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1.  Dehydroepiandrosterone Restoration of Growth Hormone Gene Expression in Aging Female Rats, in Vivo and in Vitro: Evidence for Actions via Estrogen Receptors 
Endocrinology  2005;146(12):5176-5187.
A decline in dehydroepiandrosterone (DHEA) and GH levels with aging may be associated with frailty and morbidity. Little is known about the direct effects of DHEA on somatotropes. We recently reported that 17β-estradiol (E2), a DHEA metabolite, stimulates the expression of GH in vitro in young female rats. To test the hypothesis that DHEA restores function in aging somatotropes, dispersed anterior pituitary (AP) cells from middle-aged (12–14 months) or young (3–4 months) female rats were cultured in vitro with or without DHEA or E2 and fixed for immunolabeling or in situ hybridization. E2 increased the percentage of AP cells with GH protein or mRNA in the aged rats to young levels. DHEA increased the percentages of somatotropes (detected by GH protein or mRNA) from 14–16 ± 2% to 29–31 ± 3% (P ≤0.05) and of GH mRNA (detected by quantitative RT-PCR) only in aging rats. To test DHEA’s in vivo effects, 18-month-old female rats were injected with DHEA or vehicle for 2.5 d, followed by a bolus of GHRH 1 h before death. DHEA treatment increased serum GH 1.8-fold (7 ± 0.5 to 12 ± 1.3 ng/ml; P = 0.02, by RIA) along with a similar increase (P = 0.02) in GH immunolabel. GHRH target cells also increased from 11 ± 1% to 19 ± 2% (P = 0.03). Neither GH nor GHRH receptor mRNAs levels were changed. To test the mechanisms behind DHEA’s actions, AP cells from aging rats were treated with DHEA with or without inhibitors of DHEA metabolism. Trilostane, aminogluthemide, or ICI 182,780 completely blocked the stimulatory effects of DHEA, suggesting that DHEA metabolites may stimulate aging somatotropes via estrogen receptors.
doi:10.1210/en.2005-0811
PMCID: PMC1868401  PMID: 16150906
AP, Anterior pituitary; DHEA, dehydroepiandrosterone; E2, 17β-estradiol; ER, estrogen receptor; GHRH R, GHRH receptor; HPRT, hypoxanthine guanine phosphoribosyltransferase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; IOD, integrated optical density; ITS, insulin, transferrin, sodium selenite, and BSA; QRT-PCR, quantitative RT-PCR
2.  Estrogen Mediated Cross Talk Between the Ovary and Pituitary Somatotrope. Pre-ovulatory support for reproductive activity. 
doi:10.1016/j.mce.2005.12.049
PMCID: PMC1751516  PMID: 16443322
GH; estrogen; GHRH; mRNA; estrous cycle; Immunocytochemistry; in situ hybridization; in vitro; rat
3.  Bipotential Effects of Estrogen on Growth Hormone Synthesis and Storage in Vitro 
Endocrinology  2004;146(4):1780-1788.
Increased pulses of serum GH coincide with rising estrogens during the reproductive cycle, suggesting estrogen regulation. However, there is lack of agreement about estrogen’s direct effects on the pituitary. Pituitaries from cycling female rats were dispersed and plated for 24 h in defined media containing vehicle or 0.001–250 nM 17β-estradiol. Estrogen (0.01–10 nM) increased the percentages of GH antigen-bearing cells in the anterior pituitary significantly (1.3- to 1.6-fold) and 0.01–1 nM concentrations also stimulated significant increases in GH mRNA-bearing cells and in the integrated OD for GH mRNA. However, 100–250 nM either had no effect or, inhibitory effects on the area of label for GH mRNA. To test estrogen’s effects on expression of GHRH receptors, cultures were stimulated with biotinylated analogs of GHRH and target cells detected by affinity cytochemistry. Estrogen increased GHRH target cells in populations from rats in all stages of the cycle tested. Basal expression of GHRH target cells declined at metestrus. Cultures treated with 0–1 nM estrogen were then dual labeled for bio-GHRH followed by immunolabeling for GH with the antirabbit IgG-ImmPRESS peroxidase polymer. Over 98% of GH cells bound GHRH and 90–96% of GHRH-bound cells contained GH in all treatment groups. Thus, low concentrations of estrogen may stimulate expression of more cells with GH proteins, biotinylated GHRH binding sites, and GH mRNA, whereas high concentrations have no effect, or may reduce GH mRNA. These bipotential effects may help explain the different findings reported in the literature.
doi:10.1210/en.2004-1111
PMCID: PMC1751515  PMID: 15618363
ABC, Avidin-biotin complex; AP, anterior pituitary; LSD, least significant differences
4.  Fasting and glucose effects on pituitary leptin expression. Is leptin a local signal for nutrient status? 
Leptin, a potent anorexigenic hormone is found in the anterior pituitary. The aim of this study was to determine if and how pituitary leptin-bearing cells were regulated by nutritional status. Male rats showed 64% reductions in pituitary leptin mRNA, but not serum leptin, 24 h after fasting, accompanied by significant 30-50% reductions in growth hormone (GH), prolactin, luteinizing hormone (LH), and 70-80% reductions in target cells for gonadotropin releasing hormone (GnRH) or growth hormone releasing hormone (GHRH). There was a 2—fold increase in corticotropes. Subsets (22%) of pituitary cells co-expressed leptin and GH and <5% co-expressed leptin and LH, prolactin, TSH, or ACTH. Fasting resulted in significant 55-75% losses in cells with leptin proteins or mRNA and GH or LH. To determine if restoration of serum glucose could rescue leptin, LH and GH, additional fasted rats were given 10% glucose water for 24 h. Restoring serum glucose in fasted rats resulted in pituitary cell populations with normal levels of leptin, GH, and LH cells. Similarly, LH and GH cells were restored, in vitro, after populations from fasted rats were treated for as little as 1 h in 10-100 pg/ml leptin. These correlative changes in pituitary leptin, LH and GH, coupled with leptin’s rapid restoration of GH and LH, in vitro, suggest that pituitary leptin may signal nutritional changes. Collectively, the findings suggest that pituitary leptin expression could be coupled to glucose sensors like glucokinase, to facilitate rapid responses by the neuroendocrine system to nutritional cues.
doi:10.1369/jhc.7A7214.2007
PMCID: PMC2085236  PMID: 17595338
Pituitary; Leptin; Growth Hormone; Luteinizing hormone; Adrenocorticotropin; Fasting; Glucose treatment; Cytochemistry; Cell culture; QRT-PCR; Rat
5.  Does the pituitary somatotrope play a primary role in regulating GH output in metabolic extremes? 
Circulating growth hormone (GH) levels rise in response to nutrient deprivation and fall in states of nutrient excess. Since GH regulates carbohydrate, lipid and protein metabolism, defining the mechanisms by which changes in metabolism alters GH secretion will aid in our understanding of the cause, progression and treatment of metabolic diseases. This review will summarize what is currently known regarding the impact of systemic metabolic signals on GH-axis function. In addition, ongoing studies using the Cre/loxP system to generate mouse models with selective somatotrope resistance to metabolic signals, will be discussed, where these models will serve to enhance our understanding of the specific role the somatotrope plays in sensing the metabolic environment and adjusting GH output in metabolic extremes.
doi:10.1111/j.1749-6632.2010.05913.x
PMCID: PMC3444739  PMID: 21388406
growth hormone; somatotrope; fasting; obesity
6.  Anterior Pituitary Leptin Expression Changes in Different Reproductive States: Stimulation, in vitro, by Gonadotropin Releasing Hormone (GnRH) 
This study was designed to learn more about the changes in expression of rat anterior pituitary (AP) leptin during the estrous cycle. QRT-PCR assays of cycling rat AP leptin mRNA showed 2—fold increases from metestrus to diestrus followed by an 86% decrease on the morning of proestrus. Percentages of leptin cells increased in proestrus and pregnancy to 55–60% of AP cells. Dual labeling for leptin proteins and growth hormone (GH) or gonadotropins, showed that the rise in leptin protein-bearing cells from diestrus to proestrus was mainly in GH cells. Only 10–20% of leptin cells in male or cycling female rats co-express gonadotropins. In contrast, 50–73% of leptin cells from pregnant or lactating females co-express gonadotropins and only 19% co-express GH, indicating plasticity in the distribution of leptin. Leptin cells expressed GnRH receptors; and estrogen and GnRH together increased the co-expression of leptin mRNA and gonadotropins. GnRH increased cellular leptin proteins 3–4X and mRNA 9.8X in proestrous rats and stimulated leptin secretion in cultures from diestrous, proestrous and pregnant rats. These regulatory influences, and the high expression of AP leptin during proestrus and pregnancy, suggest a supportive role for leptin during key events involved with reproduction.
doi:10.1369/jhc.6A7072.2006
PMCID: PMC1780073  PMID: 17046838
Leptin; Anterior pituitary; gonadotropes; somatotropes; gonadotropin-releasing hormone; estrous cycle; pregnancy; lactation; males; rat; QRT-PCR; in situ hybridization; immunolabeling

Results 1-6 (6)