Deficicencies in semen production linked to medical comorbidities

Researchers identified a relationship between semen production and medical comorbidities, including hypertension and endocrine disorders, according to data published in Fertility and Sterility.

“Men’s health and fertility are related,” Michael L. Eisenberg, MD, assistant professor of urology and director of male reproductive medicine and surgery at Stanford University School of Medicine, told Endocrine Today. “If one has health problems, there may be reproductive problems.”

Michael Eisenberg

Michael L. Eisenberg

With 15% of all couples experiencing fertility issues, and semen deficiencies demonstrated in half of those cases, Eisenberg said the area deserves more attention.

“If a couple is having trouble conceiving, a man should get evaluated because there may health ailments that can be treated,” he said.

Eisenberg and colleagues analyzed medical records of 9,387 men (mean age, 38 years) with semen data available. The men were evaluated at Stanford between 1994 and 2011 to examine causes for their infertility; abnormal semen was the problem in nearly half of all male fertility cases, and 44% had at least one medical diagnosis unrelated to infertility.

Using the Charlson comorbidity index, the researchers stratified the cohort and measured differences in semen parameters. Men with a higher Charlson comorbidity index score demonstrated lower semen concentration, motility, volume, total sperm count and morphology scores.

Overall health status was compared between men with semen defects and those without. Men with endocrine, circulatory, genitourinary and skin diseases all demonstrated higher rates of semen abnormalities.

Further examination into conditions of the circulatory system showed men with hypertensive disease, peripheral vascular and cerebrovascular disease and non-ischemic heart disease had higher rates of semen abnormalities.

Determining what is behind the correlation between semen deficiencies and diseases of the endocrine and cardiovascular systems was not part of the study design, but Eisenberg said most genes connected to reproduction also have functions in other bodily systems. He is currently exploring whether the treatment for disease, rather than disease itself, could be responsible for reproductive malfunction.

“As we learn more about the causes and consequences of infertility, we can better treat patients so that everyone is able to achieve their reproductive goals,” Eisenberg said. — by Allegra Tiver

A Step Closer to Predicting Preeclampsia Risk in Diabetes.

Pregnant women with type 1 diabetes have a preeclampsia risk 2 to 4 times higher than that of women without the condition, and now researchers think they have identified some novel markers that may help identify diabetic women most at risk.

Valerie A. Holmes, PhD, senior lecturer at the Centre for Public Health, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, and colleagues assessed levels of angiogenic and antiangiogenic compounds found in the maternal serum of women with type 1 diabetes in their second trimester and found that abnormal levels of these markers were present in those who developed preeclampsia.

The study, the largest of its kind to date, “would suggest that these markers may have additional predictive risk above and beyond traditional clinical risk factors,” said Dr. Holmes. The study waspublished online August 6, 2013 in Diabetes Care.

“Previous studies have reported altered angiogenic profiles in women at risk of preeclampsia, but few have specifically looked at women with type 1 diabetes,” Dr. Holmes told Medscape Medical News in an email. “Our findings, in a carefully characterized population of women with type 1 diabetes, demonstrate that adding measures of [these] factors to established clinical risk factors significantly improves the prediction of preeclampsia. These results are an important step on the road to establishing a preeclampsia ‘risk score’ for women with type 1 diabetes.”

Some Interest in Commercial Development of Tests

The researchers studied 540 women participating in the Diabetes and Preeclampsia Intervention Trial (DAPIT), which enrolled patients from 25 centers across Scotland, Northern Ireland, and England between April 2003 and June 2008. Blood samples were taken at 26 weeks’ gestation and analyzed by laboratory staff members who were blinded to each woman’s preeclampsia status.

The association of angiogenic factors, such as placental growth factor (PlGF) and antiangiogenic factors — such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) — with preeclampsia was determined through logistic regression analysis adjusted for age, body mass index (BMI), diabetes duration, parity, history of preeclampsia, current smoking, and clinical parameters such as blood pressure, hemoglobin A1c, and renal function.

Of the 540 women included in this study, 94 (17%) developed preeclampsia, and 198 (37%) gave birth prematurely (before 37 weeks’ gestation), including 61 women with preeclampsia (65% of women with preeclampsia, compared with 31% of women without preeclampsia; P < .001).

The scientists observed significantly higher levels of sFlt-1 and sEng and significantly lower levels of PlGF, as well as altered ratios of these antiangiogenic and angiogenic factors, during the second trimester in women who later developed preeclampsia compared with those who did not.

“Our findings show that established clinical risk factors, such as previous history of preeclampsia, age, BMI, diabetes duration, parity, blood glucose control, and blood pressure, are indeed reliable indicators of risk in this population,” Dr. Holmes told Medscape Medical News. But the results “also suggest that angiogenic factors provide added clinical value when predicting risk,” she said.

“These findings need to be validated in another group of women with diabetes before incorporating routine testing into the clinical context. Once they are validated, the next step would be to develop a ‘risk score’ for women with diabetes, based on a combination of established risk factors and angiogenic-factor results.”

The tests for angiogenic factors are currently restricted mainly to research settings, she noted, but there is commercial interest in developing such assays.

“With increasing evidence of the role of angiogenic factors in the pathogenesis of preeclampsia, several companies have developed commercially available assays for at least one of the angiogenic factors we investigated, PlGF, to assist with preeclampsia diagnosis and screening. It is possible that in the future, and with further testing, these assays may emerge as part of routinely available screening test to assist clinicians in determining risk,” she said.

Source: Diabetes Care.


,”san�9rf0� ��� east-font-family:”Times New Roman“; color:black’> ABCG2 (p<0.01), the group writes. In the 134 patients on atorvastatin, explainable blood-level variability was split between two polymorphisms in SLCO1B1 (p<0.01 and p<0.05, respectively) and the activity of cytochrome P3A (CYP3A). The analyses were adjusted for gender, age, body mass index, ethnicity, statin dose, and time from last dose, and echo a 2008 study which concluded that two SLCO1B1 variants were associated with simvastatin-related myopathy, as reported by heartwire . The screening concept is currently being applied to simvastatin therapy at least at one major center.


The group retrospectively tested their ideas, looking at the relationships between genotypic and clinical variables and statin dose, in a validation cohort of 579 patients taking either drug in a primary care setting in the US and at a referral clinic in Canada.

The group found that the transporter genotypes that raise statin concentrations were homogeneously distributed among patients taking a range of atorvastatin and rosuvastatin dosages. That is, the prescribing physicians, armed primarily with their clinical judgment to decide dosage levels, failed to achieve optimal dosing with respect to serum drug levels. But it seemed to be only patients receiving the highest dosages who showed higher-than-safe serum levels according to genotype- and age-based criteria.

“Although we didn’t quite get to the sample size we needed, it did seem like people with the wrong genetic makeup are more likely to stop a statin or switch to [another dyslipidemia drug],” Kim said, at least among patients on the highest statin dosages.

The group’s proposed management algorithm recommends a maximum statin dosage that will result in plasma concentrations below the 90th percentile (reflecting an assumption that 10% of patients will have statin-related muscle issues) based on patient age and transporter-related genotype.

The algorithm is based on data predominantly from whites; the group cautions that some other ethnicities, “particularly Asians,” have increased sensitivity to statins.



Exercise Alone May Help Those With Type 2 Diabetes.

Story at-a-glance

  • Engaging in a six-month moderate-intensity exercise program led to significant health improvements among people with diabetes, including decreases in fat in the abdomen, liver and around the heart, all of which is associated with an increased risk of heart disease
  • Heart disease is the number one cause of death among people with type 2 diabetes, so exercise could be potentially lifesaving for diabetics
  • Type 2 diabetes arises from faulty leptin and insulin signaling and resistance, both of which are directly related to lack of exercise and a diet high in starchy carbohydrates or sugar.
  • When you exercise for diabetes prevention or treatment, intensity is key; high-intensity interval training (HIIT) should ideally be included in your fitness program to achieve optimal results.
  • diabetes

Nearly 8 percent of the US population, or close to 26 million people, have diabetes, and another 80 million have pre-diabetes,1 which means they’re on their way to developing the full-blown version of the disease… if they don’t do something to stop it.

That something is the silver lining to this major public health epidemic, as research clearly shows lifestyle changes are extremely effective at not only preventing type 2 diabetes but also reversing it if you’ve already been diagnosed.

Among them, exercise has recently made headlines for making major improvements in diabetics’ health.

Exercise Improves Diabetics’ Health – Even Without Other Lifestyle Changes

In a new study of people with diabetes, engaging in a six-month moderate-intensity exercise program led to significant health improvements.2 Specifically, they had decreases in fat in the abdomen, liver and around the heart, all of which is associated with an increased risk of heart disease.

In case you aren’t aware, heart disease is the number one cause of death among people with type 2 diabetes. It’s estimated that at least 65 percent of those with diabetes die from some form of heart disease or stroke.3

While the exercise program didn’t lead to direct changes in heart function, the reductions in dangerous visceral fat around key organs – as well as reductions in pericardial fat, which is the second layer of fat around the heart – will undoubtedly improve heart health among this at-risk population. The study’s lead author noted:4

“ … reduction of liver fat content and visceral fat volume by physical exercise are very important to reverse the adverse effects of lipid accumulation elsewhere, such as the heart and arterial vessel wall.”

Also noteworthy about the study was the relatively small amount of exercise needed to prompt such beneficial changes. The participants exercised between 3.5 and 6 hours a week (and ended the program with a 12-day trekking expedition), which is a reasonable goal for most people.

Further, the benefits were gained from exercise alone; no other lifestyle or dietary changes were made, which shows just how powerful staying active can be in improving your health — even if you’ve already been diagnosed with a potentially chronic disease.

Why Exercise Has Been Called the ‘Silver Bullet’ in Diabetes Treatment

When diagnosed with type 2 diabetes, many believe their fate has been sealed and all they can do now is “control” it. This is far from the truth. You can essentially “cure” yourself of this disease and permanently control it. Exercise can be one of your secret weapons to doing so.

The amazing thing about exercise is that it exerts its effects very quickly. There are long-term benefits, too, of course, but you’ll also get acute, nearly instantaneous benefits as well. This should be excellent motivation to those of you who are procrastinating on your exercise program, as you don’t have to exercise for a year or six months to experience benefits!

Research published in Medicine & Science in Sports & Exercise found, for example, that one single session of moderate exercise can improve the way your body regulates glucose and reduces the spikes in blood sugar that occur after a meal (elevations in these spikes, known as postprandial glucose, or PPG, are associated with type 2 diabetes, heart disease, and death).5

When you exercise for diabetes prevention or treatment, intensity is key. A slow walk around the block, while better than watching TV on the couch, is not likely to cut it (although if you’re morbidly obese and very out of shape this is a good way to start). Instead, high-intensity interval training (HIIT), which is a core component of my Peak Fitness program, should ideally be included in your fitness program to achieve optimal results. This technique uses short bursts of intense activity followed by a longer period of recovery, and the cycle is then repeated multiple times. All you need is about 20 minutes of HIIT two or three times a week for maximum benefits. HIIT can significantly improve your insulin sensitivity, especially if you’re on a low-processed-food, low-sugar/low-grain diet as well.

If You Want to Reverse Diabetes, Diet and Exercise Changes Are Essential

Exercise is vital if you have diabetes, but even though physical activity alone is likely to give your health a boost, you should not rely on it as your sole treatment strategy. Type 2 diabetics need to address the root of the problem, which is insulin and leptin resistance—caused by faulty leptin and insulin signaling, which is directly attributable to not only lack of exercise but also the food you eat. The truth of the matter is that type 2 diabetes is a fully preventable condition and it’s also close to 100% reversible, provided you take the proper steps to heal your body.

In one study, for instance, researchers randomly assigned diabetic participants, who were also overweight or obese, to an intensive program of diet and exercise, in which they were urged to cut calories down to 1,200-1,800 calories per day and engage in nearly three hours of physical exercise per week.6

After one year, 11.5 percent of the program participants no longer needed medication to keep their blood sugar levels below the diabetes threshold – in other words, they were no longer diabetic. For comparison, only 2 percent of the non-intervention group experienced any significant improvement in their condition. Again, type 2 diabetes arises from faulty leptin signaling and insulin resistance, both of which are directly diet- and exercise-related. It is NOT a disease of blood sugar.

Once you understand that, the remedy becomes clear: To reverse the disease, you need to recover your body’s insulin and leptin sensitivities. The ONLY way to accomplish this is through proper diet and exercise, as detailed in my free Nutrition Plan. Bariatric surgery, which is being increasingly recommended as a diabetes treatment, will NOT do the trick, and there is NO drug that can correct leptin signaling and insulin resistance, either.

Why What You Eat Can Make or Break Your Health and Cause Diabetes

Let’s review the mechanics of insulin and leptin resistance

  • Leptin is a hormone produced in your fat cells. One of leptin’s primary roles is regulating your appetite and body weight. It tells your brain when to eat, how much to eat, and most importantly, when to stop eating. And leptin tells your brain what to do with the energy it has. Leptin is largely responsible for the accuracy of insulin signaling and whether or not you become insulin resistant.
  • Insulin—Sugars and grains raise your blood sugar. When this happens, insulin is released to direct the extra energy into storage. A small amount is stored as a starch-like substance called glycogen, but the majority is stored as your main backup energy supply—fat. Insulin’s major role is not to lower your blood sugar, but rather to store the extra energy for future times of need. Insulin’s effect of lowering your blood sugar is merely a “side effect” of this energy storage process.

As you can see, these two hormones work in tandem, creating either a health-damaging or health-promoting cycle, depending on what you eat. If you consume loads of sugars and grains, your blood sugar spikes will lead to increased insulin, which leads to increased fat storage. The extra fat then produces more leptin. The problem arises when your leptin levels become chronically elevated.

At this point, you become leptin resistant—your body can no longer “hear” the hormonal signals telling your brain you’re full and should stop eating. As your fat stores increase, your weight goes up, and insulin resistance sets in. Now your body has become “deaf” to the signals from both hormones (leptin and insulin), and disease follows; one of which is diabetes.

Are You Ready to Send Your Diabetes Packing?

Adhering to the following guidelines can help you do at least three things that are essential for successfully treating type 2 diabetes: recover your insulin/leptin sensitivity, normalize your weight, and normalize your blood pressure:

  • Severely limit or eliminate sugar and grains in your diet, especially fructose which is far more detrimental to your health than any other type of sugar. Following my Nutrition Plan will help you do this without too much fuss. Avoid excessive protein as your body will convert that to sugar in your liver, which will sabotage your ability to control insulin resistance. Excess protein may even be more damaging to your health than excess carbs.
  • Exercise regularly. As mentioned, exercise is an absolutely essential factor and, without it, you’re unlikely to get this devastating disease under control. It is one of the fastest and most powerful ways to lower your insulin and leptin resistance. If you’re unsure of how to get started, I recommend reviewing my Peak Fitness program for tips and guidelines.
  • Avoid trans fats.
  • Get plenty of omega-3 fats from a high-quality, animal-based source, such as krill oil.
  • Optimize your vitamin D levels. Recent studies have revealed that getting enough vitamin D can have a powerful effect on normalizing your blood pressure and that low vitamin D levels may increase your risk of heart disease.
  • Optimize your gut flora. Your gut is a living ecosystem, full of both good bacteria and opportunistic strains that can cause trouble. Multiple studies have shown that obese people have different intestinal bacteria than lean people. When the microbes in your gut exist in proper balance, your immune system will be stronger and the better your body will function overall. Fortunately, optimizing your gut flora is relatively easy. You can reseed your body with beneficial bacteria by eating fermented foods (such as fermented vegetables, natto, raw organic cheese, or raw milk kefir) or by taking a high-quality probiotic supplement.
  • Address any underlying emotional issues and/or stress. Non-invasive tools like the Emotional Freedom Technique (EFT) can be helpful and effective.
  • Get enough high-quality sleep every night.
  • Monitor your fasting insulin level. This is every bit as important as your fasting blood sugar. You’ll want your fasting insulin level to be between 2 and 4. The higher your level, the worse your insulin sensitivity is.

Diabetes is a condition that is personally close to me, as most of my paternal relatives (my dad included), have, or have died from, diabetes. But my personal experience with diabetes and subsequent review of the literature has made it very clear to me that virtually every case of type 2 diabetes is reversible. If you’ve been diagnosed with type 2 diabetes or pre-diabetes, today can be the day that you take control of your health and start the journey to cure yourself of this disease.


Androgen-secreting adrenocortical carcinoma.

A 47-year-old woman presented with abdominal pain. She had recently noticed increased growth of facial hair and loss of scalp hair, and her menstrual cycle had become erratic. Abdominal examination revealed a right upper-quadrant abdominal mass. A CT scan of the abdomen revealed a 10 cm adrenal mass (figure, A, B; green arrows) that was well encapsulated and heterogeneous. Endocrine studies were ordered to exclude a functioning adrenal neoplasm. The serum total testosterone concentration was 8·6 nmol/L (reference range 0·13—2·53 nmol/L) and the serum dehydroepiandrostenedione sulphate (DHEAS) concentration was 22 μmol/L (reference range 1·0—11·6 μmol/L). The free androgen index (ratio of testosterone to sex-hormone-binding globulin) was 30·2% (reference range <0·8%). The serum concentrations of oestradiol, progesterone, luteinising hormone, follicle-stimulating hormone, and prolactin were within normal limits. The remaining endocrine studies (thyroid function tests, serum cortisol, aldosterone-to-renin ratio, plasma free metanephrines and normetanephrines, and urine biogenic amines) were also within normal limits. The increased concentrations of DHEAS and testosterone suggested an androgen-secreting adrenal neoplasm with virilising symptoms. 18F-fluorodeoxyglucose PET (FDG-PET) showed no evidence of metastatic disease.

An open right adrenalectomy was undertaken. Histology showed a neoplasm arising from the adrenal gland, fulfilling both macroscopic (460 g and 105 cm) and four of nine microscopic (Weiss) criteria for adrenocortical adenocarcinoma (high Fuhrman nuclear grade, more than five mitoses per 50 high-power fields, eosinophilic cytoplasm >75% of tumour cells, and necrosis; figure, C [haematoxylin and eosin staining]). Immunohistochemistry was positive for melan-A, vimentin, synaptophysin, and epithelial membrane antigen. Cytoplasmic staining was positive with calretinin (figure, D) and inhibin (figure, E). The Ki-67 proliferative index was 32%. Mitotane was recommended as adjuvant therapy for 2 years. No evidence of recurrence or metastatic disease was recorded 12 months postoperatively and androgen concentrations remain suppressed.

Women presenting with hirsutism or virilisation are more likely to have polycystic ovarian syndrome than an androgen-secreting adrenal neoplasm. Assessment of patients requires thorough hormonal investigation and imaging, including CT, MRI, and FDG-PET.

Source: Lancet

Pituitary hormone deficiency due to racemose neurocysticercosis.

Neurocysticercosis is the most common parasitic infection of the brain. Infestation is with the larva of Taenia solium and occurs after faecal—oral contamination with its eggs. Neurocysticercosis often affects the highly vascular grey—white matter junction, basal cisterns, subarachnoid space, and ventricles. Involvement of the sella turcica is very rare.

Racemose neurocysticercosis is a rare variant of neurocysticercosis that is characterised by the presence of abnormally large growths of many cystic membranes without a scolex. The growths are seen in grape-like clusters, mainly in the ventricles and basal cisterns, and often cause obstructive hydrocephalus (secondary to meningeal inflammation and fibrosis), which can necessitate their surgical removal. Racemose neurocysticercosis of the pituitary gland has not previously been reported.

We diagnosed racemose neurocysticercosis in a 29-year-old woman with amenorrhoea and recurrent vomiting for 5 months, and headache and increased fatigue for 3 months. Our examination found postural hypotension, a loss of axillary and pubic hair, and breast atrophy. Investigation revealed secondary hypocortisolism (0800 h cortisol 121·39 nmol/L [132·42—535·21 nmol/L]; adrenocorticotropic hormone 1·98 pmol/L [1·58—13·93 nmol/L]), secondary hypothyroidism (free thyroxine 9·01 pmol/L [11·58—23·17 pmol/L]; thyroid-stimulating hormone 0·01 mU/L [0·40—4·20 mU/L]), and secondary hypogonadism (luteinising hormone <0·8 IU/L [1·14—5·75 IU/L], follicle-stimulating hormone 1·1 IU/L [1·37—13·56 IU/L]). Brain MRI showed racemose neurocysticercosis of the pituitary gland (figure), many single cysts in the midbrain, cerebellum, and cerebral cortex, and lateral and third ventricle dilation. ELISA of the CSF was positive for neurocysticercosis.


Our patient declined surgery. We gave hydrocortisone, albendazole, and valproic acid, followed by levothyroxine. Treatment resolved the headache and functional improvement was seen.

Racemose neurocysticercosis should always be considered in the differential diagnosis of cystic space-occupying lesions in the sella turcica. Other options include cystic pituitary adenoma, craniopharyngioma, and dermoid cysts.

Source: Lancet

Subclinical thyroid disease: where is the evidence?

Subclinical thyroid disease is very common, particularly in elderly people. Recognition of this endocrine disorder is increasing, partly due to a large increase in thyroid function testing, especially in primary care. Many cross-sectional studies have investigated whether subclinical hyperthyroidism or subclinical hypothyroidism are associated with specific symptoms, signs, or comorbidities, and a smaller number of prospective studies have examined whether subclinical thyroid disease predicts specific adverse outcomes.1

What is the latest evidence driving the need, or otherwise, for therapeutic intervention in these common, and largely asymptomatic, biochemically defined disorders? A large and seemingly irrefutable body of evidence exists supporting the association of subclinical hyperthyroidism with atrial fibrillation risk, especially when thyroid-stimulating hormone (TSH) is at undetectable concentrations.23 Subclinical hyperthyroidism is also associated with other adverse cardiac outcomes, such as coronary heart disease events and mortality, and heart failure. Evidence linking cardiovascular disorders with tests of thyroid function within the reference range, including higher circulating free thyroxine concentrations,4 suggests that the cardiovascular system is particularly sensitive to subtle changes in thyroid status. Thus, the cardiovascular system is the most important physiological system for which to consider risk, and, in turn, with the potential to benefit from treatment.

If the evidence for risk association with cardiovascular endpoints is strong, why is there controversy about intervention? Several crucial reasons exist. First, association does not prove causation, and many studies have not fully considered potential confounders for comorbidities in conditions such as coronary heart disease and heart failure. Second, nearly all studies have been based on one or two TSH measurements in individual subjects, but low TSH is often transient, especially when only slightly low, and frequently reflects non-thyroidal illnesses or drugs, rather than underlying thyroid disease such as mild Graves’ disease or toxic nodular hyperthyroidism. Third, intervention for subclinical hyperthyroidism means radioiodine therapy or antithyroid drugs, neither of which is trivial. Radioiodine is generally considered the treatment of choice for toxic nodular disease (the most common underlying thyroid diagnosis, in view of the typical age when subclinical hyperthyroidism is diagnosed). Radioiodine treatment often results in hypothyroidism and the need for permanent thyroxine replacement. Since up to half of patients taking thyroxine have subclinical hyperthyroidism or hypothyroidism biochemically, subclinical hyperthyroidism can be perpetuated or replaced with subclinical hypothyroidism. Finally, there have been no randomised controlled trials of treatment of subclinical hyperthyroidism with meaningful clinical endpoints. Two trials were stopped because of low recruitment and a third has recruitment that is lower than planned, although it is continuing. These issues were described in a recent article about the problems encountered with such trials.4 Despite this absence of evidence, expert groups recommend that treatment should be strongly considered, especially in elderly patients;5 surveys of practice show this is occurring. It seems extraordinary that evidence that the benefit of treatment outweighs the risk does not exist in the 21st century for such a common disorder. We can only hope that evidence will accrue in the next few years.

The situation regarding subclinical hypothyroidism is probably more complex and controversial than that for subclinical hyperthyroidism. The most relevant physiological system is again cardiovascular; the largest meta-analysis performed so far reports an association with cardiovascular mortality in more severe cases (ie, serum TSH >10 mIU/L).6 Again, raised TSH is frequently transient, although a persistent increase is a more specific indicator of underlying thyroid disease. However, the upper limit of the TSH reference range rises with age,7 leading to controversy about the definition of disease, especially if TSH is in the 5—10 mIU/L range in elderly people. Randomised controlled trials of treatment (thyroxine replacement) have been done, but these are largely small, heterogeneous, and underpowered, and their findings are unsurprisingly negative or conflicting. A Cochrane review indicated insufficient evidence to recommend for, or against, treatment, including in those with a TSH greater than 10 mIU/L and in very elderly patients.8 However, new evidence9 exists for improved outcomes of coronary heart disease in younger, but not older, patients treated with thyroxine, and there are new data10 showing that thyroxine treatment helps to preserve renal function in people with subclinical hypothyroidism and chronic kidney disease. Fortunately, several clinically relevant trials are underway—including one EU-funded multicentre study of patients older than 80 years that will examine cardiovascular and quality-of-life outcomes—so the evidence base for subclinical hypothyroidism should increase and better guide us in our therapeutic approach.


1 Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012; 379: 1142-1154. Summary | Full Text | PDF(416KB) |CrossRef | PubMed

2 Collet TH, Gussekloo J, Bauer DC, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.Arch Intern Med 2012; 172: 799-809. CrossRef | PubMed

3 Gammage MD, Parle JV, Holder RL, et al. Association between serum free thyroxine concentration and atrial fibrillation.Arch Intern Med 2007; 167: 928-934. CrossRef | PubMed

4 Goichot B, Pearce SH. Subclinical thyroid disease: time to enter the age of evidence-based medicine. Thyroid 2012; 22:765-768. CrossRef | PubMed

5 Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract 2011; 17: 456-520.CrossRef | PubMed

6 Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality.JAMA 2010; 304: 1365-1374. CrossRef | PubMed

7 Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C, Cappola AR. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J Clin Endocrinol Metab 2012; 97: 3944-3950.CrossRef | PubMed

8 Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev 2007; 3. CD003419

9 Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med 2012; 172: 811-817. CrossRef | PubMed

10 Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2012; 97: 2732-2740. CrossRef | PubMed

Source: Lancet

Making sense of chromogranin A in heart disease.

Chromogranin A is an acidic protein present in secretory granules of neuroendocrine cells. In plasma, chromogranin A is an important marker of neuroendocrine tumours. Chromogranin A measurement has gained interest in cardiovascular disease, because increased plasma concentrations are associated with risk of clinical deterioration and death in patients with acute coronary syndromes or chronic heart failure. Cardiac chromogranin A is stored in atrial granules with cardiac natriuretic peptides—the principal cardiac hormones associated with systemic homoeostasis of water and blood pressure. Expression of cardiac chromogranin A is decreased in patients treated with mechanical assist device therapy, which parallels findings on B-type natriuretic peptide mRNA expression and concomitant plasma concentrations.1

Support for a cardiovascular role for chromogranin A comes from mice deficient in chromogranin A gene expression, because they display a hypertensive phenotype that can be fully reversed by infusion with the chromogranin A fragment catestatin.2One proposed explanation for this is that mice deficient in chromogranin A have increased catecholamine release, which is a known mechanism in essential hypertension. The first observation of chromogranin A in myocardial infarction was reported by Omland and colleagues in 2003.3 Plasma concentrations of chromogranin A were measured in 119 patients 3 days after onset of symptoms. Increased plasma chromogranin A concentrations were associated with an increased risk of death, but the association disappeared when the results were adjusted for patient age. In a later study from the same researchers,4plasma chromogranin A concentrations were found to be predictive of patient outcomes following myocardial infarction after multivariable analyses that included patient age, diabetes, and sex. The largest study so far on chromogranin A in acute coronary syndromes included 1268 patients with a follow-up of 7·5 years.5 Basal chromogranin A concentrations in plasma were strongly associated with long-term mortality, admissions to hospital for heart failure, and recurrent myocardial infarction, with hazard ratios between 1·27 (95% CI 1·10—1·47) and 1·57 (95% CI 1·44—1·70). The association was maintained even after the results were adjusted for conventional risk markers.

Chronic heart failure is characterised by pronounced activation of the neuroendocrine system and adrenal noradrenaline release; chromogranin A could be a useful clinical marker in this syndrome.6 So far, the largest study of plasma chromogranin A measurement in chronic heart failure is the GISSI-Heart Failure trial.7 The study included 1233 patients with stable heart failure and followed them up for 4 years. In univariable analysis, increased chromogranin A plasma concentrations were associated with all-cause mortality, with hazard ratios between 1·58 (95% CI 1·17—2·11) and 2·35 (95% CI 1·78—3·10). However, after adjustment for known risk factors of mortality the association was lost. Thus, this clinically well characterised study concluded that chromogranin A measurement does not seem to be useful in the assessment of mortality risk in stable chronic heart failure beyond what physical examination, routine biochemical analyses, and cardiac natriuretic peptide measurement already offer. Since this study, two small investigations have been reported on chromogranin A as a biomarker in heart failure.89 Both suggest that chromogranin A measurement adds independent prognostic information beyond B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement.

Measurement of plasma chromogranin A is a complex matter. Chromogranin A is a protein that contains many dibasic aminoacid motifs prone to endoproteolytical cleavage. The cellular processing of chromogranin A encompasses a plethora of fragments from the primary precursor, some of which are proposed to have independent hormonal activity (figure). However, no specific receptor-mediated mechanisms have been identified for the fragments. The primary structure of the peptide fragments also challenges the idea that they act as soluble hormones in plasma. One way around the troublesome processing of chromogranin A could be to use a processing-independent assay for measurement. By production of a uniform peptide fragment for standard measurement by epitope-specific radioimmunoassay (or other types of immunoassays), the assay can be correctly calibrated and can measure the total sum of chromogranin A translational products irrespective of its variable and poorly characterised cellular processing.10 A processing-independent assay has the general advantage of storage stability of plasma samples, since they need treatment with trypsin or another suitable endoprotease to release the measured ligand. For now, we conclude that the present studies should be interpreted with caution, because plasma chromogranin A is not a uniform analyte, and the assays used so far measure different—and often unknown—epitopes within the primary protein structure.


1 Wohlschlaeger J, von Winterfeld M, Milting H, et al. Decreased myocardial chromogranin A expression and colocalization with brain natriuretic peptide during reverse cardiac remodeling after ventricular unloading. J Heart Lung Transplant 2008;27: 442-449. CrossRef | PubMed

2 Mahapatra NR, O’Connor DT, Vaingankar SM, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 2005; 115: 1942-1952. CrossRef | PubMed

3 Omland T, Dickstein K, Syversen U. Association between plasma chromogranin A concentration and long-term mortality after myocardial infarction. Am J Med 2003; 114: 25-30. CrossRef | PubMed

4 Estensen ME, Hognestad A, Syversen U, et al. Prognostic value of plasma chromogranin A levels in patients with complicated myocardial infarction. Am Heart J 2006; 152: 927e1-927e6. PubMed

5 Jansson AM, Røsjø H, Omland T, et al. Prognostic value of circulating chromogranin A levels in acute coronary syndromes.Eur Heart J 2009; 30: 25-32. CrossRef | PubMed

6 Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148-2159. CrossRef | PubMed

7 Røsjø H, Masson S, Latini Rfor the GISSI-HF Investigators. Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial. Eur J Heart Fail 2010; 12: 549-556. CrossRef | PubMed

8 Dieplinger B, Gegenhuber A, Kaar G, Poelz W, Haltmayer M, Mueller T. Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department. Clin Biochem 2010; 43: 714-719.CrossRef | PubMed

9 Zhu D, Wang F, Yu H, Mi L, Gao W. Catestatin is useful in detecting patients with stage B heart failure. Biomarkers 2011;16: 691-697. CrossRef | PubMed

10 Goetze JP, Hunter I, Lippert SK, Bardram L, Rehfeld JF. Processing-independent analysis of peptide hormones and prohormones in plasma. Front Biosci 2012; 17: 1804-1815. CrossRef | PubMed

Source: Lancet

Hormone Imbalance,Thyroid Regulation & Bipolar Disorder.

Here are two reasons to care about thyroid:

1. There is a clear connection between the process of thyroid hormoneregulation and bipolar disorder.  The problem is, this connection is only just now beginning to become evident, and how the connection works is basically a mystery.  Two studies recently showed a strikingly high rate of autoimmune-caused thyroid problems in people with bipolar disorder, far more than you would expect to find.Vonk, Kupka  Thyroid problems are more common in the complex forms of bipolar disorder (mixed states and rapid cycling) than in classic bipolar manic patients.Chang  Signs of thyroid auto-immunity are much more common in people with anxiety and depression, particularly the forms of anxiety which don’t easily fit into typical “anxiety disorder” labels.Carta

2. Two studies have shown that people with bipolar depression were less likely to get better if they had low thyroid levels, whereas the ones with higher levels responded pretty well.Cole, Frye . The same phenomenon was recently shown even in “unipolar” depression.Gitlin.  These three studies are the basis for a treatment approach you could consider, particularly if depression is your main problem:  gently pushing your thyroid status over toward the “hyperthyroid” end of normal, if you happen now to be toward the hypothyroid end of normal (the lab testing we use to place you on this spectrum is explained below). Update 4/2008: this approach, using just a little bit of the standard form of thyroid hormone — T4, explained below — was recently tested directly.  The results were very positive, but it was a preliminary test with no control group.Lojko

Update 10/09: another research team recently concluded that “reduction in thyroid function can exacerbate bipolar symptoms even in euthyroid subjects.” Frye In other words, people who are in the normal range (“euthyroid”) can see their bipolar symptoms getting worse if their thyroid levels get low, even if that reduction leaves them still in the normal range.

(Finally, you should also know that some people think the standard lab testing for thyroid status does not do a good job of figuring out who’s “normal” and who’s not.  In other words, they think that people who are not normal, who are low on thyroid hormone, will actually test “normal” using the standard measures.  More on that controversy below).

Most doctors will not raise this option of adding thyroid unless you are clearly already low. It certainly isn’t the first thing to try for depression. But if you have tried several approaches and are considering what to do next; and if you have enough “bipolarity” to make antidepressants a concern, then it might be worth considering this approach, for this reason:  as long as you and your doctor are careful, and don’t bump you right up into hyperthyroidism, there is no risk in trying this approach — just a series of bloodtests, which a lot of people hate. And there is some risk if you end up hyperthyroid.

That is all supposed to sound pretty weak, as a justification for this approach.  It is weak.  But some people with bipolar depression need to know of every option they might try before turning to antidepressants, as explained in the essay entitled Antidepressants That Aren’t Antidepressants. If that’s not you, don’t go carrying this thyroid page to your doctor, she might scoff at you, as there is a long history of unsupported use of thyroid hormone and you don’t want to get branded as “one of those people”.  Even so, the relationship of mood and thyroid is extremely complex, almost mysterious.

Let’s take a quick look at that complexity before turning back to why you might want to learn more about thyroid and bipolar disorder. There are reports linking the entire stress hormone system (here are some basics on stress and depression) to changes in thyroid function.  This part is really complicated.  The short version, translating from two amazing reviews of stress and mental health, is that stress hormones interfere with the production of thyroid hormone and with the conversion of thyroid hormone to its active form. Tsigos, Charmandari

It is also clear that people whose symptoms look the kinds of “bipolar disorder” explained on this website, have thyroid problems — and family members with thyroid problems — at a greater rate than would be expected.  Is that because the thyroid problems somehow actually cause “bipolar”-like symptoms?  Could it be that some of what looks like “bipolar” is actually a thyroid problem?  There may be some such folks.  In addition, there are clearly cases which seem to be “bipolar disorder” for sure, that get better with thyroid hormones as part of the treatment.  In many of these cases it is clear that thyroid hormone was not enough, by itself, to make mood “normal”.  So, for now I think it is safe to say that bipolar disorder has something to do with thyroid regulation in many cases, though not the majority; and that treating with thyroid alone is only rarely going to lead to full remission of symptoms (with a few notable exceptions…).

So, you need to know about thyroid and bipolar disorder for several reasons:

1. There is some relationship between the two, though poorly understood.

2. You need to make sure your thyroid is okay before you begin treatment for bipolar disorder, because

  • if it’s not okay, you might not respond fully to treatment; and
  • it’s usually pretty easy to get your thyroid hormone in the right place, which by itself could help your symptoms somewhat.

3. Thyroid hormone is sometimes used as a treatment for bipolar disorder, even if your thyroid is “normal” (by lab tests, anyway).

4.  And finally, lithium commonly interferes with the thyroid system, so you’ll need to understand a bit about thyroid if you’re going to take lithium.






Congenital adrenal hyperplasia: one hundred years of data.

It is rare to find a data-rich review of the diagnosis of only one disorder that spans over a hundred years. But, in The Lancet Diabetes & Endocrinology, Sebastian Gidlöf and colleagues1 describe the known cases of congenital adrenal hyperplasia in Sweden between 1910 and 2011, a period that encompasses the discovery and implementation of effective treatment in 1950, the gradual development of better diagnostic methods, and the introduction of early diagnosis by neonatal screening in the 1980s.

Congenital adrenal hyperplasia is the most common adrenal disorder in children. Indeed, it is a group of disorders, the most common type being 21-hydroxylase deficiency, associated with low cortisol and aldosterone production. Clinical presentation includes potentially fatal salt-wasting crises, female genital virilisation, and premature pubarche. Gidlöf and colleagues’ Article contributes to our understanding of the disorder in interesting and surprising ways. Most high-income countries have introduced neonatal screening for congenital adrenal hyperplasia, some as much as 30 years ago,2 and indeed it has recently been introduced in Laos, a country with no previous neonatal screening programme.3 However, congenital adrenal hyperplasia screening has not been implemented in either the UK4 or Australia.5 Early detection of the disorder is mainly aimed at the prevention of salt-wasting crises, wrong sex-assignment, and premature pubarche or accelerated growth.

Gidlöf and colleagues’ data clearly show the apparent increase in incidence over time, which they attribute to poor diagnosis before the 1960s and to the fact that the availability of treatment and increased awareness of the disorder increases the likelihood of physicians identifying and diagnosing the disease. Importantly, the investigators postulate that the frequency of this global disease is likely to have remained steady over the period, and thus they are able to calculate the probable number of missed cases over time, assuming that almost all severe cases (the salt-wasting phenotype) are now effectively diagnosed. Their postulations of the numbers of missed cases was enlightening. Male neonates with the severe salt-wasting phenotype are thought to have a higher risk of death than their female counterparts, because diagnosis of female neonates is easier owing to their virilised genitalia, leading to the possibility that they receive treatment earlier and more often than do boys. Findings from Gidlöf and colleagues’ study, however, showed that in people with the salt-wasting form of the disorder, the risk of death was substantial—some five to ten patients died every year before 19701—and much the same in both female and male patients without early diagnosis. Evidently, both male and female babies die undiagnosed, and not, as previously thought, only male babies.

Other important information provided by Gidlöf and colleagues—information usually unavailable in reports of screening—is an estimated false-negative rate of was almost 16%. Such estimates are not usually given in reports of screening, but one report that did, from Minnesota, USA,6 showed a false-negative rate of 22% (15 of 67 cases) for people with the classic form of the disorder during 12 years of neonatal screening between January 1999 and 2010. Of 15 missed cases, five had the salt-wasting form, but four of these five were girls who were diagnosed on the basis of their virilised genitalia. In Gidlöf and colleagues’ Swedish study, more than half of patients had late-onset, non-classic forms of the disorder that were missed by screening.1 However, the detection of late-onset cases is, arguably, not the main target of neonatal screening. Publication of more detailed data from existing screening programmes would be welcome.

It is surprising that after 30 years of neonatal screening worldwide there is still a need for additional screening data and, importantly, follow-up, so that the benefits of screening can be accurately assessed, and screening efficiency can be maximised. Uncertainty still exists about outcomes, and how screening can improve outcomes. An adrenal crisis with accompanying hyponatraemia is thought to cause brain damage, but available evidence does not lend support to the suggestion that patients with congenital adrenal hyperplasia have any intellectual deficits compared with otherwise healthy individuals.78 A clear need exists for more research in this area to be sure that more subtle learning difficulties are not present. However, there is little doubt that screening for the disorder fulfils the essential criteria for screening—it is, after all, a potentially lethal disorder—and a 2010 study in the UK concluded that a case can be made for screening.4 Certainly paediatric endocrinologists from Australia agree.5

The Swedish study underlines what can be learned from long-term follow-up, good record keeping, and registers. This type of activity should not only be encouraged but also funded if we are to make best use of our accumulated experience. At the same time, we should remember that for any long-term study, data collected at the beginning might not be entirely comparable with those collected towards the end. Medical diagnostic and therapeutic expertise moves on, so we need to draw conclusions with care.

Source: Lancet


Amputations and socioeconomic position among persons with diabetes mellitus, a population-based register study.


Objective Low socioeconomic position is a known health risk. Our study aims to evaluate the association between socioeconomic position (SEP) and lower limb amputations among persons with diabetes mellitus.

Design Population-based register study.

Setting Finland, nationwide individual-level data.

Participants All persons in Finland with any record of diabetes in the national health and population registers from 1991 to 2007 (FinDM II database).

Methods Three outcome indicators were measured: the incidence of first major amputation, the ratio of first minor/major amputations and the 2-year survival with preserved leg after the first minor amputation. SEP was measured using income fifths. The data were analysed using Poisson and Cox regression as well as age-standardised ratios.

Results The risk ratio of the first major amputation in the lowest SEP group was 2.16 (95% CI 1.95 to 2.38) times higher than the risk in the highest SEP group (p<0.001). The incidence of first major amputation decreased by more than 50% in all SEP groups from 1993 to 2007, but there was a stronger relative decrease in the highest compared with the lowest SEP group (p=0.0053). Likewise, a clear gradient was detected in the ratio of first minor/major amputations: the higher the SEP group, the higher the ratio. After the first minor amputation, the 2-year and 10-year amputation-free survival rates were 55.8% and 9.3% in the lowest and 78.9% and 32.3% in the highest SEP group, respectively.

Conclusions According to all indicators used, lower SEP was associated with worse outcomes in the population with diabetes. Greater attention should be paid to prevention of diabetes complications, adherence to treatment guidelines and access to the established pathways for early expert assessment when diabetic complications arise, with a special attention to patients from lower SEP groups.


Source: BMJ