News, Notes, & Insights

Boxers or Briefs and Other Male Fertility Factors

Boxers or briefs? A light-hearted question often asked of celebrities and politicians may be a critical decision in regards to a man’s fertility. Research from the Universities of Manchester and Sheffield in England, recently published in Human Reproduction [humrep.], shows boxers are better for fertility, but surprisingly, several other lifestyle choices seem to have little effect on sperm motility.

Men unsuccessfully attempting conception for 12 months were recruited through United Kingdom fertility clinics and assessed for job histories, lifestyle, and health factors. Those with medical conditions or treatments known to cause infertility were excluded. Those chosen to participate were interviewed about clothing choices, recreational drug use, and fertility history.

Wearing boxers was associated with higher motile sperm concentration (MSC). Previous studies have suggested that tight underwear such as briefs may elevate the temperature of the testicles and slow down production of sperm.

Low (MSC) occurred in men with previous testicular surgery, possibly due to similar factors found in undescended testicles that reduce fertility. Men doing manual work also had low MSC, and this can be explained, in part, by exposure to toxicants. Students and the unemployed are at a similarly high risk with little explanation as to why.

MSC was not lowered, however, by smoking, alcohol, or recreational drug use, the study concluded. Although direct changes to sperm were either insignificant or undetected in this study, these habits may affect fertility through other means.

Quality of Life of Pediatric Cancer Patients Better than Expected

It’s hard to hear of a child with a rare disease but surely harder to live as one. Quality of life (QOL) can suffer from even the stress of diagnosis and treatment. Pediatric differentiated thyroid cancer (DTC) spreads to the cervical lymph nodes in 40–90 percent of patients and metastasizes distantly in 20–30 percent. Despite the aggressiveness of this rare disease, QOL has gone mostly unstudied.

Researchers at the Hospital for Sick Children in Toronto predicted pediatric DTC patients to have low QOL and high anxiety. Their study, lead by Asaf Oren and to be published in The Journal of Clinical Endocrinology & Metabolism [jcem.], found the opposite. Neither age, length of time since diagnosis or therapeutic factors altered anxiety levels and QOL beyond norms in the control group or healthy population.

Assessed through 3 questionnaires, 16 DTC patients aged 10–18 years measured QOL scores and anxiety levels similar to 16 adolescents with autoimmune hypothyroidism receiving L-thyroxine (L-T4) therapy. L-T4 has been found to increase anxiety during administration with only a slight decrease during withdrawal. None of the 16 DTC patients were experiencing withdrawal at the time of the study, and their free T4 levels did not correlate to their scores.

Recombinant human thyroid stimulating hormone (rhTSH) and L-T4 withdrawal are typically used in follow-up of DTC and use of rhTSH in adult patients has been linked to improved QOL. In this study, no difference was found between the QOL scores of adolescents who received rhTSH and those managed with use of withdrawal L-T4.

Following up through an endocrinology clinic instead of an oncology clinic might influence these scores, as might discussions of “excellent prognosis.” However, QOL in other long-term pediatric cancer survivors improves from diagnosis to levels similar to those in the healthy population. Compared to healthy siblings, long-term pediatric cancer survivors have scored lower only on assessment of physical well-being. It may well be the ability of children to adapt easily and accentuate the positive that gives adolescent cancer patients a better self-perceived QOL.

Number of β-Cells Set by Age 5

Type-2 diabetes is sometimes linked to a patient’s low level of pancreatic β-cells, which control insulin. A new study investigates why some patients have lower pancreatic β-cells than others and whether the differences are genetic or environmental. A team of scientists led by Brigid Gregg, M.D., of Kovler Diabetes Center, University of Chicago, explored whether there is a baseline number of β-cells in humans. They also analyzed if this number is established by birth or if it can change later in life.

The researchers performed immunofluorescence examinations on pancreatic tissue samples from 40 human cadavers between the ages of 23 weeks premature and 72 years. None of the subjects had a personal or family history of diabetes and none were obese. Cell counts and islet size were done on at least 25 sample images from each subject’s pancreatic section.

The study, published in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals. org], found that the highest rate of β-cell creation occurred preterm and up to about 2 years of age. Afterward, the rate of β-cell proliferation dropped to about 0.5 percent.

In the article, the researchers conclude that baseline β-cell population and its link with other islet cell types are established in humans before 5 years of age. They write that genetic factors and the maternal intrauterine environment could influence the degree of human pancreatic islet formation and the size of baseline β-cell mass. If this is small, they report, then a likelihood of developing diabetes can be set very early on in life.

Exercise Increases sRAGE, Benefits Diabetes Patients

Scientists have known for some time that advanced glycation end products (AGEs) and their receptor (RAGE) play an important role in the development of atherosclerosis in patients with type 2 diabetes. New research now reveals that low levels of the soluble form of RAGE (sRAGE)—a critical risk factor for cardiovascular disease—may be improved with exercise.

Exercise helps protect against atherosclerosis by reducing or preventing oxidative stress and systemic inflammation, symptoms exacerbated by AGEs. A team of Korean researchers, led by Kyung Mook Choi, M.D., Ph.D., from the Division of Endocrinology and Metabolism in the College of Medicine at Korea University, Seoul, explored how exercise would affect the levels of sRAGE and its impact on cardiometabolic risk factors.

In their study soon to be published in The Journal of Clinical Endocrinology & Metabolism [jcem.], 75 Asian women with T2DM were randomized either into a control or aerobic exercise groups. The patients’ average age was 54.4 years, average body mass index 26.8, and all had a sedentary lifestyle. While the control group continued their normal routines, the exercise group was instructed to walk at a moderate pace for an hour five days per week for 12 weeks. Exercise sessions were monitored every two weeks by a multi-record accelerometer

After 12 weeks, the exercisers showed significant improvements in many cardiometabolic risk factors, including an increase in aerobic capacity and decreased body weight, waist size, blood pressure, cholesterol levels, glucose levels, and visceral fat area. The exercise group also had increases in sRAGE levels and decreases in high sensitive C-reactive protein levels, another cardiovascular disease risk factor. These decreases were not found in the control group.

The researchers show that sRAGE is a potential mechanism underlying the benefits of exercise in type 2 diabetes patients.

Slug’s Potential for Prostate Cancer Treatment

Like its namesake, Slug, the most recently identified member of the zinc finger transcription factor family Snail, is sticky—it binds to the androgen receptor (AR) regardless of the presence of androgen. This finding could be useful in patients with castration-resistant prostate cancer (CRPC), a deadly cancer that contains cells with altered and increased AR levels.

Led by Jer-Tsong Hsieh, Ph.D. at UT Southwestern Medical Center at Dallas, and Dalin He, M.D., at First Affiliated Hospital, Medical School of Xi’an Jiaotong University, in China, scientists stained and analyzed 400 human prostate cancer tissue specimens, categorized by hormone therapy status, Gleason score, and primary or end-stage status, to show the concurrent elevation of Slug and AR. The study also shows both Slug and AR interacting with each other, thereby forming a complex. Signifi- cantly, in the presence of Slug, AR does not need androgen to become active. Researchers backed up these observations with at least two CDNA microarrays that examined gene expression in prostate cancer tissues. In their paper, to be published soon in Molecular Endocrinology [mend.], the researchers report that the Slug–AR reciprocal relationship hyperactivates transcriptional activity of AR, which contributes to the progression of CRPC—that is, the androgen-independent form.

The researchers conclude that due to its key role in CRPC, Slug has potential in both prostate cancer prognosis as a marker and in therapy as a drug target.

Bariatric Surgery Raises Risks of Alcoholism

Patients who have gastric bypass surgery are 30 percent more likely to have problems with alcohol, according to a new prospective study.

Spurred by anecdotal reports linking bariatric surgery to an increased risk of alcohol abuse disorders, researchers led by Wendy C. King, Ph.D., of the University of Pittsburgh, designed a multicenter study to compare 1,945 patients’ experiences before and after Roux-enY gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) surgery. Participants completed preand postoperative assessments on their experience with alcohol use disorders, such as alcohol abuse and dependence. The prevalence of symptoms did not differ from the year before surgery to the first year after, but was significantly higher in the second year, going from 7.6 percent before surgery, to 7.3 percent the year after, to 9.6 percent in the second year. The increase was almost entirely among the RYGB patients, who made up 70 percent of the study group, with virtually no increase in the LAGB patients.

In an article published in JAMA [], the researchers noted evidence that some bariatric procedures, including RYGB and sleeve gastrectomy, alter the pharmacokinetics of alcohol. These patients feel the effects of alcohol more quickly and reach a higher peak alcohol level.

The researchers identi- fied several risk factors that increase the likelihood of alcohol problems: male sex, younger age, regular alcohol consumption, recreational drug use, and less interpersonal support. They recommend that alcohol screening and referral be offered to patients both before and after the surgery.

Growth Hormone Linked to Healthy Aging

If a baby continued growing at the rate she does the first year of life (about 10 inches in length), by the time she turned 60, she would be 600 inches or 50 feet tall! Luckily by 2 years of age, a baby’s height growth stabilizes at a steady rate of 2.5 inches per year until adolescence.

Growth hormone (GH) parallels this downward spiral, in that its secretion naturally declines after adolescence at a rate of 14 percent each decade. Elderly people and patients with adult onset GH deficiency have similar body compositions with reduced muscle and bone and increased fat. The converse is also true— increased adiposity reduces GH secretion. These findings have led researchers to believe that impaired GH may contribute to the development of metabolic maladies such as obesity.

Seeking to find out what happens to GH secretion in young adults with dietary-induced weight gain, Lili Huang, M.D., Frederick J. Steyn, Ph.D., and a team of scientists led by Chen Chen, M.D., Ph.D., at the School of Biomedical Sciences, University of Queensland in Brisbane, Australia, fed wild-type mice either a standard or high-fat diet until the mice reached early adulthood (~11 weeks). Blood sample analysis revealed lower serum GH levels between ages 12 and 16 weeks in the high fat-fed mice compared to those on regular chow. In their paper, to be published soon in Endocrinology [], the researchers report increased adiposity in high-fat diet mice, with adipose tissue also found in the liver, and decreased levels of insulin-like growth factor I (IGF-I), which works in concert with GH to maintain healthy aging and phenotype. IGF-I attrition is also characteristic of obesity.

The researchers conclude that weight gain speeds up GH secretion decline, which may yield gigantic health problems throughout the lifespan, including increased risk for hyperinsulinemia, obesity, and impaired liver function.

Irregular Menstrual Cycles as Markers for Health Risks

Much of a woman’s health centers on her menstrual cycle. Exposure to endogenous hormones factors into both reproductive development and risk of various cancers and diseases. Menstrual cycles are typically used to measure these risks rather than the hormones directly, but how hormone concentrations and cycle length interact is largely unknown.

Assessing 259 regularly menstruating women age 18–44 years, researchers at the National Institutes of Health and the University at Buffalo found marked differences between hormone levels of long and short cycles. Follicular phase estradiol had a late rise during longer cycles, with follicle stimulating hormone (FSH) and luteinizing hormone (LH) also peaking later. LH concentrations remained high across the cycle, which may actually delay FSH and rising estradiol production and follicular development.

Women with short cycles show concentrations of FSH higher in early follicular and late luteal phases. Follicular phase estradiol was also higher. Short cycles themselves and short follicular phases specifically are conjectured to be due to early rises in FSH and faster follicular development.

An early rise of estradiol may mean per-cycle exposure is low, but a greater number of cycles experienced over a lifetime may increase exposure to levels above even regular cycles. Early follicular phase concentrations of FSH and estradiol with low luteal phase progesterone are a classic pattern of reproductive aging.

Both short and long cycles were associated with an increased risk of anovulation as compared to regular cycles. These findings, to be published in The Journal of Clinical Endocrinology & Metabolism [jcem.], add strength to using cycle length in measuring anovulation risk and hormone exposure in normally cycling women. “[It’s] a potentially valuable tool,” writes article author Sunni Mumford, Ph.D., “for measuring a woman’s lifetime exposure to hormones and in understanding associations with health outcomes.”

Vitamin D Dietary Supplements No Help in Normal Calcium Absorption

Calcitriol, the vitamin D active metabolite, is known to mediate calcium absorption in the gut. It is dependent on an adequate substrate of serum 25OHD. Also well documented is the age-related decline in the efficiency of this mechanism and a concomitant decrease in endogenous calcitriol production. Due to the high incidence of calcium deficiency–related disorders such as osteoporosis among older adult women, health care providers have long advised dietary supplements of calcium plus vitamin D in this population. A recent crosssectional study postulated that there was a threshold of serum 25OHD of 30 ng/ mL (75 nmol/L) at which point increasing supplementary vitamin D became more effective for increasing calcium absorption.

Scientists led by Chris Gallagher, M.D., at the Creighton University Medical Center in Omaha, Nebraska, tested where this threshold lies by analyzing data from the ViDOS (Vitamin D supplementation in Older Subjects) trial, in which 143 postmenopausal women were given dietary supplements of 200 mg calcium plus one of seven levels of vitamin D supplement ranging from 400–4,800 IU or placebo daily for one year to measure calcium absorption across a range of resulting serum 25OHD levels, from 10 to 66 ng/mL (25–165 nmol/L). In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism [], the researchers report that in this longitudinal study, the threshold for normal calcium absorption occurred at a very low level of serum 25OHD, less than 5–10 ng/mL (12.5–25 nmol/L) —this being the 25OHD level at which serum 1,25(OH)2D fell—much lower than previously reported.

The researchers conclude that vitamin D supplementation may not be useful in older women unless they have severe vitamin D deficiency (< 5–10 ng/mL). This population can achieve the desired level of calcium absorption by drinking an extra 100 ml of milk or with a 100- mg calcium supplement, they add.

Building a Better Diabetes Drug

Fibroblast growth factor 21 (FGF21), a novel hormone involved in glucose and energy homeostasis, shows promise in treating obesity and diabetes. In rodents and primates, it has been shown to normalize blood sugar and lipid levels and decrease weight. The only catch is its short life. FGF21 stays in the body for only one to two hours. To get the desired effects, researchers would have to give multiple injections, thus failing to avoid the same complication that most insulin users already face.

In hopes of developing a longeracting alternative, researchers, led by Jing Xu, Ph.D. and Murielle M. Véniant, Ph.D., of Amgen, Inc., in Thousand Oaks, California, fused the hormone containing two engineered mutations with an Fc fragment to generate a molecule they called FcFGF21(RG). They then compared the efficacy of their new creation with that of hrFGF21 in diet-induced obese mice and obese rhesus monkeys.

The diet-induced obese mice treated with either compound showed several metabolic improvements: decreased body weight; decreased glucose, insulin, cholesterol, and triglyceride levels; and improved glucose tolerance. The obese rhesus monkeys showed similar results in these measures, with the Fc-FGF21(RG) having greater effects than the hrFGF21. An important difference: Both species were treated with the Fc-FGF21(RG) only once every five to seven days, compared with daily administration of hrFGF21.

In an article awaiting publication in Endocrinology [], the researchers note that finding in two species that weekly Fc-FGF21(RG) showed efficacy similar to or greater than daily hrFGF21 offers a promising avenue to explore for new therapeutic options.

Fructose Transporter Becomes Latest Obesity Drug Target

One factor in the increased obesity epidemic is the overindulgence in dietary sugars such as high-fructose corn syrup (HFCS). Researchers are honing in on how fructose is involved in fat cell formation. Data from the U.S. National Health and Nutrition Examination Survey (NHANES) suggest that about 15 percent of Americans consume greater than 25 percent of their energy from added sugars such as HFCS. Research in rhesus monkeys has shown that when these animals are fed about 30 percent of their energy intake as fructose, they develop features of metabolic syndrome such as abdominal obesity, dyslipidemia, and inflammation.

To gain greater insight into how fructose promotes fat, Anthony Heaney, M.D., and his research group from the University of California, Los Angeles, examined a mouse pre-adipocyte cell line, 3T3-L1 and mice that lacked a glucose/fructose transporter, GluT5. Their results are discussed in an upcoming issue of Molecular Endocrinology [mend.].

Preadipocytes that were incubated in fructose had a greater propensity toward differentiation into full-fledged fat cells than those on regular cell culture medium. When these cells were hit with a specific GluT5 inhibitor, differentiation decreased. Similarly, GluT5 -/- mice had less white adipose tissue compared with wild-type mice and were resistant to diet-induced obesity.

These findings suggest a new target for weight loss drugs, suggested the authors.

Gonadotropins Not Linked to Higher IVF Failures

Although it has become a popular option for women seeking treatment for infertility, the rates of in vitro fertilization (IVF) resulting in a viable pregnancy still remain low, mostly due to the high numbers of embryos produced with chromosomal abnormalities.

Researchers from the University of Valencia in Spain, led by Elena Labarta, M.D., explored whether the high chromosomal abnormality rates, as compared with the rates in embryos produced from natural fertilization, could be traced to the use of gonadotropins to stimulate the ovaries during IVF.

The study took place in a private infertility clinic over a four-year period. Researchers recruited healthy, fertile oocyte and sperm donors between the ages of 18 and 34. An unstimulated IVF cycle was first conducted on 51 oocyte donors, which resulted in 35.3 percent of the embryos having chromosomal abnormalities. Of those 51 women, 46 later completed a second stimulated cycle—taking about 10 days of a combination dose of 150 IU follicle-stimulating hormone and 75 IU of highly purified human menopausal gonadotropin. The same sperm donor was used for both cycles.

In the women who completed both cycles, 34.8 percent of the embryos showed chromosomal abnormalities in the unstimulated cycle compared with 40.6 percent in the stimulated cycle. The study found no differences between the unstimulated and stimulated cycles in embryo quality and type of chromosomal abnormalities.

The researchers conclude in their upcoming article in The Journal of Clinical Endocrinology & Metabolism [jcem.] that the use of moderate doses of gonadotropins for ovarian stimulation during an IVF cycle does not significantly increase the abnormality rate in young women with normal ovulation.

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