Neonatal Steroid Treatment Research Articles

Intrauterine growth restriction and postnatal steroid treatment effects on insulin sensitivity in preterm neonates

Objectives: To study whether intrauterine growth restriction (IUGR) is associated with decreased sensitivity to the main fetal growth factor, insulin, and the effect of glucocorticoid therapy on insulin sensitivity in preterm infants. Study design: Newborn infants with a birth weight (BW) of< 1500 g were classified as appropriate for gestational age ([AGA], BW within ± 1 SD, n = 10), or small for gestational age ([SGA], BW <–2 SD, n = 13); 5 AGA infants and 8 SGA infants received systemic steroids. An abbreviated modified minimal model test was performed, consisting of sequential blood samples for glucose and insulin assays, and intravenous infusions of 0.3 g/kg glucose and 0.02 U/kg regular human insulin. The insulin sensitivity index (SI) was calculated using a computer program. Results: The basal insulin/glucose ratio (I/G) and SI did not differ between the AGA and SGA groups. Steroids did not influence the I/G nor the SI of AGA infants (10.2 ± 6.7 vs 8.2 ± 2.3), but decreased the SI in the SGA group (12.2 ± 5.1 vs 5.3 ± 2.7, P <.05). Conclusions: Insulin sensitivity of neonates can be measured by the modified minimal model. IUGR is not associated with impaired fetal glucose tolerance. Early neonatal steroid treatment decreases insulin sensitivity in SGA infants, which may contribute to their risk of having hyperglycemia. (J Pediatr 2002;141:472-6)

Effect of neonatal allylestrenol treatment and adult benzpyrene treatment on rat thymus glucocorticoid receptors

1. 1. Neonatal treatment with allylestrenol caused an increase in the number of glucocorticoid receptors in the thymus in the adult. 2. 2. Benzpyrene treatment of adult animals persistently reduced the glucocorticoid receptor number in rats that were not submitted to neonatal treatment. This effect was not observed in adult animals following neonatal treatment with allylestrenol. 3. 3. The experiment calls attention to the permanent effect of steroid imprinting and to the developmental stage dependence of the direction of imprinting. 4. 4. The effect of neonatal steroid treatment on a later steroid influence is also demonstrated.

Mast cells in the testis, epididymis and accessory glands of the rat: effects of neonatal steroid treatment.

Mast cells in the testis of control adult rats were found almost exclusively around subcapsular blood vessels. Discrete mast cells were distributed throughout the stroma of the epididymis and sex accessory glands. In neonatally estrogen-treated rats, a greater number of mast cells was present in the testicular interstitium, whereas no significant increase in the number of mast cells per square millimeter of stroma was found for the epididymis and sex accessory glands, despite stromal proliferation. On the other hand, androgen-treated rats did not have increased mast cell numbers in any organ. These results indicate that the increase in mast cell numbers was estrogen-dependent, specifically related to the testis and did not seem to be a consequence of the increase in the connective interstitial tissue.

Alteration of prolactin control in adult rats treated neonatally with sex steroids.

Androgenized, oestrogenized and control female and male rats were used to establish possible differences in the alteration of the prolactin control system. Neonatal treatment involved administration of oestradiol benzoate or testosterone propionate (TP) on days 1 and 5 to the males and on day 5 to the females. Oil-treated animals were used as controls. Plasma prolactin levels were measured in these animals during adulthood (a) before gonadectomy, performed on day 80, and 27 days after gonadectomy and (b) on the 2 days (at 10.00 and 17.00 h) after administration of a single dose of TP to gonadectomized animals. Oestrogenized rats had the highest plasma prolactin concentrations just before and after gonadectomy. Testosterone propionate increased plasma prolactin levels in all groups. This response was more notable in the female than in the male groups, and was highest in the oestrogenized animals. Temporal rhythms of the prolactin response to TP were daily, perhaps circadian, with increased levels in the afternoon compared with those in the morning. This pattern was not present in oestrogenized females and androgenized males. Results suggest (a) that oestrogens and androgens given neonatally differ in their ability to alter the prolactin control system, and (b) that females seem to be more sensitive than males to changes in hypothalamic differentiation induced by neonatal steroid treatment.

Sex differences in the response to neonatal steroid treatment in the Mongolian gerbil

The present study examines whether genetic male and female gerbils differ in response to neonatal steroid treatment as evidenced by the display of sexually dimorphic territorial marking behavior in adulthood. The advantage of this behavioral endpoint is that male and female marking differs only in frequency, permitting direct between-sex comparison of neonatal treatment effects. Females and day-2 castrated males received a single SC injection of 10 to 100 μg testosterone propionate (TP) or estradiol benzoate (EB) between birth and day-14 postpartum. Between 7 and 9 months of age, the territorial marking behavior response to exogenous TP was determined in all animals. Based on marking frequency, the time of greatest sensitivity to TP administered during the critical neonatal period occurred earlier in the male (days 3–5) than in the female (days 5–7). In addition females consistently showed greater sensitivity to given dose of either TP or EB than did males. EB was more effective than TP at the 10 μg dose in both sexes. These results indicate that sex differences exist in timing and steroid sensitivity in the sexual differentiation of the neural substrate regulating territorial marking behavior.

Depressed T Cells Following Neonatal Steroid Treatment

Fourty-four patients received two doses of 12.5 mg/kg of hydrocortisone or placebo on the first day of life in attempted therapy for respiratory distress syndrome. Follow-up studies were performed on survivors at 5 years of age in ten steroid-treated and seven placebo-treated respiratory distress syndrome subjects. There were no significant differences in growth, intelligence tests, or neurologic examinations in the patients assessed. Abnormal EEGs are present in both groups. Immunologic tests showed no differences in lymphocyte counts, immunoglobulin levels, diphtheria and tetanus antibody titers, or complement components. Diminished percentages of T lymphocytes were found in steroid patients (53%) compared to control subjects (69%). There were also increased percentages of lymphocytes with C3 receptors in steroid patients (20.1%) compared to control patients (13.8%). Episodes of otitis and/or pneumonia were documented in eight of 11 steroid-treated patients between the ages of 1 and 5 years, compared to two of seven patients in the placebo group in the same time period. It is concluded that large doses of steroids on the first day of life may induce lasting immunologic abnormalities and may predispose to an increased incidence of infections.

Ontogenesis of intestinal bile salt absorption in the neonatal rat.

In vitro uptake of taurocholate by weanling rat ileum was characterized. The neonatal development of the ileal mechanism was determined, and the effect of steroid treatment on this development was assessed. Mucosal uptake of taurocholate by ileum of 26-day-old and adult rats was linear with time and, when measured as a function of concentration, tended toward a plateau. Mucosal concentration of taurocholate was significantly reduced by metabolic inhibitors and was competitively inhibited by taurochenodeoxycholate. The capacity to concentrate taurocholate in ileal mucosa was undemonstrable in 12-day-old neonates, first appeared at 15 days, and reached adult levels by 26 days of age. Mucosal uptake of taurocholate by ileum of 12-day-old offspring of steroid-treated mothers or of 12-day-old neonates given dexamethasone directly was significantly increased over control values. The results indicate that the ileal bile salt absorption found in weanling rats is an active process that does not begin to develop in neonatal rats until 15 days after birth, and that the appearance of ileal active transport can be accelerated by maternal or neonatal steroid treatment.

Masculinized female hamsters do not require steroid treatment when adult for activation of the male copulatory response pattern

(1) Female hamsters which received 500 μg testosterone propionate (TP) at 12 or 24 hr after birth displayed the male orienting response and copulatory pattern towards a lure female with frequencies and durations of response similar to those found in the normal male. (2) Injection of 250 μg estradiol benzoate (EB) at 12 or 24 hr after birth also resulted in the treated females displaying the male level of response towards a lure female for all elements of behavior measured except intromission. (3) Injection of either TP or EB at 48, 72, 96 or 120 hr after birth was less effective than 12 or 24 hr treatment for induction of the male orienting and copulatory pattern in the treated female. (4) Male hamsters given similar EB or TP treatment between 12 and 120 hr after birth showed no change in orienting or copulatory behavior towards a lure female. (5) All behavioral measures were made while the treated females were intact and not receiving any exogenous hormone treatment. This indicates that expression of the male orienting response and copulatory pattern by the female hamster as a result of neonatal steroid treatment (organizational event) is not dependent upon a series of hormone injections (activational event) in the adult animal.

Histometric study of the pituitary in mice treated neonatally with steroids and the relationship between prolactin cells and mammary tumorigenesis.

Neonatal female mice of the BALB/cC3H/Crgl strain were given daily injections of 17 beta-estradiol, progesterone and prolactin, singly and in some combinations, for 5 days beginning within 36 hr after birth. Mice were killed at tumor age or by 12 months of age. Differential cell counts of the anterior pituitary showed that prolactin cells were more numerous in neomatally estrogen-treated mice and progesterone-treated intact mice than in control mice. Paired analysis of tumor-bearing and non-tumor-bearing mice of all groups revealed that the occurrence of prolactin cells was greater in the former than the latter. Counts of gonadotropes and thyrotropes did not show any significant correlation with mammary tumorigenesis. However, neonatal estrogen and/or progesterone treatment resulted in significantly decreased numbers of gonadotropes in intact mice. In ovariectomized mice, gonadotropes were significantly increased regardless of neonatal treatment. The present results support the suggestion that the stimulatory effects of neonatal steroid treatment of mammary tumorigenesis may be a consequence of increased prolactin secretion, resulting from sustained minimal estrogen secretion by the ovary.

Long-Term Effects of Neonatal Steroid Exposure on Mammary Gland Development and Tumorigenesis in Mice2

Newborn female mice of three strains--BALB/cfC3H [mammary tumor virus (MuMTV)-infected], BALB/c, and C57BL (both virus-free)--were given injections of 17beta-estradiol or testosterone, alone or in combination with ovine prolactin, for the first 5 days of life. Half of each group of mice were ovariectomized at 40 days of age, and all mice were killed between 6 and 16 months of age. Mammary glands of BALB/cfC3H mice receiving steroid hormones were better developed than those of mice not receiving steroids. Androgen induced a higher incidence of grossly dilated ducts and secretion-filled alveoli. Mammary nodule and tumor incidences were higher in steroid-treated mice than in controls; androgen resulted in higher incidences than did estrogen. The age of onset of mammary tumors was also earlier after neonatal steroid treatment. In BALB/c mice, neonatal injections of estrogen induced some alveolar development of the mammary gland; neonatal injections of ovine prolactin had a greater effect. The mammary glands of C57BL mice did not show any evidence of stimulation by neonatal hormone treatment, which indicated the probability of strain differences. However, no nodules or tumors occurred in these MuMTV-free strains. Therefore, MuMTV was essential for neoplastic mammary responses to neonatal hormone treatment. Ovariectomy prevented alveolar development and abnormal changes in the mammary glands of all groups, thus indicating that ovary-independent alterations in the mammary gland were not induced by neonatal steroid treatment. We concluded that neonatal steroid exposure resulted in increased mammary tumor risk in mice, but only in the presence of both MuMTV and ovaries.

Action of testosterone administered neonatally on the rat perineal complex.

Wainman & Shipounoff (1941) found a stimulatory effect of testosterone upon the perineal complex. The development of perineal tissues may be altered by neonatal steroid treatment. Seminal vesicles of both rats and mice castrated at birth are more responsive to adult testosterone treatment, if the same hormone has been injected in early life (Tucker, 1964; Bronson, Whitsett, & Hamilton, 1972). The present experiments are concerned with such sensitization of the perineal complex (penis and its bulb and levator ani muscles). The object of this study was to examine the effect of neonatal androgenization on testosterone-induced nucleic acid synthesis in the levator ani muscles and to compare such results with the seminal vesicle, which is a relatively uncontaminated example of biochemical priming (Bronson et al. 1972). Seventy-four male Wistar rats from the randomly mated closed colony maintained in the Anatomy Department were used. Males were castrated on day 2 after birth

Effect of constant light and androgen-sterilization on the amine turnover of the tubero-infundibular dopamine neurons: blockade of cyclic activity and induction of a persistent high dopamine turnover in the median eminence.

ABSTRACT The dopamine (DA) turnover in the median eminence and in the neostriatum in the rat has been studied during the normal ovarian cycle, in rats exposed to constant light and in androgen-sterilized rats treated with the tyrosine hydroxylase inhibitor α-methyl-tyrosine-methylester. The rate of depletion of DA provides an estimation of the turnover and this can be evaluated semi-quantitatively by means of the highly sensitive and specific histochemical fluorescence method of Falck and Hillarp for the demonstration of catecholamines (CA). The results reveal cyclic turnover changes in the tubero-infundibular DA neurons during the ovarian cycle but not in the neostriatal DA neurons. The turnover is decreased during pro-oestrus and early oestrus. In the persistent oestrous rats, whether induced by constant light or by neonatal steroid treatment, no cyclic changes in DA turnover in the median eminence occurred. The turnover remained at a constant high level in these rats, similar to that found in dioestrus of normal cycling rats. The high oestrogen secretion in persistent oestrous rats was probably responsible for the high DA turnover, since in these rats castration caused a marked reduction in the DA turnover. Testosterone and oestrogen caused a dosedependent increase in DA turnover in the median eminence in androgensterilized castrated rats. The DA neurons of the androgen-sterilized castrated rats were found to be somewhat less sensitive to treatment with oestrogen than those of normal castrated rats. The present results support the view that the tubero-infundibular DA neurons participate in the inhibition of the cyclic release of LHRF and FSHRF from the median eminence and that the inhibitory feed-back action of oestrogen and testosterone is partly mediated via an increase in DA turnover and release in the median eminence, resulting in inhibition of LHRF and-FSHRF release.

Nature of Induced Persistent Vaginal Cornification in Mice. IV. Changes in the Vaginal Epithelium of Old Mice Treated Neonatally With Estradiol or Testosterone&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;

BALB/cCrgl female mice were treated with different doses of estradiol or testosterone for the first 5 days of life. Some mice in each group were ovariectomized at 110–120 days of age, and all mice were killed at 15–17 months of age. Vaginas, uteri, ovaries, adrenals, and mammary glands were examined, and the long-term effects of neonatal steroid treatment on these organs are described. Hyperplastic epithelial lesions resembling epidermoid carcinomas were found in the vaginas of both intact and ovariectomized mice treated with either steroid at dose levels associated with the induction of ovary-independent persistent vaginal cornification, although ovariectomy reduced the incidence of such lesions. Vaginal lesions also occurred in intact mice with ovary-dependent persistent estrus, but not in ovariectomized mice from these groups that had been treated with low steroid doses. It was concluded that the development of hyperplastic changes in the vaginal epithelium depends on factors which also control the development of persistent cornification, though vaginal hyperplasia is more frequently an ovary-dependent phenomenon.