Developmental and sex-related changes of the growth hormone axis in lean and obese Zucker rats.

The development and sex-related changes in the hypothalamic-pituitary GH axis were examined in lean and obese Zucker male and female rats from 6 to 12 weeks of age. Pituitary GH content was not different in any phenotype/sex group at 6 weeks. GH content increased with age in male rats, but at 10 and 12 weeks content was decreased in obese male rats relative to lean rats. GH content did not increase in female rats and there was no difference in content between lean and obese female rats. Hypothalamic GHRH content was not different between the groups. Hypothalamic SS content was decreased in obese male rats compared to lean male rats (95%) and in obese female rats compared to lean female rats (78%). Individual 6-hour plasma GH profiles from rats 6-7 weeks of age showed the characteristic sexually dimorphic GH secretory patterns. However, spontaneous GH secretion was dramatically reduced in obese animals when compared to sex-matched lean rats. GH peak amplitude (25% of lean) and mean GH concentration (19% of lean) were decreased in obese male rats without a significant alteration in GH peak frequency or baseline level. In obese female rats, the number of GH peaks, peak amplitude, baseline GH, and mean GH concentration were all decreased compared to lean. The reduction in peak amplitude (14% of lean) and in mean GH concentration (20% of lean) was similar to the reduction in obese male rats. Serum IGF-I concentrations were not different among the groups at 6 weeks. IGF-I levels in male rats increased with age but were not different between lean and obese rats. IGF-I concentrations in female rats were unchanged with time and were not different between lean and obese rats. Serum insulin was increased in obese male and female rats at 6 through 12 weeks. We conclude (1) GH secretion is depressed at 6-7 weeks in obese male and female rats with the magnitude of reduction similar to previous observations in male rats 12 weeks or older; (2) pituitary GH content is depressed only in obese male rats and occurs after the defect in GH secretion; (3) hypothalamic GHRH content is unchanged and hypothalamic SS is slightly to moderately decreased in obese rats; (4) serum IGF-I is not different between lean and obese rats; (5) obese male and female rats were hyperinsulinemic.(ABSTRACT TRUNCATED AT 400 WORDS)

Opiate stimulation of prolactin secretion is reversed by ovarian hormone treatment.

Previous studies have indicated that during the estradiol- and progesterone (P4)-induced surge in luteinizing hormone (LH), the effects of opiates on behavioral, autonomic and neuroendocrine functions are altered. In the present study, we further evaluated the apparent universality of alterations in opiate-mediated function during the LH surge by investigating the effects of morphine sulfate (MS) on prolactin (PRL) secretion during both the estradiol benzoate (EB) and the EB + P4-induced LH surges. All doses of MS tested (0.5, 2.0 and 5.0 mg/kg) resulted in significant increases in PRL secretion in nonestrogen-treated animals which did not show LH/PRL surges. During the LH/PRL surge induced by EB/P4 treatment, MS caused no change in the PRL secretion, while in EB/oil treated animals, a paradoxical and dose-dependent decrease in PRL secretion was observed. The suppression of PRL was 52, 68 and 80% of baseline respectively for the 3 doses of MS. Evaluation of the time dependence of MS on PRL secretion showed that the paradoxical suppression in EB/oil-treated animals was seen only during the LH/PRL surge, occurring at 17.30 h (7.5 h post P4 injection), and not before (12.30 h) or after (23.00 h) the steroid-induced LH/PRL surge. Finally, we assessed the role of pituitary dopamine receptors on the phenomenon of MS-induced PRL suppression in EB/oil rats. Domperidone (1mg/kg), a peripherally active D2 receptor antagonist, administered prior to the morphine challenge, attenuated the opiate-induced PRL suppression in EB/oil-treated animals suggesting that a dopaminergic mechanism is involved in this paradoxical response to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Opiate modulation of growth hormone secretion is compromised during the steroid-induced luteinizing hormone surge.

Earlier studies from our laboratory have shown that treatments with gonadal steroids which cause a surge of luteinizing hormone (LH) blunt the effects of morphine on LH secretion, locomotor activity, nociception and temperature regulation. The present study was conducted to determine if the growth hormone (GH) response to morphine sulfate (MS) was also affected during steroid-induced LH surges. Adult ovariectomized female rats were primed with estradiol benzoate (EB: -49 h prior to P4 or oil injection) and/or progesterone (P4; 10.00 h). Seven and one half hours after P4 treatment, at the time of the steroid-induced LH surge, the GH response to an intravenous dose of 0.5, 2.0 or 5.0 mg/kg MS was determined. A GH peak response occurred at 15 min after drug administration and was maximal at the dose of 2 mg/kg MS in all groups. Although the timing of the GH rise was not altered in either EB/oil- or EB/P4-treated animals, a significant blunting of MS-induced GH secretion was observed across all doses of MS with a greater reduction being observed in EB/P4-treated animals. In a second study the GH response to opiates was investigated prior to and following the steroid-induced LH surge to determine if the suppression of opiate-induced GH secretion was confined to the time of the preovulatory LH surge. Before the LH surge (2.5 h), a mild suppression of opiate-induced GH secretion was observed only in EB/oil-treated animals. After the LH surge (13 h after P4 administration), morphine-induced GH secretion was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of efficacy of cysteamine in depleting prolactin immunoreactivity in different hyperprolactinemic animal models.

We have examined the effects of cysteamine on its ability to deplete prolactin in various states of hyperprolactinemia. Administration of subtoxic doses of cysteamine (75 and 150 mg/kg,sc) dramatically reduces serum prolactin levels as well as pituitary prolactin content in a dose-dependent manner in estrogen-primed brown Irish ACI female rats. A similar dose-dependent decrease in anterior pituitary prolactin levels was observed in two ectopic prolactin secreting pituitary tumor models (MtTW15 and 7315a). However, a significant reduction in serum prolactin levels was seen in these same tumor bearing animals at only the 150 mg/kg dose of cysteamine. Interestingly, the prolactin content of each of the prolactin secreting tumors, although reduced by cysteamine administration, the effect was neither dose-dependent nor as dramatic as that observed in the anterior pituitary gland proper. These data demonstrate that cysteamine can significantly lower prolactin concentrations in hyperprolactinemia. Further, ectopic prolactin secreting pituitary tissue appears less sensitive to the prolactin-depleting effects of cysteamine. This latter finding may explain, in part, why serum prolactin levels were not as severely reduced in the ectopic tumor bearing female rats as in estrogen-induced hyperprolactinemic animals.

Growth hormone secretion in the obese male rat: modulation by the gonadal and thyroid axes.

The present study was designed to determine if either the testes or thyroid plays a role in the blunted GH secretion observed in the obese male rat. Analysis of individual GH secretory profiles in adult lean and obese Zucker rats revealed a severe attenuation of both mean GH levels and individual GH pulse amplitudes in obese rats as well as a significant lowering of circulating testosterone levels. Normalization of the testosterone levels by the use of sc Silastic capsules elevated but did not normalize GH pulse amplitudes in obese animals. Further, the GH response to either rat GH-releasing factor (5 mu/kg) or morphine (1 mg/kg) were reduced in obese male rats. In contrast, the thyroid axis showed minimal change in obese animals. A slight reduction in free T3 levels in serum was observed while free and total T4 and total T3 were normal in obese rats. Further, mean circulating TSH levels and the TSH response to 500 ng/kg TRH were not altered in fat rats. Thus, the reduced GH secretion observed in the obese rat is not paramount to an alteration in either gonadal or thyroid function. This alteration of the GH secretory axis may not be attributable to one factor but more likely caused by a number of concomitant deficits which may act in concert to manifest impaired GH secretion.

Growth hormone (GH) secretory dynamics in animals administered estradiol utilizing a chemical delivery system.

We have utilized a redox chemical delivery system (CDS) for the brain targeting of estradiol (E2) to ascertain its effects on GH secretory patterns in adult intact male rats. The E2-CDS (1.0 mg/kg) dissolved in 20% hydroxypropyl-cyclodextrin (HPCD), E2 (1.0 mg/kg) alone in 20% HPCD, or 20% HPCD was administered intravenously. GH secretory profiles, plasma steroid levels, and anterior pituitary levels of hormones were determined 1 week following steroid injection. Whereas E2 in HPCD and HPCD treatment did not alter masculine GH secretory patterns, animals administered the E2-CDS displayed disrupted GH patterns with attenuated individual pulse amplitudes and significantly elevated GH baseline levels. Moderate pituitary hyperplasia was evident only in the E2-CDS group of animals. Plasma testosterone (T) concentrations were reduced in only the E2-CDS group. T replacement reduced E2-CDS-associated pituitary hyperplasia and preserved the masculine GH secretory profiles, with only a slight reduction in individual GH peak amplitudes being observed. T replacement did not prevent the increase in pituitary and plasma levels of PRL associated with E2-CDS treatment but did block both the increase in pituitary GH content and the hyperplasia associated with prolonged E2 exposure. E2 given alone induced a significant increase in both GH and PRL in the pituitary without establishment of pituitary hyperplasia or elevated plasma PRL levels. These data indicate that E2-CDS is an effective mode of steroid administration. Changes in GH secretory dynamics, pituitary levels of GH, and degree of hyperplasia are dependent upon the chemical design of the delivery system for E2. Concomitant T therapy can prevent some of the changes in GH secretion associated with high-dose E2 exposure.

Growth hormone and thyrotropin secretory profiles and provocative testing in aged rats.

The impact of aging on both basal and induced GH and TSH secretion in male and female rats was investigated. Analysis of the individual GH secretory profiles in young (3-4 month) and old (19-20 month) rats indicated that sex-dependent patterns of GH secretion was preserved in old animals. However, we observed a reduction of individual GH peak amplitudes of 66% in old males and 53% in old females when compared to their respective young animals. Further, the GH response to an intravenous bolus of GH-releasing factor (GRF), morphine and clonidine was dramatically blunted or absent in old male and female animals. In contrast to GH, basal TSH secretion was elevated, while the TSH response to thyrotropin-releasing hormone (TRH) was not significantly affected in old animals of either sex. The present data provide evidence that reduced pituitary sensitivity to GRF may be a possible cause for reduced GH secretion in old animals. Further, the elevation in plasma TSH observed in old animals is not the result of an increased pituitary sensitivity to TRH.