Intermedin’s Role in FERTILITY
Intermedin, a peptide expressed in many of the body’s major organs, has been shown to have important benefits in establishing pregnancy. A new study seeks to discover how intermedin (IMD)—found in organs such as the gastrointestinal tract, lungs, placenta, uterus, and ovaries—is expressed during reproductive implantation.
Madhu Chauhan, PhD, led a team of investigators from the University of Texas at Galveston who examined human abortion tissues from 5–14 weeks pregnancies. The team reported finding the presence of IMD at day 5 after fertilization. IMD levels were significantly lower in the serum of pregnancies spontaneously aborted compared to electively aborted pregnancies.
In their article published in The Journal of Clinical Endocrinology & Metabolism, the authors say their study is the first to show a likely involvement of IMD in human embryo implantation and placental development via regulation of trophoblast invasion at the maternal-fetal interface. This suggests a physiological role for this novel peptide in establishment of human pregnancy, they added.
The researchers also reported that treatment with IMD may have positive effects on the outcomes of assisted fertilization procedures and further improve the success rates of fresh embryo transfer.
—Glenda Fauntleroy
Gene Affects FISH SEXUALITY
A newly discovered gene could play a role in the ability of some fish to change their sex as adults. When researchers led by Kataaki Okubo, PhD, of the University of Tokyo screened for genes in the medaka, a member of the large teleost family, they discovered a new member of the heme-binding protein gene family that they named hepb3. Expressed in the meninges, the membrane enveloping the brain parenchyma, hepb3 is a transcriptional target of estrogens of ovarian origin.
The expression of hepb3 appears to contribute to the development of sex differences in the teleost brain, the researchers write in Endocrinology.
—Eric Seaborg
GASTRIC BYPASS Device Aids in Diabetes Treatment
Obese patients with type 2 diabetes may have good results with a device used in gastric bypass surgeries, finds a study in The Journal of Clinical Endocrinology & Metabolism.
For one year, researchers evaluated 20 obese patients with diabetes who were implanted with a duodenal-jejunal bypass liner (DJBL). Participants all had a 10-year history of diabetes with hemoglobin A1c levels above 7.5 percent. At the end of study, patients lost an average of 6.5 kg and had significantly lower blood glucose levels.
The authors, led by Ricardo Cohen from the Center of Excellence of Metabolic and Bariatric Surgery in Brazil, concluded that the DJBL might represent an effective adjuvant to standard treatment of type 2 diabetes patients.
—Glenda Fauntleroy
Estrogen Mitigates Female Mid-Life MEMORY LOSS
Recently, scientists led by Jill M. Daniel, PhD, at Tulane University in New Orleans found that prior estradiol administration improved spatial memory in middle-aged rat dams and increased expression of the estrogen receptor a (ERa) in the hippocampus, but the impact duration was unknown. “Our data indicate that mid-life estrogen exposure can have positive impacts on memory and the hippocampus well beyond its period of exposure,” Daniel says of the scientists’ latest study.
In their paper, first published online in Endocrinology, the researchers report that ovariectomized dams treated wiThestradiol exhibited the expected enhancements in memory, as indicated by their better ability to navigate a maze 8 months postexposure, and hippocampal ERa expression compared to vehicle-treated controls. However, half of the hormone group was subsequently given the insulin-like growth factor-1 (IGF-1) receptor antagonist JB1, which disrupted the ERK/MAPK pathway necessary for activating IGF-1 and ERa receptors, with consequent decline in maze performance.
The researchers conclude that even short-term estrogen use during the “critical period” in recently menopausal women may confer long-term cognitive benefits. “Further, [our data] suggest that IGF-1, which can activate ERa via ligand-independent mechanisms, mediates the effects,” adds Daniel.
—Kelly Horvath
BPA Found in FETAL LIVERS
A new study has found the ubiquitous chemical bisphenol A (BPA) in the liver tissue of fetuses, raising concerns that not only are fetuses exposed to this endocrinedisrupting chemical, but they lack the ability to metabolize and eliminate it as adults do. BPA has been found in the urine of about 95 percent of the people who have been tested, but few studies have looked for it in tissues. Researchers led by Dana Dolinoy, PhD, of the University of Michigan School of Public Health in Ann Arbor, examined the livers of 50 first- and second-trimester fetuses from a fetal tissue bank for a study that can be found online in The Journal of Biochemical and Molecular Toxicology.
The researchers detected no conjugated BPA in a pair of adult liver specimens used as controls, whereas more than 70 percent of the fetal liver samples contained it. The amount varied widely, with some fetuses showing high levels of exposure. The fetal livers contained free BPA at levels three times those of the conjugated form, a notable finding because free BPA normally represents only 10 to 30 percent of total BPA in adult urine samples. A potential explanation for the difference is that the fetal livers contained low levels of several enzymes responsible for metabolizing the chemical compared with adult livers. Although BPA is hard to avoid given its widespread use in plastics and cans, its danger is sometimes downplayed because it is metabolized quickly. But this argument does not hold true in fetuses, according to Dolinoy.
The data indicates that BPA poses a greater risk to fetuses, which are unable to metabolize the compound as well as adults.
—Eric Seaborg
CORTISOL and INTERFERON TAU May Affect Pregnancy
The biological mechanics that occur in the uterus to support a fertilized egg during early pregnancy involve a complicated role of hormones, according to a new study.
Researchers investigated whether HSD11B1-derived cortisol has a biological role in endometrial function and embryo development during the early days of pregnancy in sheep.
In one of two separate experiments, for example, bred female sheep (ewes) were administered an inhibitor of HSD11B1 or recombinant ovine interferon tau at 10 to 14 days after being mated with fertile rams. The inhibition of HSD11B1 activity in the uterus was shown to prevent development of the embryo; however, interferon tau had a positive effect on embryo implantation in ewes that were administered prostaglandins.
“Our study provides novel insights into the biological roles of HSD11B1 and cortisol during early pregnancy,” says study author Thomas Spencer, PhD, of the Department of Animal Sciences at Washington State University.
In their article appearing in Endocrinology, the researchers conclude that interferon tau, prostaglandins, and cortisol together regulate endometrial functions crucial for the embryo development and implantation during early pregnancy in sheep.
—Glenda Fauntleroy
Teenage Girls Who Smoke Face Greater OSTEOPOROSIS RISK
Teenage girls who smoke accrue less bone during this critical growth period, which could raise their risk of osteoporosis later in life.
Researchers led by Lorah D. Dorn, Ph.D., of the Cincinnati Children’s Hospital Medical Center, looked at that the effects of self-reported smoking, symptoms of depression and anxiety, and alcohol use on bone accrual in 262 healthy girls aged 11 to 19. The girls received three annual clinical exams where they were measured for total body bone mineral content and bone mineral density (BMD).
A higher rate of smoking was associated with lower bone accrual, with the greatest impact seen in the lumbar spine region and the hips, areas of particular concern in osteoporosis. Bone mass was essentially equal among participants at age 13, but the difference grew as the girls progressed through their teen years. By age 19, a heavy smoker had foregone the equivalent of a year of BMD gain compared with a nonsmoker.
Girls who reported depressive symptoms had lower lumbar spine BMD, but their total bone mineral content was not affected. The researchers called this effect worrisome because it occurred at sub-clinical levels of depression. Alcohol use had no effect on any bone outcomes.
Studies in adults have shown a link between smoking and decreased bone health, the researchers write in the Journal of Adolescent Health, but this is the first to draw the link in the critical adolescent period, when 50 percent of bone accural occurs.
—Eric Seaborg
Swap Sugary Soda for COFFEE
Substituting a cup of coffee for a sugar-sweetened soda could lower one’s risk of diabetes, and caffeine doesn’t appear to be the difference.
That conclusion comes from a study comparing the effects of caffeinated and caffeine-free forms of coffee, tea, sugarsweetened beverages, and artificially sweetened beverages. A team led by Frank B. Hu, MD, MPH, PhD, of the Harvard School of Public Health, followed 75,000 women from the Nurses’ Health Study and 39,000 men from the Health Professionals Follow-up Study to look for an association between self-reported beverage consumption and the development of type 2 diabetes.
After the researchers controlled for major lifestyle and dietary risk factors, they found a significantly greater risk of diabetes among subjects with a higher intake of sugar-sweetened beverages, with or without caffeine, in both groups. Coffee consumption, with or without caffeine, was associated with a lower diabetes risk in both groups.
Despite some short-term metabolic studies that suggest caffeine increases blood glucose concentrations and decreases insulin sensitivity, the authors suggest in the American Journal of Clinical Nutrition that the association between sugary beverage consumption and diabetes is a result of sucrose and high–fructose corn syrup and not a joint effect of caffeine and sugar.
—Eric Seaborg
PCOS and the Brain
Polycystic ovarian syndrome (PCOS) affects more than 100 million women around the world and is a common cause of infertility and irregular menstrual cycles.
While the cause of PCOS is unknown, most women with the disorder show a significant increase in luteinizing hormone (LH) pulse frequency and decreased follicle stimulating hormone production, which is suggestive of increased gonadotropin-releasing hormone (GnRH) pulse frequency.
It is becoming increasingly clear that the syndrome may derive from altered regulation of reproduction by the brain,” says study author Rebecca Campbell, PhD, of the University of Otago School of Medical Studies in New Zealand.
In their study published in Endocrinology, researchers aimed to determine the negative and positive feedback effects of estrogens on the pituitary regulation of LH with the use of prenatal androgen (PNA)-treated mouse model of PCOS. Mice were administered estradiol and examined for hormonal changes and GnRH neuron activation. The study reported that PNA-treatment results in PCOS-like phenotype that included impaired estradiol negative feedback.
Researchers “hope to be able to advance what little understanding we have about the neuroendocrine pathology of PCOS in order to shape novel therapeutic targets and preventative technology for the future treatment of PCOS,” Campbell says.
—Glenda Fauntleroy
ROR Decrease Linked to LIVER DISEASE
Retinoid-related orphan receptors (RORs), intracellular transcription factors best known for their tissue development and circadian rhythm roles, are now the subject of a study suggesting a novel function. RORs negatively regulate SULT2A1 in rodents, but the mechanism remains unclear; moreover, their involvement with human SULT2A1 was unknown.
Wen Xie, MD, PhD, at the University of Pittsburgh School of Pharmacy, and his team used promoter reporter gene and electrophoretic mobility shift assays to demonstrate that RORs bind to ROR and constitutive androstane receptor (CAR) response elements found in the SULT2A1 gene promoter.
In their paper, to be published soon in Molecular Endocrinology, the researchers report a positive correlation between the expression of hydroxysteroid sulfotransferase (SULT2A1), an enzyme that detoxifies bile acids and deactivates androgens, and RORs in human livers, the converse of its negative regulation by RORs in rodents.
The researchers conclude that SULT2A1 is a transcriptional target of ROR and CAR.
—Kelly Horvath
EDVs May Improve PLACENTAL Overgrowth Treatment
Ectopic and molar pregnancies, along with placental accrete are characterized by placental overgrowth. A new drug delivery system under investigation may provide more effective and less invasive treatments.
Researchers from the University of Melbourne reported the results of a proof of principle study testing the EnGeneIC delivery vehicle’s (EDV) effectiveness in treating trophoblast growth on the placental surface. A proof of principle study occurs in the early stages of clinical drug development after a medication shows promising results in animals. Its purpose is to determine whether an investigation drug is active on a pathophysiological mechanism and works effectively.
In the current study, researchers discovered EDVs using a targeting antibody to pinpoint Epidermal Growth Factor Receptor on the placental surface provided a significantly greater uptake of the drug doxorubicin than the same system used without the targeted antibody or the drug used alone.
Researchers are finalizing phase I studies where they note the drug is tolerated in humans. University of Melbourne Associate Professor S tephen Tong says it’s conceivable researchers will soon be using the EDV system to deliver doxorubicin in drug trials to treat ectopic pregnancy, placenta accreta, and choriocarcinoma, the latter of which sometimes results from molar pregnancies. The study is to be published in Endrocrinology [endo.endojournals.org].
—Carol Bengle Gilbert
Adipokine Plays Role in Regulating FOOD INTAKE
The complex process of hormone signaling plays a key role in regulating food intake, and a new study points to a previously unsuspected role of plasminogen activator inhibitor 1 (PAI-1) in suppressing satiety signals from the upper gut.
PAI-1 is an adipokine that is present at higher levels in the plasma of obese individuals and in the stomachs of those infected with Helicobacter. It is known as the principal extracellular inhibitor of urokinase and tissue plasminogen activators, but its roles in gastric and metabolic functions have not been explored.
G.J. Dockray, PhD, and a team from the University of Liverpool in the U.K. used transgenic mice that overexpressed PAI-1 to look for the adipokine’s effects on gut-brain signaling. In wild type mice, the signaling peptide cholecystokinin inhibited food intake, but the mice that overexpressed PAI-1 in gastric parietal cells were insensitive to its signals. Infecting mice with H. felis increased the gastric abundance of PAI-1 and reduced the satiating effects of cholecystokinin. PAI-1 also inhibited cholecystokinin activity in cultured vagal afferent neurons.
In an article awaiting publication in Endocrinology, the researchers say this evidence that PAI-1 suppresses foodintake signals suggests that the links between adipokines and the gastrointestinal tract are stronger than hitherto supposed.
—Eric Seaborg
FETAL GROWTH RESTRICTION Linked to High Glucocorticoid Exposure
While fetal growth restriction affects between 4 and 8 percent of all pregnancies and has been strongly associated with stillbirth and neonatal deaths, the condition’s cause remains unknown.
In a new study published in Endocrinology, researchers examined whether increased exposure to glucocorticoids could play a role in fetal growth restriction by altering the fetus’ chorionic plate arteries and contributing to the change in blood flow.
“Glucocorticoids have potent effects on the blood vessels in the placenta that deliver oxygen and nutrients to the baby,” says author Rebecca Lee Jones, PhD, from the University of Manchester, United Kingdom. “These vessels constrict more following chronic exposure to glucocorticoids and this could contribute to the baby being growth restricted, due to reduced supply of nutrients to the baby.”
The study’s investigators examined placentas obtained soon after full-term vaginal and Caesarean deliveries and performed biopsies of the chorionic plates. They concluded that chronic exposure to elevated glucocorticoids did show increased vascular resistance.
Jones explained that women most at risk for chronic exposure to elevated glucocorticoids includes those who are stressed and will have raised levels of the stress hormone cortisol and women in threatened preterm labor who are given synthetic glucocorticoids to help to mature the premature baby’s lungs.
—Glenda Fauntleroy
Gas6 Linked to CHILDHOOD OBESITY
In the context of alarming rises in worldwide childhood obesity and concomitant metabolic disorders, most notably type 2 diabetes mellitus, clues to obesity’s pathogenesis are invaluable.
Fone-Ching Hsiao, MD, at the Taipei Medical University in Taiwan, led a team to follow the trail of one such clue. Growth arrest–specific 6 (Gas6), a vitamin K–dependent protein expressed widely in both immune and fat cells, has been shown to promote adipocyte survival in mice. Added to another clue that the presence of abundant immune cells within adipocytes corresponds with inflammation and insulin resistance, the researchers homed in on Gas6 as a potential mediator and determinant of adipocyte numbers, conducting a crosssectional study of 832 Taiwanese adolescents, average age 13.3 years, grouped as lean, overweight, or obese.
In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism, the researchers report that the overweight and obese groups had higher levels of circulating Gas6, which correlated positively with greater insulin resistance and circulating proinflammatory cytokine levels.
The researchers conclude for the first time that Gas6 plays a significant role in childhood obesity and its resulting diseasecausing inflammation. Future studies should clarify this role and whether it is a causative one, they add.
—Kelly Horvath
Lower Fat Consumption Contributes to WEIGHT LOSS
When it comes to weight loss, all calories are not created equal. Lee Hooper, PhD, at the University of East Anglia, United Kingdom, and her team of scientists turn the “calories in, calories out” aphorism on its head in an attempt to once more determine the ideal proportion of dietary fat.
Commissioned by the World Health Organization Nutrition Guidance Expert Advisory Group, meta-analyses of 33 randomized controlled trials, in North America, Europe, and New Zealand involving 73,589 men, women, and children, consistently showed that without changing total energy intake but reducing the proportion of fat for at least 26 weeks resulted in average weight loss of 3.8 pounds, a .51 loss in BMI, and a reduction in waist circumference of .3 centimeters. In their paper, published in British Medical Journal, the researchers report that each one percent reduction in fat intake corresponds to 0.67 pounds lost; they also report lower total cholesterol and low-density lipoprotein levels, total/ high-density lipoprotein ratio, and systolic and diastolic blood pressures.
“The results prove for the first time that weight loss can happen without trying to lose weight simply by choosing foods lower in fat,” says Hooper. Although the effect was the same regardless of type of fat, it makes sense to cut down primarily on saturated fat to also reap cardiovascular benefits along with weight loss, she adds.
—Kelly Horvath
Bisphosphonates Contribute to Atypical FEMUR FRACTURE
The debate continues: Does bisphosphonate use contribute to atypical, lowenergy femoral fracture risk as studies have suggested, or are other risk factors more pertinent?
Nicola Napoli, MD, PhD, at the Università Campus Bio-Medico di Roma, Italy, and Washington University in St. Louis, led a team to find out. The team used Study of Osteoporotic Fractures data, which uniquely included prospective risk factor data prior to patients sustaining fractures. Using radiographic reports (rather than ICD codes), they identified 45 subtrochanteric/ diaphyseal femur fractures out of a total of 1,722 hip and femur fractures among 9,704 women.
In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism, the researchers report increasing age, positive diabetes mellitus status, and low hip bone mineral density as independent risk factors for atypical femoral fractures as well as a marginal risk increase among bisphosphonate users (9 of the 45 women who sustained atypical fractures), which corresponds with other study findings. However, because their study was limited to U.S. white women over age 65 years, results may differ among other groups. Incidentally, the researchers also found a positive correlation between femoral neck hip fractures and oral steroid use and a negative correlation between atypical femur fractures and oral estrogen use.
Although incidence of the atypical fractures compared to other hip fractures as well as overall bisphosphonate use (11.7%) was low, the researchers conclude that bisphosphonate use cannot be excluded as a risk factor. Future studies should clarify how bisphosphonate use interacts with preexisting risk factors to contribute to increased fracture incidence, they add.
—Kelly Horvath
PHPT More Symptomatic in China
Primary hyperparathyroidism (PHPT), the third most common endocrinopathy in Western countries, is typically asymptomatic; however, in developing countries as recently as 1994, specifically China, it not only commonly presents acutely symptomatically but also with a different biochemical profile.
Jian-min Liu, PhD, at the Shanghai Jiao-tong University School of Medicine and the Shanghai Clinical Center for Endocrine and Metabolic Diseases, led a team of scientists to characterize any changes in the clinical picture of PHPT in Chinese patients visiting their clinic between 2000 and 2010 and determine what might contribute to symptom development.
In their paper, soon in The Journal of Clinical Endocrinology & Metabolism, the researchers report that both asymptomatic and total PHPT incidence increased and that serum calcium and parathyroid hormone (PTH) levels higher than 2.77 mmol/L and 316.3 pg/ dl, respectively, cause clinical manifestations including polydipsia, polyuria, urolithiasis, bone pain, and fatigue. Parathyroid carcinoma has decreased from its peak of 5.96 percent of cases, which was the highest rate worldwide, and all of those patients were symptomatic with significantly higher PTH levels.
Researchers conclude that PHPT in China is evolving clinically and biochemically, and they attribute the increase in diagnosis of asymptomatic PHPT to routine thyroid ultrasonography.
-Kelly Horvath
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