Diurnal rhythm of testosterone secretion before and throughout puberty in healthy girls: correlation with 17beta-estradiol and dehydroepiandrosterone sulfate

The regulation of androgen synthesis during puberty in females is complicated, with changes in steroidogenic and peripheral interconversion capacity. In the present study we have investigated the diurnal rhythm of testosterone secretion in 56 healthy girls before and during puberty, up to 2 yr postmenarche. The girls' ages ranged between 4.6-16.5 yr, and their height SD scores ranged between -3.6 and +3.7. One to 5 serum profiles (seven samples per 24 h) were taken from each girl for steroid measurements, and a total of 84 serum profiles were obtained. Serum testosterone concentrations were determined using a RIA with a detection limit of 30 pmol/L. The results demonstrate that there is a diurnal rhythm of testosterone secretion during both prepuberty and puberty in girls. The pattern has its nadir in the late evening or just after midnight, with the highest levels in the morning (0600-1000 h). Serum testosterone concentrations in prepubertal girls were significantly lower than those in pubertal girls and were significantly lower in early puberty than in girls in mid- or late puberty. No differences were found in levels between girls in midpuberty or late puberty. Before puberty, serum testosterone concentrations correlated with serum dehydroepiandrosterone sulfate, consistent with the adrenals being the major source of testosterone. After the onset of puberty, a correlation between testosterone and 17beta-estradiol was seen, consistent with the ovaries being the major source of testosterone during puberty. Furthermore, the present study showed that there is a relative hyperandrogenicity in early puberty, with high levels of androgens relative to estrogens.     

Leptin secretion in Cushing's syndrome: preservation of diurnal rhythm and absent response to corticotropin-releasing hormone.

The normal inverse relationship between leptin and cortisol is lost in chronic hypercortisolism. We studied this apparent dysregulation in patients with Cushing's syndrome to investigate 1) the effect of chronic hypercortisolemia on the circadian rhythm of leptin secretion, 2) the response of leptin after administration of CRH, and 3) the short term effect of curative surgery on leptin. The preoperative morning leptin concentration was 54.2 +/- 8.1 ng/mL, and the nighttime value was 68.6 +/- 9.8 ng/mL, reflecting a mean rise of 32.8 +/- 7.6%, similar to the nocturnal increase observed in normal subjects. By contrast, cortisol's diurnal variation (21.8 +/- 1.7 vs. 16.9 +/- 1.1 mg/dL) was blunted. In women, but not men, body mass index correlated with leptin (P = 0.001). Preoperative ACTH and cortisol (both P < 0.0001), but not leptin levels increased after CRH. Ten days after surgery, basal cortisol values were subnormal (1.1 +/- 0.6 mg/dL), but leptin levels remained unchanged and did not increase after CRH. Body mass index and insulin also remained unchanged. Insulin, but not age, urinary free cortisol, or plasma cortisol correlated with leptin (P < 0.05). In summary, patients with Cushing's syndrome have moderately elevated leptin levels that maintain an intact circadian rhythm but do not respond to acute or subacute alterations of cortisol.     

Postnatal penile length and growth rate correlate to serum testosterone levels: a longitudinal study of 1962 normal boys

OBJECTIVE: Infant boys show a brief activation of their hypothalamic-pituitary-gonadal axis shortly after birth, the physiological significance of which is poorly understood. The objective of the study was to investigate the correlation between endogenous testosterone levels and penile size and growth. DESIGN: Prospective, longitudinal population-based study taking place at two large primary obstetric centres at the University Hospitals of Copenhagen, Denmark, and Turku, Finland. METHODS: Infant boys, 728 Danish and 1234 Finnish, underwent clinical examinations at 0, 3, 18 and 36 months in Denmark and at 0, 3 and 18 months in Finland with blood samples taken at 3 months (n = 630). Penile length and growth were registered and reproductive hormones (testosterone, sex hormone binding globulin, oestradiol) were analysed. RESULTS: Penile length increased from birth (3.49+/-0.4 cm) to 3 years of age (4.53+/-0.51 cm) with the highest growth velocity from birth to 3 months (1.0 mm/month). Penile length and growth were significantly, positively correlated to serum testosterone (r = 0.31 and 0.076, P = 0.006 and 0.001 respectively) and to free testosterone index (r = 0.385 and 0.094, P = 0.0001 and 0.0001 respectively). CONCLUSIONS: We found that endogenous testosterone was significantly associated with penile size and growth rate in infant boys. Thus, the postnatal surge in reproductive hormones appears to be important for genital growth. Our data may serve as an updated reference for normal penile length in Caucasian boys up to 3 years of age.     

Serum concentrations of free and total insulin-like growth factor-I, IGF binding proteins -1 and-3 and IGFBP-3 protease activity in boys with normal or precocious puberty

OBJECTIVE  Circulating IGF-I and IGF binding protein-3 (IGFBP-3) levels both increase in puberty where growth velocity is high. The amount of free IGF-I is dependent on the IGF-I level and on the concentrations of the specific IGFBPs. Furthermore, IGFBP-3 proteolysis regulates the bioavailability of IGF-I. However, the concentration of free IGF-I and possible IGFBP-3 proteolytic activity in puberty has not previously been studied.
SUBJECTS AND MEASUREMENTS  We investigated serum levels of easily dissociable IGF-I concentrations and ultrafiltrated free IGF-I levels by specific assays in 60 healthy boys and in 5 boys with precocious puberty before and during GnRH agonist treatment. In addition, total serum IGF-I, IGFBP-1 and IGFBP-3 levels as well as IGFBP-3 protease activity were determined.
RESULTS  Free (dissociable and ultrafiltrated) IGF-I concentrations were significantly higher in pubertal boys than in prepubertal children and correlated significantly with the molar ratio between IGF-I and IGFBP-3 ( r =0.69, P <0.0001 and r =0.54, P =0.0008, respectively) and inversely with IGFBP-1 ( r =−0.47, P <0.0001 and r =−0.43, P =0.0003, respectively). Multiple regression analysis suggested that IGFBP-3 level, and not IGFBP-1, was the major determinant of the free IGF-I serum level in normal boys. Free IGF-I levels were elevated in boys with precocious puberty and decreased during GnRH treatment. IGFBP-3 proteolysis was constant throughout puberty (mean 20%).
CONCLUSIONS  We conclude that easily dissociable and ultrafiltrated free IGF-I serum levels are increased in boys with normal and precocious puberty and suggest that the increased free IGF-I serum concentration in puberty primarily reflects changes in total concentrations of IGF-I and IGFBPs secondary to increased GH secretion, but that it is not influenced by changes in IGFBP-3 proteolysis.     

Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications

BACKGROUND: Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels. METHODS: We studied nine patients and nine controls, individually matched by gender, age (+/-5 yr), body mass index (+/-2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms. RESULTS: MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings. CONCLUSIONS: We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD.     

Intratesticular factors and testosterone secretion: the role of luteinizing hormone in relation to changes during puberty and experimental cryptorchidism

Testicular interstitial fluid (IF) from the rat contains a nongonadotropic polypeptide factor (or factors) which can enhance human CG (hCG)-stimulated testosterone production by Percoll-purified Leydig cells in vitro. The potential importance of this factor has been investigated by measuring its effective levels in testicular IF from individual rats during sexual maturation or after the induction of unilateral cryptorchidism (UCD). In both situations, the effect of modulating LH drive to the testis was also assessed. In abdominal testes from UCD rats, levels of the IF factor were nearly doubled (P less than 0.001) when compared to levels in the contralateral scrotal testis; this was associated with more than an 85% reduction in IF testosterone levels. Further lowering of testosterone levels by the injection of an antiserum to LH beta, raised levels of the IF factor by 30-40% (P less than 0.01) in both scrotal and abdominal testes. Conversely, raising of testosterone levels by injection of hCG caused more than a 90% reduction (P less than 0.001) in levels of the IF factor in both scrotal and abdominal testes. During sexual maturation, levels of the IF factor doubled (P less than 0.01) between 30 and 40 days of age, remained high until 70 days of age, and then decreased to the lower levels found in adult rats. High pubertal levels of the IF factor were associated with the most rapid phase of testicular growth and with a steady increase in the IF levels of testosterone. Injection of pubertal or adult rats with antiserum to ovine LH (oLH) reduced testosterone levels by approximately 85% and doubled (P less than 0.01) levels of the IF factor(s) in both groups. It is concluded that levels of the IF-factor are influenced: by testosterone levels and/or LH drive and by the maturational and/or functional status of the testis. These results also suggest that changing levels of the IF factor may be of physiological significance during puberty.     

Patterns of pulsatile luteinizing hormone secretion before and during the onset of puberty in boys: a study using an immunoradiometric assay

To study spontaneous pulsatile LHRH/LH secretion around the onset of puberty, nocturnal plasma LH was measured by means of a highly sensitive immunoradiometric assay in 30 boys (aged 5.6-16.8 yr) investigated for potential problems with growth and/or development. Blood was withdrawn at 10- to 20-min intervals from 2000-0800 h. Pulse analysis was accomplished by a computerized peak detection algorithm. Pituitary and gonadal responsiveness was assessed by a standard exogenous LHRH challenge and testosterone. Subsequent clinical progress was monitored for a mean duration of 2.08 +/- 0.16 yr and used as the basis for classifying patients retrospectively into three groups: 1) prepubertal (n = 14), 2) peripubertal (n = 11), and 3) pubertal (n = 5). LH pulses were undetectable in 9 and present in 5 prepubertal subjects, the youngest of whom was aged 7.3 yr. In peripubertal and pubertal individuals, 2-7 LH pulses/12 h were detectable. LH pulses were detectable before sleep by midpuberty (Tanner stage 3). There was a highly significant (P less than 0.0001) increase in LH/LHRH pulse frequency from 0.93 +/- 0.38 to 4.55 +/- 0.43/12 h (mean +/- SEM) between the prepubertal and peripubertal groups and a further increase to 6.20 +/- 0.37/12 h in the pubertal group. LH pulse amplitude remained under 1.0 U/L in both the prepubertal and peripubertal groups and only increased significantly to 2.02 +/- 0.17 U/L in pubertal boys. Response to LHRH increased significantly between the prepubertal (2.47 +/- 0.49 U/L) and peripubertal (6.53 +/- 2.02 U/L) patients. T increased significantly at each stage, with the greatest rise between the peripubertal and pubertal stages.(ABSTRACT TRUNCATED AT 250 WORDS)     

Septic shock and sepsis: a comparison of total and free plasma cortisol levels

CONTEXT: Severe systemic infection leads to hypercortisolism. Reduced cortisol binding proteins may accentuate the free cortisol elevations seen in systemic infection. Recently, low total cortisol increments after tetracosactrin have been associated with increased mortality and hemodynamic responsiveness to exogenous hydrocortisone in septic shock (SS), a phenomenon termed by some investigators as relative adrenal insufficiency (RAI). HYPOTHESIS: Free plasma cortisol may correspond more closely to illness severity than total cortisol, comparing SS and sepsis (S). DESIGN: This was a prospective study. SETTING: This study took place in a tertiary teaching hospital. PATIENTS: Patients had SS (n = 45) or S (n = 19) or were healthy controls (HCs; n = 10). AIM: The aim of the study was to compare total with free cortisol, measured directly and estimated by Coolens' method, corticosteroid-binding globulin (CBG), and albumin in patients with SS (with and without RAI) and S during acute illness, recovery, and convalescence. RESULTS: Comparing SS, S, and HC subjects, free cortisol levels reflected illness severity more closely than total cortisol (basal free cortisol, SS, 186 vs. S, 29 vs. HC, 13 nmol/liter, P < 0.001 compared with basal total cortisol, SS, 880 vs. S, 417 vs. HC, 352 nmol/liter, P < 0.001). Stimulated free cortisol increments varied greatly with illness category (SS, 192 vs. S, 115 vs. HC, 59 nmol/liter, P = 0.004), whereas total cortisol increments did not (SS, 474 vs. S, 576 vs. HC, 524 nmol/liter, P = 0.013). The lack of increase in total cortisol with illness severity is due to lower CBG and albumin. One third of patients with SS (15 of 45) but no S patients met a recently described criterion for RAI (total cortisol increment after tetracosactrin < or = 248 nmol/liter). RAI patients had higher basal total cortisol (1157 vs. 756 nmol/liter; P = 0.028) and basal free cortisol (287 vs. 140 nmol/liter; P = 0.017) than non-RAI patients. Mean cortisol increments in RAI were lower (total, 99 vs. 648 nmol/liter, P < 0.001; free, 59 vs. 252 nmol/liter, P < 0.001). These differences were not due to altered CBG or albumin levels. Free cortisol levels normalized more promptly than total cortisol in convalescence. Calculated free cortisol by Coolens' method compared closely with measured free cortisol. CONCLUSIONS: Free cortisol is likely to be a better guide to cortisolemia in systemic infection because it corresponds more closely to illness severity. The attenuated cortisol increment after tetracosactrin in RAI is not due to low cortisol-binding proteins. Free cortisol levels can be determined reliably using total cortisol and CBG levels.     

Hormonal changes in puberty III: Correlation of plasma dehydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with premature or late adrenarche.

In 104 normal boys, aged 7 to 14 years (bone ages 5 to 15 years), plasma dehydroepiandrosterone (DHEA) rose from 52.7 at 7 years, to 112.0 ng/100 ml at 10 years. A further rise occurred at 12 years (188 ng/100 ml). In relation to the bone age, DHEA increased from a mean plasma level of 31.1 at a bone age of 5 years to 77.1 ng/100 ml at one of 7 years. Further increases were observed with mean values of 163.2 at a bone age of 11 years, and of 221.2 at a bone age of 12 years, with a maximum of 333.4 ng/100 ml at bone ages of 14-15 years. The first significant increase of plasma testosterone (T) was noted at a bone age of 12 years (54.8 ng/100 ml). The major rise of T was preceded by the rise of plasma LH and was accompanied by the rise of plasma FSH. Plasma DHEA and T were also measured in 123 normal girls, ages 6 to 13 years (bone ages 5 to 15 years). DHEA rose significantly from a mean level of 44.7 at 6 years, to 80.9 ng/100 ml at 8 years, with further increases between 9 and 10 years and between 10 and 11 years. In relation to bone age, DHEA increased significantly from a mean plasma concentration of 30.9 at a bone age of 5 years, to that of 58.6 ng/100 ml at 7 years. Further increases were observed with values of 191.1 at a bone age of 10 years and 485.6 ng/100 ml at a bone age of 13 years. The first significant rise of testosterone (T) occurred at 10 years of both chronological and bone age. DHEA rose before the increase of gonadotropins. The major rise of T at a bone age of 10 years occurred concurrently with increases in plasma FSH and LH. Low levels of DHEA were observed in Addison's disease. In hypogonadotropin hypogonadism and in anorchia, DHEA levels were normal, suggesting that DHEA is produced primarily in the adrenal gland. In seven girls with early adrenarche, plasma concentrations of DHEA were in the upper range of normal values, whereas T levels were within the normal range. Conversely in girls with late adrenarche, plasms DHEA was lower than normal but T was within the normal limits. The elevation of DHEA prior to the first signs of puberty suggests that DHEA may play a role in the maturation of the hypothalamic-hypophysealgonadal axis. However, the mechanism that triggers the secretion of DHEA is not known.     

Individual variation in plasma testosterone levels and its relation to badge size in House Sparrows Passer domesticus: it's a night-and-day difference

The steroid hormone testosterone (T) plays a central role in the regulation of reproduction in animals. Although seasonal variation in T levels is well-studied, differences between day and night have only been described in relatively few species, and daily within-individual variation has been largely neglected when evaluating the relationship between T and the expression of sexual ornaments or behavior. We measured plasma T levels during day and night in a captive population of House Sparrows, and analyzed their relationship with an important male ornament - badge size. T levels were on average twice as high at night than during daytime. This was true in all seasons, and in both males and females. Disturbance of the birds at night, but not during the day, led to significantly lower T levels, suggesting a rapid drop after an individual wakes up. The relationship between T levels and badge size depended on the time when T was measured. During the breeding season, badge size was strongly positively correlated with night-time, but not with daytime T levels. This suggests that badge size signals information related to an individual’s maximum potential T level such as social dominance. Our study highlights that integrative research on the endocrine control of ornament expression needs to take diel variation in hormone levels into account.     

Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: evidence for stimulatory effects of low estrogen levels

This study investigated whether neonatal exposure of male rats to estrogenic compounds altered pubertal spermatogenesis (days 18 and 25) and whether the changes observed resulted in long-term changes in testis size, mating, or fertility (days 90-100). Rats were treated neonatally with a range of doses (0.01-10 microg) of diethylstilbestrol (DES; administered on alternate days from days 2-12), a high dose of octylphenol (OP; 2 mg administered daily from days 2-12) or bisphenol A (Bis-A; 0.5 mg administered daily from days 2-12), or vehicle, while maintained on a standard soy-containing diet. The effect on the same parameters of rearing control animals on a soy-free diet was also assessed as was the effect of administering such animals genistein (4 mg/kg/day daily from days 2-18). Testis weight, seminiferous tubule lumen formation, the germ cell apoptotic index (apoptotic/viable germ cell nuclear volume), and spermatocyte nuclear volume per unit Sertoli cell nuclear volume were used to characterize pubertal spermatogenesis. Compared with (soy-fed) controls, DES administration caused dose-dependent retardation of pubertal spermatogenesis on day 18, as evidenced by decreases in testis weight, lumen formation, and spermatocyte nuclear volume per unit Sertoli cell and elevation of the germ cell apoptotic index. However, the two lowest doses of DES (0.1 and 0.01 microg) significantly increased spermatocyte nuclear volume per unit Sertoli cell. Similarly, treatment with either OP or Bis-A significantly advanced this and some of the other aspects of pubertal spermatogenesis. Maintenance of control animals on a soy-free diet also significantly advanced lumen formation and spermatocyte nuclear volume per unit Sertoli cell compared with controls fed a soy-containing diet. Administration of genistein reversed the stimulatory effects of a soy-free diet and significantly retarded most measures of pubertal spermatogenesis. In general, plasma FSH levels in the treatment groups changed in parallel to the spermatogenic changes (reduced when pubertal spermatogenesis retarded, increased when pubertal spermatogenesis advanced). By day 25, although the changes in FSH levels largely persisted, all of the stimulatory effects on spermatogenesis seen on day 18 in the various treatment groups were no longer evident. In adulthood, testis weight was decreased dose dependently in rats treated neonatally with DES, but only the lowest dose group (0.01 microg) showed evidence of mating (3 of 6) and normal fertility (3 litters). Animals treated neonatally with OP or Bis-A had normal or increased (Bis-A) testis weights and exhibited reasonably normal mating/fertility. Animals fed a soy-free diet had significantly larger testes than controls fed a soy-containing diet, and this difference was confirmed in a much larger study of more than 24 litters, which also showed a significant decrease in plasma FSH levels and a significant increase in body weight in the males kept on a soy-free diet. Neonatal treatment with genistein did not alter adult testis weight, and although most males exhibited normal mating and fertility, a minority did not mate or were infertile. It is concluded that 1) neonatal exposure of rats to low levels of estrogens can advance the first wave of spermatogenesis at puberty, although it is unclear whether this is due to direct effects of the estrogen or to associated elevation of FSH levels; 2) the effect of high doses of OP and Bis-A on these processes is essentially benign; and 3) the presence or absence of soy or genistein in the diet has significant short-term (pubertal spermatogenesis) and long-term (body weight, testis size, FSH levels, and possibly mating) effects on males.     

Effect of melatonin on the reproductive systems of male and female Syrian hamsters: a diurnal rhythm in sensitivity to melatonin.

Hamsters were maintained on a long photoperiod (14L:10D) and were injected once daily with melatonin (10-25 mug) or sesame oil. Males which received melatonin during the afternoon (e.g., 6.5-13.75 h after lights-on) showed regressed testes and decreased levels of serum LH and FSH after several weeks of treatment. Injections of the oil vehicle or injections of melatonin given in the morning (3 h after lights-on) had no detectable effect on testicular size or on serum gonadotropins. Females which received melatonin during the afternoon became acyclic after several weeks of treatment and showed a diurnal pattern of LH secretion. The acyclic females required 4-6 weeks to resume estrous cyclicity following termination of the melatonin injections. The effects of melatonin on gonadal function and on serum gonadotropin concentrations in both sexes were similar to the previously observed effects of prolonged exposure to short photoperiods. These results indicate that chronic daily injections of melatonin can depress reproductive function in hamsters and that the effectiveness of the injections is dependent upon the time of day at which they are administered.     

Temperature and ration effects on components of the IGF system and growth performance of rainbow trout (Oncorhynchus mykiss) during the transition from late stage embryos to early stage juveniles

The study investigated the effects of incubation temperature, and the size of ration fed to the transitional embryo/juvenile stage of rainbow trout (Oncorhynchus mykiss) on growth, liver and gastrointestinal (GI) tract IGF-1 content, and the expression of insulin-like growth factor-related genes (IGF-1, IGF-2, IGF-RIa, and IGF-RIb) by the liver and GI tract. Embryos were reared from zygote to "swim-up" at either 8.5 degrees C (E(8.5)) or 6.0 degrees C (E(6.0)); at "swim-up" (51-days post-fertilization [dpf] and 72-dpf for the E(8.5) and E(6.0) groups, respectively), the embryos were transferred to grow-up tanks supplied with water at 8.5 degrees C. Late stage embryos (LSEs) at the same developmental stage from the two temperature treatment groups (64-dpf and 86-dpf for the E(8.5) and E(6.0) groups, respectively) were fed with salmonid starter diet at levels of 5.0%, 2.0%, and 0.5% of live body mass per day. Embryos were sampled just prior to first feeding (PFEs), and before complete absorption of the yolk [late stage embryos (LSEs)], and early stage juveniles (ESJs) were sampled after yolk sac absorption when they were fully reliant on exogenous sources of food. The early incubation temperature and ration levels had significant affects on mortality (with lower mortalities in the E(6.0) group) and growth performance of the fish; dry body mass values for fish fed the 5.0% ration were significantly lower in the E(6.0) group of LSEs and ESJs compared with the respective treatment in the E(8.5) group; a similar pattern was seen for total body length, although this was only significant for the LSEs. Whole embryo IGF-1 content was significantly lower in the E(6.0) group compared with the E(8.5) group of PFEs, and hepatic IGF-1 content was significantly lower in the E(6.0) group fed the maintenance ration (0.5%) compared with the E(8.5) fed a similar ration; restricted ration significantly elevated hepatic IGF-1 content in the LSE stage for both temperature treatment groups. GI tract IGF-1 levels were considerably lower than in liver tissue, and there were no differences among treatment groups. Ration size-related differences were found for the expression of genes encoding for hepatic IGF-1, IGF-2, and IGF-RIb, and GI tract IGF-1, and IGF-2. Rearing temperature-related differences were also found for genes encoding for GI tract IGF-1, IGF-RIa, and IGF-RIb. The results of the study showed that the early rearing temperature of the embryos affected subsequent growth, and hepatic and GI tract gene expression by the LSEs and ESJs. As was the case for tissue IGF-1 content, with some exceptions, a restricted ration significantly elevated the expression of the targeted genes indicative of an important metabolic-regulating role for the IGF system during this transitional developmental phase. In addition, the higher abundance of IGF-2 mRNA compared with IGF-1 mRNA, and the higher abundance of IGF-RIa, relative to IGF-RIb, suggests that these two genes may also play a regulatory role during this transitional developmental phase.     

The nutrition transition to a stage of high obesity and noncommunicable disease prevalence dominated by ultra-processed foods is not inevitable

The Nutrition Transition model is presented with the nature and pace of change in key stages varying by location and subpopulations. At present, all high-income and many low- and middle-income countries are in a stage of the transition where nutrition-related noncommunicable diseases including obesity, type 2 diabetes, and hypertension are dominating adult morbidity and mortality and are very high or growing rapidly in prevalence. Some countries still have key subpopulations facing hunger and undernutrition defined by stunting or extreme thinness among adults. We call these double burden of malnutrition countries. All low- and middle-income countries face rapid growth in consumption of ultra-processed food and beverages, but it is not inevitable that these countries will reach the same high levels of consumption seen in high-income countries, with all the negative impacts of this diet on health. With great political and civil society commitment to adoption of policies shown in other countries to have improved dietary choices and social norms around foods, we can arrest and even reverse the rapid shift to diets dominated by a stage of high ultra-processed food intake and increasing prevalence of nutrition-related noncommunicable diseases.     

Estrogen receptor gene polymorphism, but not estradiol levels, is related to bone density in healthy adolescent boys: a cross-sectional and longitudinal study

The purpose of the present study was to investigate the influence of estrogen receptor alpha gene polymorphism and estradiol on height and bone density during and after puberty in males. Using the restriction enzymes XbaI and PvuII, the allelic variants XX, Xx, xx, PP, Pp, and pp were identified in 90 Caucasian boys 16.9+/-0.3 yr of age (mean +/- SD). Bone mineral density (BMD; g/cm2) of the total body, head, femoral neck, and lumbar spine was measured using dual-energy x-ray absorptiometry. Volumetric BMD (vBMD; mg/cm3) was estimated for the spine. The XbaI or PvuII genotypes were not related to the levels of estradiol, and the levels of estradiol were not related to BMD (P > 0.05). The xx allelic variant was associated with a higher spine vBMD than the Xx allelic variant (361 vs. 340 mg/cm3, P = 0.04). In a multivariate analysis including pubertal development, physical activity, and body weight, the XbaI genotype independently predicted total body BMD, head BMD, and spine vBMD (P < 0.05). The PvuII genotype independently predicted spine vBMD (pp > PP, P = 0.01). The 20 boys with the PP allelic variant were found to have a greater body height than the other 70 boys (182 cm vs. 179 cm, P = 0.03). At a 2-yr follow-up the XbaI genotype was still independently related to total body BMD, head BMD, and spine vBMD. In conclusion, estrogen receptor gene polymorphism is related to bone density and height during late puberty and at attainment of peak bone density in young men.     

Identification of the cytochrome P-450 isozymes responsible for testosterone oxidation in rat lung, kidney, and testis: evidence that cytochrome P-450a (P450IIA1) is the physiologically important testosterone 7 alpha-hydroxylase in rat testis

Previous studies have shown that several forms of cytochrome P-450 present in rat liver microsomes oxidize testosterone with a high degree of regio- and stereospecificity. The aim of this study was to characterize the pathways of testosterone oxidation catalyzed by rat extrahepatic microsomes. Lung, kidney, testis, prostate, and brain were isolated from 3- and 14-week-old-male Sprague-Dawley rats. Microsomes from lung, kidney, and testis catalyzed distinctly different pathways of testosterone oxidation, whereas microsomes from prostate and brain failed to hydroxylate testosterone directly in a time- and protein-dependent manner. Lung microsomes from immature and mature rats converted testosterone to 16 alpha-hydroxytestosterone, 16 beta-hydroxytestosterone, and androstenedione. Lung microsomes were shown by Western immunoblot to contain cytochrome P-450b (P450IIB1), which has been shown previously to catalyze these three pathways of testosterone oxidation. Antibody against cytochrome P-450b strongly inhibited (greater than 80%) androstenedione formation and completely inhibited (greater than 95%) the 16 alpha- and 16 beta-hydroxylation of testosterone catalyzed by lung microsomes (as did carbon monoxide and antibody against NADPH-cytochrome P-450 reductase). Kidney microsomes from mature male rats converted testosterone to 2 alpha-hydroxytestosterone, 16 alpha-hydroxytestosterone, and androstenedione, whereas only the latter pathway was catalyzed by kidney microsomes from immature rats. Kidney microsomes from mature male rats were shown by Western immunoblot to contain cytochrome P-450h (P450IIC11), which has been shown previously to convert testosterone to 2 alpha-hydroxytestosterone, 16 alpha-hydroxytestosterone, and androstenedione. Antibody against cytochrome P-450h completely inhibited (greater than 95%) the 2 alpha- and 16 alpha-hydroxylation of testosterone by kidney microsomes, but had little effect on androstenedione formation, which is catalyzed by 17 beta-hydroxysteroid dehydrogenase. Testicular microsomes from mature, but not immature, rats catalyzed the 7 alpha-hydroxylation of testosterone. Previous studies have shown that this reaction is catalyzed in liver microsomes by cytochrome P-450a (P450IIA1). Testicular microsomes from mature, but not immature, rats were shown by Western immunoblot to contain cytochrome P-450a. Antibody against cytochrome P-450a or NADPH-cytochrome P-450 reductase completely inhibited (greater than 95%) the 7 alpha-hydroxylation of testosterone by testicular microsomes. A 90:10 atmosphere of carbon monoxide and oxygen did not appreciably block the 7 alpha-hydroxylation of testosterone by testicular microsomes, wh     

Coronary late lumen loss of drug eluting stents is associated with increased serum levels of the complement components C3a and C5a

ObjectiveDrug eluting stents (DES) reduce recurrent luminal narrowing through anti-migratory and anti-proliferative effects. However, recent concerns arose that DES may also induce significant chronic inflammatory responses that may impair vascular healing and lead to in-stent restenosis (ISR). As the complement components C3a and C5a exert particularly strong chemotactic and proinflammatory effects, we examined the association of serum levels of C3a and C5a and ISR after implantation of DES.MethodsWe included 82 patients that were treated with 151 DES. Blood samples were taken directly before and 24 h after PCI. Serum levels of C3a and C5a were measured by specific ELISA and restenosis was evaluated at 6–8 months by coronary angiography.ResultsC5a but not C3a increased after implantation of DES (p < 0.05). During the follow-up period, two patients (2.4%) died of cardiovascular causes and 12 patients (7.9% of stents, 15% of patients) developed ISR. Serum levels of C3a before and 24 h after PCI as well as C5a levels at baseline were significantly higher in patients that developed ISR at follow-up. C3a and C5a at baseline were significantly associated to angiographic late lumen loss independent from clinical and procedural risk factors.ConclusionIncreased complement activation as measured by higher levels of C3a and C5a before PCI is significantly associated with late lumen loss. Inhibition of the complement cascade to prevent ISR warrants further investigation.