A look at the latest research

Mouse Model Pathways Could Predict Prostate Cancer Progression

Researchers have used mouse models to examine the complex interplay of several pathways to predict prostate cancer (PCa) progression, which can be diffi cult to analyze in humans. The study was published recently in Hormones and Cancer.

The investigators, led by Diane M. Robins, PhD, of the Department of Human Genetics at the University of Michigan, used mouse models designed to perturb sequentially androgen receptor (AR), ETV1, and phosphatase and tensin homolog (PTEN) pathways to examine the impact of common somatic mutations in PCa on AR signaling. Th e authors wrote that they humanized the mice with “AR (hAR) alleles that modified AR transcriptional strength by varying polyglutamine tract (Q-tract) length, and then these mice were crossed with mice expressing a prostate-specifi c, AR-responsive ETV1 transgene (ETV1 Tg).”

They found that ETV1 strongly antagonized global AR regulation and repressed androgen-induced diff erentiation and tumor suppressor genes, and when PTEN was varied to determine its impact on PCa’s progression, the mice lacking one PTEN allele (Pten +/−) developed more frequent prostatic intraepithelial neoplasia (PIN). “Yet,” Robins and her team wrote, “only those with the ETV1 transgene progressed to invasive adenocarcinoma. Furthermore, progression was more frequent with the short Q-tract (stronger) AR, suggesting that the AR, ETV1, and PTEN pathways cooperate in aggressive disease.” Upregulation of the gene Cxcl16 (a strong infl ammatory gene expression signature) was induced by ETV1.

The researchers concluded that concerted use of these mouse models “illuminates the complex interplay of AR, ETV1, and PTEN pathways in pre-cancerous neoplasia and early tumorigenesis, disease stages diffi cult to analyze in man.”

“Critical Window” of Menopause Hormone Therapy Examined

A new study from the University of Texas has looked at whether, when, and how long women should undergo hormone therapy for menopause. The results were published recently in Endocrinology.

The researchers, led by Andrea C. Gore, PhD, of the University of Texas, developed a rat model to test the “critical window” of the eff ects of timing and duration of estradiol (E2) treatment, since the loss of ovarian E2 necessitates the adaptation of estrogen-sensitive neurons in the hypothalamus to an estrogendepleted environment. They pointed out that “profound depletion of ovarian estrogens with menopause in women requires the resetting of, and adaptation to, a new homeostatic environment.”

Gore and her team ovariectomized rats at two different ages (reproductively mature or aging), then gave the rats E2 or vehicle replacement regimes of differing timing and duration. They identified gene modules differentially regulated by age, timing, and duration of the E2 treatment and found that E2 status differentially affected suites of genes in the hypothalamus involved in energy balance, circadian rhythms, and reproduction. “In fact,” the authors wrote, “E2 status was the dominant factor in determining gene modules and hormone levels; age, timing, and duration had more subtle effects.”

The authors concluded that these results “highlight the plasticity of hypothalamic neuroendocrine systems during reproductive aging and its surprising ability to adapt to diverse E2 replacement regimes.” They also noted that this result is of particular importance because of the ongoing debates about E2 replacement therapy, and the study provides “novel insights into how the timing and duration of E2 treatment and chronological age interact to affect expression of genes in the [arcuate nucleus (ARC) and the medial preoptic area (mPOA)] involved in neuroendocrine function.”

Late-Onset Central Hypogonadism May Not Be Associated with Gene Mutation

A study presented at ENDO 2015 looked at the case of a healthy 16-year-old male who presented with hypogonadism, as well as fatigue, depressed mood, cold intolerance, and decreased libido, symptoms which had been occurring for nine months prior to evaluation. Th e patient also said he had been under a lot of stress, as well as exercising strenuously, and restricting his diet. Th e patient was diagnosed with central hypothyroidism (CeH) and hypogonadotropic hypogonadism (HH) and was prescribed levothyroxine 100 mcg/ day to determine whether his HH was secondary to CeH.

According to lead author Angela Delaney, MD, a pediatric endocrinologist with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the patient “had a remarkable response with resolution of all symptoms, improved growth, with an additional 4 cm gained over the subsequent year with final height and weight at the 50th percentile, consistent with familial height. TSH after six weeks was 0.36 mcIU/ml (0.3 – 5.0), T3 was 130 ng/dL (80 – 200), and free T4 was 1.16 ng/dL (0.7 – 2.0). After four months on therapy, he reported normal sexual function and libido and total testosterone was 376 ng/dL (262 – 1593). The patient has remained in good health on levothyroxine therapy.”

The researchers then collected genomic DNA and sequenced the IGSF1 gene to determine the etiology of this clinical presentation of CeH with testicular enlargement despite biochemical evidence of HH. “No mutations in IGSF1 were identified,” they wrote. This led the team to the conclusion that the patient’s testicular volume was likely normal due to the onset of HH occurring in late puberty and did not represent macroorchidism in combination with CeH due to a mutation in the coding sequence of IGSF1. “This suggests that late-onset CeH may not be associated with IGSF1 mutations,” they wrote.

CeH usually presents much earlier, and Delaney and her team knew they would probably not find any mutations in the genes that they screened, because those phenotypes are usually associated with an earlier onset presentation. The IGSF1 gene has been described as having a somewhat more variable presentation, and since the patient’s symptoms pointed to the gene as a possible culprit, they thought it was worth screening. “We weren’t surprised that he did not have a mutation in that gene,” Delaney says, “because it didn’t exactly fit the phenotype, but we were curious.”

“What evolved and became more interesting over time was that his condition was reversible,” Delaney says. “In the end, we believe it was a combination of significant stress… because once all those things reversed, he recovered,” she says.

The implications of the study, according to Delaney, is that we tend to think of this hypothalamic dysregulation as only occurring in women, but we know that stress, strenuous exercise, and/or a restricted diet can be associated with hypogonadism and can affect multiple hypothalamic hormones. “But we really don’t think about it in a male population,” Delaney says. “It’s clearly not as common in men, but if you look back at the literature and cases like his, it’s clear that it does happen in some cases, and so the implication is that we should think about it.”

“Down the line, it’ll be interesting to have a better understanding of what the factors are that might make one man susceptible to it, compared to the rest of the men who don’t experience that,” she says.

Prevalence of Metabolic Syndrome in the U.S. Has Leveled Off

According data from the National Health and Nutrition Examination Survey (NHANES), about 35% of U.S. adults had metabolic syndrome in 2011 – 2012, which is about the same rate as earlier samples. The results were published recently in a research letter in the Journal of the American Medical Association.

Researchers led by Maria Aguilar, MD, of the Alameda Health System-Highland Hospital in Oakland, Calif., noted that from 1999 – 2006, the U.S. had a reported metabolic syndrome prevalence of 34%. “Understanding updated prevalence trends may be important given the potential eff ect of the metabolic syndrome and its associated health complications on the aging U.S. population,” the authors wrote. “We investigated trends in the prevalence of the metabolic syndrome through 2012.”

The researchers used 2003 – 2012 NHANES data and a definition of metabolic syndrome based on the National Cholesterol Education Program Adult Treatment Panel III, updated by the American Heart Association, as having three or more of the following: a large waistline (35 inches or more for women; 40 inches or more for men), high triglyceride level (150 mg/dL or higher), low HDL cholesterol level, high blood pressure, high fasting blood sugar. They used weighted samples to get a better picture representative of the U.S.

Aguilar and her team found that from 2003 to 2012, the overall prevalence of metabolic syndrome in the U.S. was 33%. From 2003 – 2004 the prevalence was 32.9%. That jumped to 34.7% in 2011 – 2012. The authors wrote that metabolic syndrome prevalence remained stable from 2007 – 2008 (36%) to 2011 – 2012 (34.7%). In 2011 – 2012, women showed a higher prevalence than men (36.6% versus 32.8%), and Hispanics had the highest prevalence of metabolic syndrome from 2011 – 2012 at about 39%. The data also show that metabolic syndrome prevalence appears to increase with age, which the authors called a “concerning observation in the aging U.S. population.”

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