and T secretion either awake or asleep.

Granulosa cell-derived insulin-like growth factor (IGF) binding proteins are inhibitory to IGF-I hormonal action. Evidence derived from the use of a truncated IGF-I analogue.

An increasing body of information now suggests that insulin-like growth factor (IGF) binding proteins (BPs) may serve as antigonadotropins at the level of the ovary. It is the objective of the present communication to evaluate the functional role of endogenous (granulosa cell-derived) IGFBPs by exploiting the unique properties of des(1-3)IGF-I, a naturally occurring IGF-I analogue characterized as a weak ligand of IGFBPs but not of type I IGF receptors. Given IGFBP-replete circumstances, des(1-3)IGF-I proved more potent (10-fold) than its intact counterpart in promoting the follicle stimulating hormone (FSH)-stimulated accumulation of progesterone by cultured rat granulosa cells. In contrast, des(1-3)IGF-I proved virtually equipotent to the unmodified principle under IGFBP-deplete circumstances. Taken together, these findings are in keeping with the notion and that the apparently enhanced potency of des(1-3)IGF-I (under IGFBP-replete conditions) is due to its diminished affinity for endogenously generated IGFBPs and that rat granulosa cell-derived IGFBPs are inhibitory to IGF (and thus inevitably to gonadotropin) hormonal action. Accordingly, the reported ability of gonadotropins to attenuate IGFBP release by granulosa cells may be designed to enhance the bioavailability of endogenously generated IGFs in the best interest of ovarian steroidogenesis.

Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor beta2-induced growth inhibition in human breast cancer cells.

Retinoic acid (RA) is a potent in vitro inhibitor of cell proliferation in various malignant cell lines. The exact mechanisms of its actions, however, are not fully understood. To further elucidate the nature of this inhibition, we investigated the effects of RA in an estrogen receptor-negative human breast cancer cell line, MDA-MB-231. RA (0.01-5 microM) significantly inhibited MDA-MB-231 cell growth by 35-40% as compared with untreated controls. Similar growth inhibitory actions were observed when cells were treated with transforming growth factor beta2 (TGF-beta2), another factor with antiproliferative actions in breast cancer cells. Both RA and TGF-beta2 increased the levels of insulin-like growth factor binding protein (IGFBP) 3 (2-3-fold) and mRNA (1.5-2-fold), whereas IGFBP-4 levels remained essentially unchanged. The direct involvement of IGFBP-3 in cell growth inhibition was further confirmed by its action on cell growth: exogenous IGFBP-3 directly and significantly inhibited MDA-MB-231 cell number by 40%. These results provided circumstantial evidence that IGFBP-3 may mediate RA and TGF-beta2 growth inhibitory actions in human breast cancer cells. To test this hypothesis, we used an antisense IGFBP-3 oligodeoxynucleotide (ODN) which specifically inhibits IGFBP-3 expression. The antisense IGBP-3 ODN dramatically blocked both RA- and TGF-beta2-induced increases in IGFBP-3 protein (90%) and mRNA levels (90%). This effect was not observed when RA- or TGF-beta2-exposed cells were treated with sense IGFBP-3 ODN. Moreover, antisense ODN did not significantly affect IGFBP-4 protein or mRNA levels, strongly supporting the specificity of the antisense IGFBP-3 ODN effect on IGFBP-3 mRNA. This specific effect of antisense IGFBP-3 ODN on IGFBP-3 protein and mRNA levels was accompanied by significant attenuation of the inhibition of cell proliferation attained with RA or TGF-beta2 (approximately 40% of either RA- or TGF-beta2-induced inhibition). The control sense IGFBP-3 ODN did not reduce the growth inhibition observed with either RA or TGF-beta2. These results indicate that IGFBP-3 is an important mediator of RA- and TGF-beta2-induced cell growth inhibition in human breast cancer cells.

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor protein for prostate cancer.

Insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) has been shown to have decreased expression in the progression from benign to malignant prostate epithelial cells (V. Hwa et al., J. Clin Endocrinol. Metab., 83: 4355-4362, 1998). The present study was undertaken to determine the effects of the re-expression of IGFBP-rP1 in a cell line from a model of human prostate cancer, M12, in which IGFBP-rP1 expression had been demonstrated to decrease from the parent epithelial cell, P69, to the malignant subline, M12. An IGFBP-rP1 cDNA encoding the protein was transfected into M12 cells in a plasmid that resulted in constitutive-expression of IGFBP-rP1. Clones of transfected M12 cells were selected for low (L) and high (H) levels of expression, and the plasmid vector alone was transfected into M12 as a control. After transfection, there was a marked alteration in the morphology of the M12 cells such that the H clones had an elongated appearance when compared with the M12 control cells. The M12 clones overexpressing IGFBP-rP1 had a dose-related increase in population doubling time, decreased colony formation in soft agar, an increased propensity to undergo apoptosis in response to 6-hydroxyurea, and decreased tumor formation in male athymic, nude mice. These data suggest that IGFBP-rP1 may have a suppressive effect on prostate cancer development.

Steroid hormone accumulation in human breast cyst fluid.

Elevated concentrations of peptide hormones have been described previously in human breast fluid. In the current study, the levels of cortisol, progesterone, testosterone, dihydrotestosterone, androsterone, androsterone sulfate, dehydroisoandrosterone, dehydroisoandrosterone sulfate, estradiol, estrone, estradiol sulfate, and estrone sulfate were measured. The levels of the four 17-ketosteroids and the two estrogen sulfates were markedly elevated over the plasma level, while that of the other compounds was the same or only slightly higher than the plasma levels of the same compounds.

PIP: As part of a program to explore whether a relationship existed between the compounds present in breast cyst fluid and the risk for breast cancer, concentrations of a wide variety of hormones, enzymes, tumor-associated antigens, and ions in breast cyst fluid were determined. In this report, the concentrations of steroid hormones in cyst fluid samples from the same population used for previously published studies of peptide hormone concentrations were measured. This study determined the levels of cortisol, progesterone, testosterone, dihydrotestosterone, androsterone, androsterone sulfate, dehydroisoandrosterone, dehydroisoandrosterone sulfate, estradiol, estrone, estradiol sulfate, and estrone sulfate. In previous studies, levels of peptide hormones were shown to be elevated in breast cyst fluid, and in this study, the levels of the 4 17-ketosteroids and the 2 estrogen sulfates were markedly elevated in the breast cyst fluid over the plasma level. The concentrations of the other compounds were either the same or only slightly higher than plasma levels of the same compounds. To date, however, no correlation has been obtained between the occurrence of breast cancer and levels of any of these assayed hormones.

Abnormal 24-hr mean plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer.

The 24-hr mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate were measured in 11 women with primary operable breast cancer, ages 31 to 78 years, and in 37 normal women, ages 21 to 75 years. In contrast to the marked and progressive decline of DHA and dehydroisoandrosterone sulfate concentration with age in the normal women, the concentrations of both steroids were age invariant in the cancer patients. The premenopausal patients had subnormal plasma DHA and dehydroisoandrosterone sulfate levels, while the post menopausal patients had supranormal levels. Since the plasma DHA/androsterone ratio was normal in the premenopausal patients and significantly elevated in the postmenopausal patients, it is postulated that the subnormal plasma adrenal androgen levels in the premenopausal patients were due principally to diminished production of these steroids, while the elevated plasma levels in the postmenopausal patients were due principally to slowed metabolic removal. Reports in the literature that DHA inhibits the development of breast cancer in mice suggest that the subnormal plasma DHA levels in premenopausal breast cancer may have clinical significance.

Abnormal estrogen conjugation in women at risk for familial breast cancer at the periovulatory stage of the menstrual cycle.

The present study was designed to establish whether women with a family history of breast cancer exhibit endocrine abnormalities which could be responsible for their increased risk for the disease. Plasma hormone levels were measured every second day throughout the menstrual cycle in 30 women at risk for familial breast cancer and in an equal number of matched controls. Thirteen of the 14 substances measured exhibited no differences between the two populations, but plasma androsterone sulfate was significantly lower in the high-risk subjects. Thirteen urinary hormones were measured every day throughout the cycle with only the mean estrone and estradiol glucuronide but not estriol glucuronide content being significantly lower in the high-risk subjects. A compensatory increase in the urinary estrogen sulfates was observed. Daily analysis of these differences showed that they were most pronounced in thry day throughout the cycle with only the mean estrone and estradiol glucuronide but not estriol glucuronide content being significantly lower in the high-risk subjects. A compensatory increase in the urinary estrogen sulfates was observed. Daily analysis of these differences showed that they were most pronounced in thry day throughout the cycle with only the mean estrone and estradiol glucuronide but not estriol glucuronide content being significantly lower in the high-risk subjects. A compensatory increase in the urinary estrogen sulfates was observed. Daily analysis of these differences showed that they were most pronounced in the periovulatory period of the cycle. These results suggest that the genetic risk for breast cancer is associated with an abnormality in estrogen conjugation at a specific time of the ovulatory cycle.

Plasma hormone profiles of young women at risk for familial breast cancer.

The plasma hormone concentrations of 30 young women, who were judged by genetic analysis to be at high risk for familial breast cancer, were compared with those of 30 matched controls identified as at low risk for the disease. The hormone measurements were obtained every second day throughout the menstrual cycle, and the results were analyzed in terms of follicular, luteal, and full-cycle mean concentrations. Comparison was carried out in a paired fashion with each high-risk and low-risk pair matched closely for height, weight, age, and reproductive history. No statistically significant differences were found in prolactin, gonadotropin, estrone, estradiol, or estriol plasma concentrations although the high-risk group displayed consistently lower values in all of the above except estriol.

GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.

Insulin-induced loss of insulin-like growth factor-I receptors on IM-9 lymphocytes.

Preexposure of IM-9 lymphocytes to the somatomedin peptide insulin-like growth factor-I (IGF-I) results in a time- and concentration-dependent reduction in specific receptors for IGF-I. Since insulin and proinsulin are structurally homologous to IGF-I, we investigated the ability of insulin analogues to compete for occupancy and to directly modulate IGF-I receptor concentrations. IGF-I binds rapidly and reversibly to IM-9 cells at 15 degrees C, with half-maximal displacement of 125I-I-IGF-I at IGF-I concentrations of 3.6 X 10(-9) M and insulin concentrations of 5 x 10(-7) M. Preexposure of cells at 37 degrees C to either IGF-I or insulin produced a concentration-dependent reduction in binding of 125I-IGF-I. A 50% decrease in binding was observed following preincubation of cells with IGF-I at 2.5 x 10(-9) M and insulin at 2 x 10(-7) M. At higher insulin concentrations (10(-6)-10(-5) M), up to 70% reduction in 125I-IGF-I binding occurred. Bovine proinsulin and guinea pig insulin competed less potently than porcine insulin for the IGF-I receptor, and produced receptor loss in proportion to their ability to occupy the IGF-I receptor. Scatchard analysis indicated that at all insulin concentrations, the decrease in binding was secondary to loss of available IGF-I receptors, with no change in affinity. Receptor loss was evident following 1-2 h preexposure to insulin, with a t1/2 of 4 h and maximal receptor loss within 10 h. Similarly, IGF-I and IGF-II competed for occupancy of the IM-9 insulin receptor, with 50% displacement of 125I-insulin occurring at peptide concentrations of 3.5 x 10(-9) M (insulin), 3.5 x 10(-8) M (IGF-II), and 3 x 10(-7) M (IGF-I). Preexposure of cells to these peptides at 37 degrees C for 20 h resulted in a concentration-dependent reduction in binding of 125I-insulin, with the order of analogue effectiveness being insulin greater than IGF-II greater than IGF-I. These data emphasize the structural and functional homology of insulin and the somatomedin peptides, IGF-I and II, as well as their respective receptors. Additionally, the data support the conclusion that the insulin and somatomedin peptides not only bind to both receptors, but downregulate each receptor in proportion to their ability to occupy that receptor.