Omid Khorram

Down-regulation of transcription factor peroxisome proliferator-activated receptor in programmed hepatic lipid dysregulation and inflammation in intrauterine growth–restricted offspring

OBJECTIVE Intrauterine growth-restricted (IUGR) newborns have increased risk of obesity-induced fatty liver and inflammation. We hypothesized that IUGR-induced inhibition of hepatic peroxisome proliferator-activated receptors (PPARs) is associated with an increased inflammatory response. STUDY DESIGN Rat control dams received ad libitum food, whereas study dams were 50% food restricted from pregnancy day 10 to 21 (IUGR). Pups were nursed by control dams and weaned to ad libitum feed. Hepatic protein expression of transcription factors, lipid enzymes, triglyceride content, and C-reactive protein (CRP) levels were analyzed in 1 day and 9 month old male offspring. RESULTS At 1 day of age, IUGR pups showed down-regulation of PPARalpha and PPARgamma and up-regulation of hepatic lipase and CRP. At 9 months of age, IUGR exhibited continued down-regulation of PPARalpha and PPARgamma with up-regulation of sterol regulatory element-binding protein-1 and fatty acid synthase. Furthermore, IUGR adults had increased hepatic triglyceride content and plasma CRP levels. CONCLUSIONS The results suggest that developmental hepatic dysregulation may contribute to programmed obesity-induced inflammation in IUGR offspring.

Physiologic role of nitric oxide and nitric oxide synthase in female lower urinary tract.

Purpose of review In recent years nitric oxide (NO) has gained increasing recognition as an important neurotransmitter and cell signaling molecule with a broad range of functions in the lower urinary tract. This review discusses recently published data related to the physiologic and pathophysiologic roles of NO and nitric oxide synthase (NOS) in the female lower urinary tract. Recent findings Expression of three isoforms of NOS, namely endothelial NOS, neuronal NOS and inducible NOS, has been identified in various tissues of the lower urinary tract in animals and humans. In addition to its relaxation effects on bladder and urethra, NO also serves as a neurotransmitter in the lower urinary tract. The physiologic roles of NO in overactive bladder, bladder outlet obstruction, diabetic cystopathy, interstitial cystitis, and bladder inflammation have been demonstrated. Summary NO plays an important role in the micturition process and in disorders of the lower urinary tract. Improved understanding of the pathophysiologic role of NO/NOS system and of the L-arginine-NO-cGMP pathway may allow us to identify suitable therapeutic targets for lower urinary tract disorders. However, there is a need for further investigation to determine the precise function of NO in human lower urinary tract because most work thus far has been done in animal models.

Nutrient restriction in utero induces remodeling of the vascular extracellular matrix in rat offspring.

The uterine environment may influence the development of chronic diseases later in life. The authors hypothesized that maternal nutritional restriction prenatally induces remodeling of offspring blood vessels such that they become stiff and contribute to the development of adult hypertension. To test this hypothesis, the authors studied the blood vessels of offspring of dams that were exposed to 50% maternal food restriction (MFR) from e10 to term as compared to age-matched controls. In aortas of MFR offspring, there was a significant increase in elastin and glycosaminoglycans (GAG) at 1 day of age. By 2 months of life, there was a significant increase in collagen and a decrease in GAG in MFR offspring aortas. A redistribution of elastin was also noted in MFR offspring, with a significant decrease in the interelastin laminae at both 1 day and 2 months. In mesenteric arterioles of MFR offspring, there was a decrease in GAG in 1-day-old and 2-month-old MFR offspring. There were no changes in elastin in both age groups in mesenteric arterioles, and by 2 months of life, collagen deposition was also found in these resistance vessels. There was a significant increase in expression of matrix metalloproteinase 9 (MMP-9) mRNA in 1-day-old MFR aortas, while both MMP-9 and MMP-2 expression was increased in the 4-month-old MFR aortas. These results indicate a significant remodeling of the extracellular matrix occurs in both conduit and resistance vessels. By 2 months of life, the compositions of both vessel types are consistent with stiff vessels, a contributing factor to hypertension.

Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial.

ObjectiveThis study aims to determine the dose-dependent effects of testosterone on sexual function, body composition, muscle performance, and physical function in hysterectomized women with or without oophorectomy. MethodsSeventy-one postmenopausal women who previously underwent hysterectomy with or without oophorectomy and had total testosterone levels less than 31 ng/dL or free testosterone levels less than 3.5 pg/mL received a standardized transdermal estradiol regimen during the 12-week run-in period and were randomized to receive weekly intramuscular injections of placebo or 3, 6.25, 12.5, or 25 mg of testosterone enanthate for 24 weeks. Total and free testosterone levels were measured by liquid chromatography–tandem mass spectrometry and equilibrium dialysis, respectively. The primary outcome was change in sexual function measured by the Brief Index of Sexual Functioning for Women. Secondary outcomes included changes in sexual activity, sexual distress, Derogatis Interview for Sexual Functioning, lean body mass, fat mass, muscle strength and power, and physical function. ResultsSeventy-one women were randomized; five groups were similar at baseline. Sixty-two women with analyzable data for the primary outcome were included in the final analysis. The mean on-treatment total testosterone concentrations were 19, 78, 102, 128, and 210 ng/dL in the placebo, 3-mg, 6.25-mg, 12.5-mg, and 25-mg groups, respectively. Changes in composite Brief Index of Sexual Functioning for Women scores, thoughts/desire, arousal, frequency of sexual activity, lean body mass, chest-press power, and loaded stair-climb power were significantly related to increases in free testosterone concentrations; compared with placebo, changes were significantly greater in women assigned to the 25-mg group, but not in women in the lower-dose groups. Sexual activity increased by 2.7 encounters per week in the 25-mg group. The frequency of androgenic adverse events was low. ConclusionsTestosterone administration in hysterectomized women with or without oophorectomy for 24 weeks was associated with dose and concentration-dependent gains in several domains of sexual function, lean body mass, chest-press power, and loaded stair-climb power. Long-term trials are needed to weigh improvements in these outcomes against potential long-term adverse effects.

Effect of maternal undernutrition on vascular expression of micro and messenger RNA in newborn and aging offspring

The aim of this study was to test the hypothesis that maternal undernutrition (MUN) alters offspring vascular expression of micro-RNAs (miRNAs), which, in turn, could regulate the expression of a host of genes involved with angiogenesis and extracellular matrix remodeling. The expression of miRNA and mRNA in the same aortic specimens in 1-day-old (P1) and 12-mo-old offspring aortas of dams, which had 50% food restriction from gestation day 10 to term, was determined by specific rat miRNA and DNA arrays. MUN significantly downregulated the expression of miRNAs 29c, 183, and 422b in the P1 group and 200a, 129, 215, and 200b in the 12-mo group, and upregulated the expression of miRNA 189 in the P1 group and 337 in the 12-mo group. The predicted target genes of the miRNAs altered in the two age groups fell into the categories of: 1) structural genes, such as collagen, elastin, and enzymes involved in ECM remodeling; and 2) angiogenic factors. MUN primarily altered the expression of mRNAs in the functional category of cell cycle/mitosis in the P1 group and anatomic structure and apoptosis in the 12-mo age group. Several of the predicted target genes of miRNAs altered in response to MUN were identified by the DNA array including integrin-beta(1) in the P1 aortas and stearoyl-CoA desaturase-1 in the 12-mo age groups. These results are consistent with the hypothesis that MUN modulation of offspring gene expression may be mediated in part by a miRNA mechanism.

Cigarette smoke inhibits endometrial epithelial cell proliferation through a nitric oxide–mediated pathway

OBJECTIVE To determine the direct effects of cigarette smoke (CS) on human endometrial surface epithelial cell line proliferation. DESIGN In vitro study using HES cells and primary human endometrial cells. SETTING University-based academic center. PATIENT(S) Premenopausal women in the proliferative phase of the cycle. INTERVENTION(S) The HES cells and primary human endometrial cells were exposed to cigarette smoke-saturated solution. MAIN OUTCOME MEASURE(S) Cell proliferation and expression of different isoforms of nitric oxide synthase. RESULT(S) Cigarette smoke inhibited HES cell proliferation in a dose- and time-dependant manner. The inhibitory effect of CS was blocked by hemoglobin and enhanced by L-arginine (L-Arg). Cigarette smoking and nicotine stimulated the expression of endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) whereas benzo[a]pyrene (BP) only stimulated the expression of eNOS in HES cells. Cigarette smoke stimulated the expression of eNOS/iNOS in primary human endometrial cells, comprised of epithelial and stromal cells. The effect of CS on eNOS/iNOS expression in HES cells was blocked by ascorbic acid but not by glutathione. CONCLUSION(S) Cigarette smoke inhibits endometrial cell proliferation through a nitric oxide-mediated pathway.

Maternal undernutrition induces premature reproductive senescence in adult female rat offspring.

OBJECTIVE To determine the effects of maternal undernutrition (MUN) on the reproductive axis of aging offspring. DESIGN Animal (rat) study. SETTING Research laboratory. ANIMAL(S) Female Sprague-Dawley rats. INTERVENTION(S) Food restriction during the second half of pregnancy in rats. MAIN OUTCOME MEASURE(S) Circulating gonadotropins, antimüllerian hormone (AMH), ovarian morphology, estrous cyclicity, and gene expression studies in the hypothalamus and ovary in 1-day-old (P1) and aging adult offspring. RESULT(S) Offspring of MUN dams had low birth weight (LBW) and by adult age developed obesity. In addition, 80% of adult LBW offspring had disruption of estrous cycle by 8 months of age, with the majority of animals in persistent estrous. Ovarian morphology was consistent with acyclicity, with ovaries exhibiting large cystic structures and reduced corpora lutea. There was an elevation in circulating T, increased ovarian expression of enzymes involved in androgen synthesis, an increase in plasma LH/FSH levels, a reduction in E2 levels, and no changes in AMH in adult LBW offspring compared with in control offspring. Hypothalamic expression of leptin receptor (ObRb), estrogen receptor-α (ER-α), and GnRH protein was altered in an age-dependent manner with increased ObRb and ER-α expression in P1 LBW hypothalami and a reversal of this expression pattern in adult LBW hypothalami. CONCLUSION(S) Our data indicate that the maternal nutritional environment programs the reproductive potential of the offspring through alteration of the hypothalamic-pituitary-gonadal axis. The premature reproductive senescence in LBW offspring could be secondary to the development of obesity and hyperleptinemia in these animals in adult life.

Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries.

Chronic hypoxia increases vascular endothelial growth factor (VEGF) and thereby promotes angiogenesis. The present study explores the hypothesis that hypoxic increases in VEGF also remodel artery wall structure and contractility through phenotypic transformation of smooth muscle. Pregnant and nonpregnant ewes were maintained at sea level (normoxia) or 3,820 m (hypoxia) for the final 110 days of gestation. Common carotid arteries harvested from term fetal lambs and nonpregnant adults were denuded of endothelium and studied in vitro. Stretch-dependent contractile stresses were 32 and 77% of normoxic values in hypoxic fetal and adult arteries. Hypoxic hypocontractility was coupled with increased abundance of nonmuscle myosin heavy chain (NM-MHC) in fetal (+37%) and adult (+119%) arteries. Conversely, hypoxia decreased smooth muscle MHC (SM-MHC) abundance by 40% in fetal arteries but increased it 123% in adult arteries. Hypoxia decreased colocalization of NM-MHC with smooth muscle α-actin (SM-αA) in fetal arteries and decreased colocalization of SM-MHC with SM-αA in adult arteries. Organ culture with physiological concentrations (3 ng/ml) of VEGF-A(165) similarly depressed stretch-dependent stresses to 37 and 49% of control fetal and adult values. The VEGF receptor antagonist vatalanib ablated VEGFs effects in adult but not fetal arteries, suggesting age-dependent VEGF receptor signaling. VEGF replicated hypoxic decreases in colocalization of NM-MHC with SM-αA in fetal arteries and decreases in colocalization of SM-MHC with SM-αA in adult arteries. These results suggest that hypoxic increases in VEGF not only promote angiogenesis but may also help mediate hypoxic arterial remodeling through age-dependent changes in smooth muscle phenotype and contractility.

Influence of progesterone on endometrial nitric oxide synthase expression

OBJECTIVE To determine the effect of P on nitric oxide synthase (NOS) expression in human endometrial epithelial cells. DESIGN Laboratory-based study. SETTING University-based research institute. PATIENT(S) None. INTERVENTION(S) The effect of P on the expression of NOS protein isoforms was examined in an in vitro preparation. MAIN OUTCOME MEASURE(S) The expression of NOS and phosphorylated endothelial NOS (peNOS) protein in human endometrial-derived epithelial cells (HES cells) and messenger RNA (mRNA) in human primary endometrial cell culture. RESULT(S) Progesterone induced a concentration- and time-dependent stimulation of endothelial NOS (eNOS), inducible NOS (iNOS), and peNOS protein in HES cells. Progesterone also stimulated eNOS and iNOS mRNA in human primary endometrial cells. The effect of P on eNOS and iNOS was completely blocked by RU486 but was partially blocked in case of phosphorylated eNOS. RU486 alone had an inhibitory effect on expression of eNOS but not iNOS protein at a concentration of 10(-5) mol/L. Progesterone stimulated phosphorylation of eNOS within 30 minutes, and this effect was completely blocked by an inhibitor of PI3/Akt pathway, wortmannin, and by the extracellular signal-regulated kinase 1,2 pathway blocker UO126. CONCLUSION(S) Progesterone has both genomic and nongenomic effects to stimulate the expression of NOS in HES cells. The nongenomic action of P on NOS phosphorylation is mediated by the PI3/Akt and extracellular signal-regulated kinase 1,2 pathways.

Use of growth hormone and growth hormone secretagogues in aging: help or harm.

Growth hormone (GH) is a 191-amino acid peptide, synthesized and secreted by the somatotropic cells of the anterior pituitary gland. It is secreted in pulsatile fashion, with two-thirds of daily secretion taking place at night, especially during slow-wave sleep. The synthesis and secretion of GH are the result of two hypothalamic peptides: growth hormone-releasing hormone (GHRH), which stimulates the synthesis and secretion of GH, and somatostatin, which has an inhibitory influence. Many of the target effects of GH are mediated by insulin-like growth factor I (IGF-I), which is predominantly produced in the liver. The secretion of IGF-I is regulated by GH. Growth hormone has anabolic, lipolytic, and antinatriuretic actions. It increases fat mobilization by hydrolysis of triglycerides into glycerol and free fatty acids. It also promotes redistribution of body fat from an abdominal (android) to a more peripheral (gynoid) distribution. Although in children GH is known to play a vital role in normal growth and development into adulthood, its physiologic function in adult life is unclear. In adults, a specific syndrome of GH deficiency with characteristic signs and symptoms has been recognized. These patients are overweight, with excessive body fat, and they have decreased extracellular water volume and a low bone mineral content. They have lipid abnormalities, decreased insulin sensitivity, and decreased fibrinolysis, and they have an impaired quality of life, with low energy. Many of the physical and metabolic changes in this syndrome are also found in normal aging. The age-associated decrease in the secretion of GH and its tissue mediator IGF-I has been termed “somatopause.” This decrease begins in the third decade of life for both GH and IGF-I secretion, and it is the result of a reduction of the net stimulation of the pituCorrespondence: Omid Khorram, MD, PhD, Department of Obstetrics and Gynecology, Box 489, Harbor–UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502. CLINICAL OBSTETRICS AND GYNECOLOGY Volume 44, Number 4, pp 893–901