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Online Only Articles
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Endocrine News Online-Only Articles: May 2012
To view the papers on which these articles were based, click the link at the end of each article. The abstracts posted online ahead of publication are included below each article here.
Gastric bypass surgery has varied effectiveness. A functional melanocortin-4 receptor (MC4R) gene increases the odds of success? Patients who undergo gastrointestinal weight loss surgery, particularly Roux-en-Y gastric bypass (RYGB), lose on average 70% of their excess body weight and maintain approximately 80% of this weight loss over decades. Yet the success rate in individual patients varies widely. The mechanisms driving this variability are largely unknown, but pathways balancing energy intake and expenditure appear to play a crucial role. MC4R serves as a critical node in these systems. Patients who harbor MC4R mutations are at increased risk for developing severe early-onset obesity, possibly making it harder to shed the pounds. To determine if this is the case, a research team looked at MC4R heterozygous (+/-) and null (-/-) mice and sequenced the MC4R gene in 972 patients undergoing RYGB. Their results are detailed in a pending article in The Journal of Clinical Endocrinology & Metabolism.* MC4R-/- mice lost significantly less weight after surgery than MC4R+/- and wild-type animals. Similarly, humans heterozygous for MC4R slimmed down at the same rate as those who had two normal copies of the gene. The research group concludes that patients with even one normal copy of the MC4R gene are appropriate candidates for RYGB. These findings underscore the physiological mechanisms of action of this surgical therapy, they add. ABSTRACT: Context. Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. Objective. Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB. Methods and Results. Here we report that MC4R-/- mice lost substantially less weight after surgery than wild type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that while two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB. Conclusions. MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent upon the normal pathways that regulate energy balance.
Life After Cancer Children with cancer face grown-up decisions such as what to do to preserve their fertility. Anti-Müllerian hormone (AMH) might help in this dilemma. Over 80% of children diagnosed with cancer survive, yet the cytotoxic treatments performed can wreak havoc on their gonads. Female patients face the possibility of having their oocyte supply rapidly diminished and undergoing premature menopause. To counteract these events, many patients opt for egg and ovarian tissue banking. For these procedures, measurements of gonadotropins (FSH, LH), estradiol, and progesterone are needed, but these hormones are not informative in prepubertal girls whose hypothalamic-pituitary-gonadal axis has not quite awakened. Enter AMH. Originally thought to be an ovarian reserve marker in adult females, researchers have now found that it can work in prebuscent girls. In an upcoming article in The Journal of Clinical Endocrinology & Metabolism,* a British research group conducted a prospective, longitudinal study in which 22 females (17 prepubertal) had their AMH, inhibin B, and FSH levels measured at diagnosis, after each chemotherapy course, and at follow-up. Both inhibin B and FSH showed no changes in their concentrations either before or after treatment. Conversely, AMH amounts dropped during chemotherapy, to the point of being immeasurable in half the patients. Patients classified as low/medium risk for gonadotoxicity had their AMH levels restored following treatment; those at high risk for gonadal failure continued to have undetectable AMH post follow-up. "AMH is therefore a clinically useful maker of damage to the ovarian reserve in girls receiving treatment for cancer," the authors write. ABSTRACT: Context. Cytotoxic treatment may accelerate depletion of the primordial follicle pool leading to impaired fertility and premature menopause. Assessment of ovarian damage in pre-pubertal girls is not currently possible, but Anti-Müllerian Hormone (AMH) is a useful marker of ovarian reserve in adults. Objective. To prospectively evaluate AMH measurement in children as a marker of ovarian toxicity during cancer treatment. Design and setting. Prospective, longitudinal study at a University Hospital Patients. 22 females (17 pre-pubertal), median age 4.4 y (range 0.3–15 y), were recruited before treatment for cancer. Main outcome measures. AMH, inhibin B and FSH at diagnosis, after each chemotherapy course and during follow-up. Risk of gonadotoxicity was classified as low/medium (n = 13) or high (n = 9) based on chemotherapy agent, cumulative dose, and radiotherapy involving the ovaries. Results. Pre-treatment AMH was detectable across the age range studied. AMH decreased progressively during chemotherapy (P < 0.0001) in both pre-pubertal and pubertal girls becoming undetectable in 50% of patients, with recovery in the low/medium risk groups following completion of treatment. In the high-risk group, AMH became undetectable in all patients and showed no recovery. Inhibin B was undetectable in most patients pre-treatment, and, with FSH, showed no clear relationship to treatment. Conclusion. AMH is detectable in girls of all ages, and falls rapidly during cancer treatment in both prepubertal and pubertal girls. Both the fall during treatment and recovery thereafter varied with risk of gonadotoxicity. AMH is therefore a clinically useful marker of damage to the ovarian reserve in girls receiving treatment for cancer.
Declining sex hormones have been linked to Alzheimer's disease. A study in aged hypogonadal (hpg) mice reveals that males are at greater risk than females. Male and female patients with Alzheimer's disease respectively have lower levels of testosterone and estradiol. Likewise, prostate and breast cancer patients who have undergone chemical depletion of gonadal hormones have increased levels of Alzheimer's disease–plaque precursors such as plasma beta amyloid. Scientists are looking for better physiological models other than chemically castrated or gonadectomized animals, to study the disease. Australian researchers may have found the perfect model: hpg mice that are genetically programmed from birth to endure lifelong sex steroid depletion. Although reproductive studies have been conducted on these animals, few have focused on age-related disease. Molecular analysis on these mice revealed low levels of amyloid precursor protein and high levels of presenilin 1, APP C-terminal fragment, and beta amyloid 42 in male, but not female brains; these levels were confined to the hippocampus, the region primarily affected in Alzheimer's disease. Male mice also had reduced levels of choline acetyltransferase per neuron compared with controls. Writing in an upcoming article in Endocrinology,* the authors conclude that hpg mice are a novel model for studying Alzheimer's disease-related pathologies, and support a link between androgen depletion and disease onset. ABSTRACT: Age-related depletion of estrogens and androgens is associated with an increase in Alzheimer’s disease (AD) brain pathology and diminished cognitive function. Here we investigated AD-associated molecular and cellular changes in brains of aged hypogonadal (hpg) male and female mice. Hpg mice have a spontaneous, inactivating genetic mutation in the gonadotropin-releasing hormone gene resulting in life-long deficiency of gonadotropins and gonadal sex hormones. Western blot analysis revealed low levels of amyloid precursor protein (APP) and high levels of presenilin 1, APP C terminal fragment, and beta amyloid 42 (Aβ42) in brains of aged male, but not female, hpg mice. Changes were confined to the hippocampus and were not evident in the cerebellum or other brain tissues. Male hpg mice tended to have lower levels of IL-1β protein than male littermate controls. Immunohistochemical staining of the basal forebrain revealed that male hpg mice had lower choline acetyltransferase levels per neuron compared to controls. These AD-like changes specific to male hpg mice supports a link between androgen depletion and the development of AD pathology.
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