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[Michael Scally MD]

A Practical Guide To Male Hypogonadism In The Primary Care Setting.

There is a high prevalence of hypogonadism in the middle- and older-aged male population and various prevalence figures have been described in a number of studies. A consistent feature of these studies is that hypogonadism increases with age. As the number of individuals aged 65 years and over in the US population is projected to rise from approximately 40 million (13.0%) in 2010 to approximately 60 million (17.9%) in 2025, the number of men, who presently comprise approximately 43% of this population, that are hypogonadal will also increase. As a result, physicians will be increasingly likely to encounter men with the symptoms of hypogonadism in the clinic.

The purpose of this review is to summarize the current understanding of male hypogonadism, with particular reference to the needs of the primary care physician. A key consideration for any physician is to understand the clinical significance of low testosterone levels and how hypogonadal men are likely to benefit from testosterone replacement therapy. It is also important to have a good understanding of the contraindications and risks associated with the therapy as well as the necessary treatment monitoring required.


Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract 2011;64(6):682-96. A practical guide to male hypogonadism in the primary care setting - Dandona - 2010 - International Journal of Clinical Practice - Wiley Online Library

There is a high prevalence of hypogonadism in the older adult male population and the proportion of older men in the population is projected to rise in the future. As hypogonadism increases with age and is significantly associated with various comorbidities such as obesity, type 2 diabetes, hypertension, osteoporosis and metabolic syndrome, the physician is increasingly likely to have to treat hypogonadism in the clinic. The main symptoms of hypogonadism are reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, osteoporosis/low bone mass, depressed mood and fatigue. Diagnosis of the condition requires the presence of low serum testosterone levels and the presence of hypogonadal symptoms. There are a number of formulations available for testosterone therapy including intramuscular injections, transdermal patches, transdermal gels, buccal patches and subcutaneous pellets. These are efficacious in establishing eugonadal testosterone levels in the blood and relieving symptoms. Restoration of testosterone levels to the normal range improves libido, sexual function, and mood; reduces fat body mass; increases lean body mass; and improves bone mineral density. Testosterone treatment is contraindicated in subjects with prostate cancer or benign prostate hyperplasia and risks of treatment are perceived to be high by many physicians. These risks, however, are often exaggerated and should not outweigh the benefits of testosterone treatment.

 

[Michael Scally MD]

Hypogonadotropic Hypogonadism And Congenital Adrenal Hypoplasia

DAX-1 [Dosage sensitive sex-reversal, Adrenal hypoplasia congenita, on the X chromosome gene 1], alternatively called NR0B1, is a gene that encodes an orphan member of the nuclear hormone receptor family. The protein translated from this gene, called DAX-1, is essentially expressed in tissues involved in steroid hormone production and reproductive function such as the adrenals, hypothalamus and pituitary, as well as the testes. Clinically, NR0B1/DAX1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) (MIM # 300200) associated with hypogonadotropic hypogonadism (HH).

In mice, Nr0b1 null homozygous male mice have adrenal insufficiency as well as testicular disorganization, dilated seminiferous tubules and failed spermatogenesis. The dilated tubules in the adult reflect impaired testis cord morphogenesis during embryonic development. Histological examination revealed a progressive degeneration of seminiferous tubule epithelium, hyperplasia of Leydig cells and sloughing of germ cells. A Sertoli-cell-specific expression of a DAX1 transgene is sufficient to partially rescue the primary testicular defect of the male Dax-1-deficient mouse.

Relatively few data are currently available concerning the testicular function and fertility of men with X-linked AHC harbouring DAX1 mutations. Some cases of azoospermia as well as failure of gonadotrophin treatment have been described. Oligospermia has been reported in a rare case of late-onset AHC associated with a partial loss-of-function mutation. The failure of the gonadotrophin treatment described was judged on semen quality, and open testicular biopsy had not been attempted previously in order to treat male infertility.

Researchers report the first birth of a child after a successful assisted reproductive technique (ART) in a man with classic AHC and HH due to a DAX1 mutation, using TESE–ICSI.


Frapsauce C, Ravel C, Legendre M, et al. Birth after TESE-ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation. Hum Reprod 2011;26(3):724-8. Birth after TESE–ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation

DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported.

We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12-40) with low FSH and LH levels at 2.1 IU/l (N: 1-5 IU/l) and 0.1 IU/l (N: 1-4 IU/l), respectively. Baseline semen analysis revealed azoospermia.

Menotropin (Menopur((R)):150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used.

After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen-thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy.

We report the first case of paternity after TESE-ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH.

 

[Michael Scally MD]

Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity

Super-Sticky 'Ultra-Bad' Cholesterol Revealed in People at High Risk of Heart Disease
Super-sticky 'ultra-bad' cholesterol revealed in people at high risk of heart disease

ScienceDaily (May 26, 2011) — Scientists from the University of Warwick have discovered why a newly found form of cholesterol seems to be 'ultra-bad', leading to increased risk of heart disease. The discovery could lead to new treatments to prevent heart disease particularly in people with type 2 diabetes and the elderly.

The research, funded by the British Heart Foundation (BHF), found that 'ultra-bad' cholesterol, called MGmin-low-density lipoprotein (LDL), which is more common in people with type 2 diabetes and the elderly, appears to be 'stickier' than normal LDL. This makes it more likely to attach to the walls of arteries. When LDL attaches to artery walls it helps form the dangerous 'fatty' plaques' that cause coronary heart disease (CHD).

CHD is the condition behind heart attacks, claiming 88,000 lives in the UK every year.

The researchers made the discovery by creating human MGmin-LDL in the laboratory, then studying its characteristics and interactions with other important molecules in the body.

They found that MGmin-LDL is created by the addition of sugar groups to 'normal' LDL -- a process called glycation -- making LDL smaller and denser. By changing its shape, the sugar groups expose new regions on the surface of the LDL. These exposed regions are more likely to stick to artery walls, helping to build fatty plaques. As fatty plaques grow they narrow arteries -- reducing blood flow -- and they can eventually rupture, triggering a blood clot that causes a heart attack or stroke.

The discovery might also explain why metformin, a widely prescribed type 2 diabetes drug, seems to lead to reduced heart disease risk. Metformin is known to lower blood sugar levels, and this new research shows it may reduce the risk of CHD by blocking the transformation of normal LDL to the more 'sticky' MGmin-LDL.

Dr Naila Rabbani, Associate Professor of Experimental Systems Biology at Warwick Medical School, who led the study, said:

"We're excited to see our research leading to a greater understanding of this type of cholesterol, which seems to contribute to heart disease in diabetics and elderly people. Type 2 diabetes is a big issue -- of the 2.6 million diabetics in the UK, around 90 per cent have type 2. It's also particularly common in lower income groups and South Asian communities.

"The next challenge is to tackle this more dangerous type of cholesterol with treatments that could help neutralise its harmful effects on patients' arteries."

Dr Shannon Amoils, Research Advisor at the BHF, which funded the study, said:

"We've known for a long time that people with diabetes are at greater risk of heart attack and stroke. There is still more work to be done to untangle why this is the case, but this study is an important step in the right direction.

"This study shows how the make-up and the shape of a type of LDL cholesterol found in diabetics could make it more harmful than other types of LDL. The findings provide one possible explanation for the increased risk of coronary heart disease in people with diabetes.

"Understanding exactly how 'ultrabad' LDL damages arteries is crucial, as this knowledge could help develop new anti-cholesterol treatments for patients."


Rabbani N, Godfrey L, Xue M, et al. Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity. Diabetes. Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity /
ftp://ftp.sheridan.com/pub/content_services/ADA/Diabetes/Rabbani_db110085_qb9d30.pdf

OBJECTIVE To study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.

RESEARCH DESIGN AND METHODS Human LDL was isolated and modified by MG in vitro to minimal extent (MGmin-LDL) as occurs in vivo. Atherogenic characteristics of MGmin-LDL were characterized: particle size, proteoglycan-binding, susceptibility to aggregation, LDL and non-LDL receptor–binding, and aortal deposition. The major site of modification of apolipoprotein B100 (apoB100) modification was investigated by mass spectrometric peptide mapping.

RESULTS MGmin-LDL contained 1.6 molar equivalents of MG modification—mostly hydroimidazolone—as found in vivo. MGmin-LDL had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall. Mass spectrometry peptide mapping identified arginine-18 as the hotspot site of apoB100 modification in MGmin-LDL. A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.

CONCLUSIONS MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.

 

[Michael Scally MD]

Does Our Personality Affect Our Level of Attractiveness?
Does our personality affect our level of attractiveness?

ScienceDaily (May 27, 2011) — Part of what determines how much success you will have in the dating world is whether you have a good sense of whether people find you attractive. A new study published in Psychological Science, a journal of the Association for Psychological Science, finds that certain personality traits contribute to being a good judge of whether someone else thinks you're worth meeting again.

The study is one of a series to come out of a big speed-dating experiment held in Berlin about five years ago. "Most of the prior research had worked with hypothetical scenarios, where people are asked by a questioner, 'What kind of people would you like to get to know?' and so on," says Mitja Back of the Johannes Gutenberg University of Mainz, who co-wrote the new paper with Lars Penke of the University of Edinburgh, Stefan Schmukle of Westfälische Wilhelms-Universität Münster, and Jens Asendorpf of Humboldt University Berlin. The problem, of course, is that what people say they like -- honesty, humor, and so on -- may have little to do with what they actually like -- for example hotness.

In this case, Back was interested in another question: is there's something about personality that makes some people better at predicting whether others will want to meet them? In 17 groups, a total of 190 men and 192 women met members of the opposite sex -- basically the standard speed dating routine, but this time, with psychologists collecting a lot of data. Among that data was personality information and the all-important question after each three-minute date: for each person you talk to, do you want to see that person again? They were also asked if they thought the other person would want to meet them.

On the whole, people are very bad at guessing how many of the other persons will want to meet them. Some people had no clue at all. But others did better. Success was correlated with particular traits that are stereotypically associated with the sexes: Men who have a more promiscuous orientation were better at guessing if a woman would want to meet them, and women whose personality was very agreeable were better at guessing if a man would meet them.

Back thinks men who are inclined toward casual sex are displaying behavior that's very stereotypically associated with their sex; this may in turn evoke more typical behavior in the woman they're talking to, which could make them more accurate at predicting whether the woman will be interested. Women who are agreeable, on the other hand, might make men more comfortable and more willing to flirt -- which could make it easier to judge whether the man will want to meet them again.

"Speed dating is a very good context to study dating behavior," Back says. "It's almost like psychologists could have invented this."

The article title is, "Knowing your own mate value: Sex-specific personality effects on the accuracy of expected mate choices.”


Back, M. D., Penke, L., Schmukle, S. C., & Asendorpf, J. B. (in press). Knowing your own mate value: Sex-specific personality effects on the accuracy of expected mate choices. Psychological Science. http://www.larspenke.eu/pdfs/Back_Penke_Schmuckle_Asendorpf_in_press_-_Mate_value_accuracy.pdf

Knowing one’s mate value (mate value accuracy) is an important psychological mechanism that ultimately fosters reproductive success. Here, we investigated interindividual differences in this ability within a real-life speed-dating context. A total of 190 men and 192 women filled out a personality questionnaire and participated in speed dating sessions. Immediately after each date, choices and expected choices were recorded. In line with evolutionarily informed hypotheses, sociosexually unrestricted men and more agreeable women showed greater mate value accuracy. Results have important implications for understanding mating behavior and the origin of sex differences in personality.

 

[Michael Scally MD]

Optimizing Nutrition For Performance At Altitude

Human beings are unique for their capacity to maximize their physical potential through various means. High altitude mountaineering is one such way that people challenge generally accepted notions about what is biologically and evolutionarily possible. While a 20,000+ft summit may be uninhabitable for extended periods of time, enterprising individuals have demonstrated that even the most remote locations are accessible with sufficient physical effort and proper strategy. High altitude athletes, and the scientists who study them, generally focus their research and preparation on physiological parameters, with a particular emphasis on the cardiopulmonary system. While careful scrutiny in this area is certainly justified, the relationship between physiological output at altitude and nutrition is somewhat neglected in the literature. Many athletes, alpinists included, consider eating to be instinctive and mundane. However, very few activities at 30,000 ft or even 15,000 ft are intuitive. Furthermore, nutrition is one of the few variables mountain athletes can control in an otherwise unpredictable environment. Despite the intrinsic limitations and seemingly contradictory findings often associated with performance nutrition studies at high altitude, mountain athletes should adhere to certain dietary guidelines related to macronutrient composition, micronutrient supplementation, and hydration status.

Kechijan D. Optimizing nutrition for performance at altitude: a literature review. J Spec Oper Med 2011;11(1):12-7. http://www.socom.mil/jsom/documents/2011112Kechijan.pdf

 

[Michael Scally MD]

Impact of Common Medications on Serum Total Prostate-specific Antigen Levels

Chang et al. [Chang SL, Harshman LC, Presti JC. Impact of Common Medications on Serum Total Prostate-Specific Antigen Levels: Analysis of the National Health and Nutrition Examination Survey. Journal of Clinical Oncology 2010;28(25):3951-7. Impact of Common Medications on Serum Total Prostate-Specific Antigen Levels: Analysis of the National Health and Nutrition Examination Survey ] recently published a large cross-sectional study on the impact of nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide diuretics, statins and seven other commonly prescribed medication classes on serum total prostate-specific antigen (PSA) levels. The study included men older than 40 years of age (median age 53 years, median PSA 0.8 ng/ml) without prostate cancer from the 2003-2004 and 2005-2006 cycles of the U.S.A. National Health and Nutrition Examination Survey (n=1,864). Five-years use of NSAIDs, statin and thiazide diuretic was associated with PSA levels lowered by 6, 13 and 26%, respectively. PSA is one of the crucial baseline parameters, together with Gleason score and clinical T stage, that form the basis of the U.S.A. National Comprehensive Cancer Network (NCCN) prostate cancer risk group classification. For example, a patient with a PSA value of 9.1 ng/ml, Gleason score of 3+3, and T1c cancer would be classified as being at low risk and treated accordingly. If the same patient had hypertension and had been treated with thiazide diuretics, his true PSA value would have been >10 ng/ml, provided the hypothesis of 26% lower PSA level among thiazide diuretics users is true in prostate cancer patients. With a PSA level >10 ng/ml, the patient would belong to the intermediate-risk group and management according to low risk category guidelines may then result in under treatment. Based on these considerations, there is an urgent need to extend the study by Chang et al. to men with histologically confirmed prostate cancer diagnosis. This study examined a cohort of men with clinically localized prostate cancer, diagnosed and treated in a well-defined geographical region of Norway to estimate the impact of use of NSAIDs, statins and thiazide diuretics on NCCN risk group classification.


Nieder C, Norum J, Geinitz H. Impact of Common Medications on Serum Total Prostate-specific Antigen Levels and Risk Group Assignment in Patients with Prostate Cancer. Anticancer Res 2011;31(5):1735-9. Impact of Common Medications on Serum Total Prosta... [Anticancer Res. 2011] - PubMed result

A recent study in men without prostate cancer suggested that extended use of common medications (nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide diuretics and statins) may lower serum total prostate-specific antigen (PSA) levels by clinically relevant amounts. The present study evaluated the impact of these drugs in patients with clinically localized prostate cancer. A retrospective analysis of 177 patients was performed. The multivariate regression analyses were adjusted for age, prostate volume, Gleason score, T stage, diagnostic setting (clinical symptoms versus elevated PSA only) and presence of diabetes mellitus.

Drug use increased with age, e.g. to 50% in patients >/=70 years. The most commonly used drugs were statins (32% of all patients, including those who used drug combinations), followed by NSAIDs (21%) and thiazide diuretics (13%). Drug use was associated with a statistically significant PSA reduction (12%, when comparing 104 non-users to 73 users of any of the three drug types; adjusted analysis, p=0.01). Compared to the U.S.A. National Comprehensive Cancer Network risk group assignment based on measured PSA level, reassignment after correcting for medication use resulted in 8 changes among 57 patients with low or intermediate risk (14%). No such changes can be expected in patients belonging to the high-risk group.

These results support the concerns expressed previously, given that risk group assignment, which may be inaccurate in patients using concomitant medications, eventually guides choice of treatment.

 

[Michael Scally MD]

Post Coital Gross Hematuria/Hematospermia

Male post-coital gross hematuria is a rare clinical symptom, which can be caused by different pathological entities. Post-coital gross hematuria, which is quite uncomfortable, is an unsettling condition. The objectives of this study were to analyze clinical features of male patients exhibiting post-coital massive hematuria and to identify underlying serious and/or malignant disease.


Amano T, Otani T, Ryuge Y, Senda M, Imao T, Takemae K. Male post-coital gross hematuria: are there any complications? 2011;8(2):136-9. http://www.jmhjournal.org/article/S1875-6867(11)00037-6/abstract (Elsevier)

Background - Male post-coital gross hematuria is an unsettling condition, and various causes have been reported. However, despite the clinical investigation of this disease, many questions remain unresolved. The objective of this study was to analyze clinical features of male patients displaying post-coital massive hematuria.

Materials and Methods - From 2002 to 2010, 15 males complaining of massive hematuria following sexual intercourse presented to our clinic. Backgrounds and general conditions were analyzed. Furthermore, medical findings and clinical course were evaluated.

Results - The mean age of the 15 patients was 45.0 ± 15.1 (range = 26–70) years. Three patients exhibited bladder tamponade, which necessitated the removal of blood clots from the urinary bladder by trans-urethral irrigation. Hematospermia was observed in four subjects. Anti-coagulation agents were administered in three cases. Benign prostatic hyperplasia and cystic lesion of the prostate were diagnosed in three and one patient, respectively. Positive urine cytology was not detected. Treatment for post-coital gross hemorrhage included administration of antibiotics, hemostatic agents, and careful observation. Ten patients experienced recurrent post-coital gross hematuria; however, this condition generally resolved without serious complications.

Conclusions - Male post-coital gross hematuria is an unsettling condition characterized by occasional recurrence. However, no serious underlying diseases were observed.

 

[Michael Scally MD]

Translation Matters in Choices on Data
http://www.nytimes.com/2011/05/31/health/31data.html?_r=1

By NICHOLAS BAKALAR
Published: May 30, 2011

If your doctor tells you that highly reliable studies have shown that taking a certain pill will cut your risk of getting a serious disease in half, would you take it?

Suppose he adds that the risk is 2 percent for people who do not take the pill, but your risk will be reduced to 1 percent if you do. Would you still take it? And what would you do if he told you that only one of every 100 patients who take the drug will actually benefit from it?

The doctor could have said any of these things, all truthfully, because they are just different ways of describing the same data.

In a review of studies published in The Cochrane Library - Using alternative statistical formats for presenting risks and risk reductions, researchers found that both doctors and patients are largely unaware of these different and equally accurate ways of presenting the same information, and that the format in which data is presented can have a profound influence on health care decisions.

In the first example above, the doctor cited the relative risk reduction — an impressive-sounding 50 percent. In the second, he described the absolute risk reduction, only 1 percent. And in the last, in which he mentioned what appears to be the futility of taking the pill at all, he was reporting the number needed to treat: one case of the disease prevented for every 100 people treated.

The researchers, led by Dr. Elie A. Akl, an associate professor of medicine at the University at Buffalo, part of the State University of New York system, analyzed 35 studies that used hypothetical examples like the one above, and recorded the responses to statistics presented in different formats.

Some of the studies tested persuasiveness — the willingness of a patient to start a treatment, or that of a doctor to prescribe it. Others examined ability to understand — for example, by presenting data and seeing if the subject could accurately estimate the probability of getting the disease.

And some looked at perception, by offering statistics in various formats and having people rate how effective they believed the treatment to be.

The researchers tested health professionals, patients, students and the general public. Perhaps surprisingly, there were no significant differences among them in the accuracy with which they interpreted the various statistical presentations.

Both patients and doctors viewed a treatment as more effective when presented with its relative risk reduction rather than its absolute risk reduction.

Apparently, to health professionals and laymen alike, a 50 percent risk reduction sounds much bigger than a reduction from 2 percent to 1 percent, even though they are identical. When statistics were presented as number needed to treat — 100 people treated to prevent one case of the disease — they were least persuasive of all.

Dr. Akl believes that doctors need to be careful in reporting statistics to patients because how doctors describe the numbers affects decisions.

“Based on what we know,” he said, “the best thing is to present both sides of the story: If you don’t take the medication, your risk is 2 percent, and if you do take it your risk will be 1 percent. This is the most transparent way to present it.”

Still, he added, it depends on the patient. Some like to hear the numbers, while for others numbers only increase anxiety without increasing understanding.

“It’s good to know your patient and know how much they expect,” he said.

Dr. Akl had a warning for health writers and reporters as well, and, at least implicitly, for those who read them.

“Journalists have to be careful about press releases with ‘new’ or ‘groundbreaking’ studies presented with relative risk reductions,” he said. “For example, a study might claim a risk reduction of 50 percent. If the risk goes from 20 percent to 10 percent, that’s impressive. If it goes from 4 percent to 2 percent, it’s not. And both of them are 50 percent reductions.”


Akl EA, Oxman AD, Herrin J, et al. Using alternative statistical formats for presenting risks and risk reductions. Cochrane Database Syst Rev 2011;3:CD006776. Using alternative statistical formats for presenting risks and risk reductions

BACKGROUND: The success of evidence-based practice depends on the clear and effective communication of statistical information.

OBJECTIVES: To evaluate the effects of using alternative statistical presentations of the same risks and risk reductions on understanding, perception, persuasiveness and behaviour of health professionals, policy makers, and consumers.

SEARCH STRATEGY: We searched Ovid MEDLINE (1966 to October 2007), EMBASE (1980 to October 2007), PsycLIT (1887 to October 2007), and the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2007, Issue 3). We reviewed the reference lists of relevant articles, and contacted experts in the field.

SELECTION CRITERIA: We included randomized and non-randomized controlled parallel and cross-over studies. We focused on four comparisons: a comparison of statistical presentations of a risk (eg frequencies versus probabilities) and three comparisons of statistical presentation of risk reduction: relative risk reduction (RRR) versus absolute risk reduction (ARR), RRR versus number needed to treat (NNT), and ARR versus NNT.

DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, extracted data, and assessed risk of bias. We contacted investigators to obtain missing information. We graded the quality of evidence for each outcome using the GRADE approach. We standardized the outcome effects using adjusted standardized mean difference (SMD).

MAIN RESULTS: We included 35 studies reporting 83 comparisons. None of the studies involved policy makers. Participants (health professionals and consumers) understood natural frequencies better than probabilities (SMD 0.69 (95% confidence interval (CI) 0.45 to 0.93)). Compared with ARR, RRR had little or no difference in understanding (SMD 0.02 (95% CI -0.39 to 0.43)) but was perceived to be larger (SMD 0.41 (95% CI 0.03 to 0.79)) and more persuasive (SMD 0.66 (95% CI 0.51 to 0.81)). Compared with NNT, RRR was better understood (SMD 0.73 (95% CI 0.43 to 1.04)), was perceived to be larger (SMD 1.15 (95% CI 0.80 to 1.50)) and was more persuasive (SMD 0.65 (95% CI 0.51 to 0.80)). Compared with NNT, ARR was better understood (SMD 0.42 (95% CI 0.12 to 0.71)), was perceived to be larger (SMD 0.79 (95% CI 0.43 to 1.15)).There was little or no difference for persuasiveness (SMD 0.05 (95% CI -0.04 to 0.15)). The sensitivity analyses including only high quality comparisons showed consistent results for persuasiveness for all three comparisons. Overall there were no differences between health professionals and consumers. The overall quality of evidence was rated down to moderate because of the use of surrogate outcomes and/or heterogeneity. None of the comparisons assessed behaviour.

AUTHORS' CONCLUSIONS: Natural frequencies are probably better understood than probabilities. Relative risk reduction (RRR), compared with absolute risk reduction (ARR) and number needed to treat (NNT), may be perceived to be larger and is more likely to be persuasive. However, it is uncertain whether presenting RRR is likely to help people make decisions most consistent with their own values and, in fact, it could lead to misinterpretation. More research is needed to further explore this question.


Using different statistical formats for presenting health information

Examples illustrating the statistical terms used in this summary:

You read that a study found that an osteoporosis drug cuts the risk of having a hip fracture in the next three years by 50%. Specifically, 10% of the untreated people had a hip fracture at three years, compared with 5% of the people who took the osteoporosis drug every day for three years. Thus 5% (10% minus 5%) less people would suffer a hip fracture if they take the drug for 3 years. In other words, 20 patients need to take the osteoporosis drug over 3 years for an additional patient to avoid a hip fracture. "Cuts the risk of fracture by 50%" represents a relative risk reduction. "Five per cent less would suffer a fracture" represents an absolute risk reduction. "Twenty patients need to take the osteoporosis drug over 3 years for an additional patient to avoid a hip fracture" represents a number needed to treat.

You read that another study found that the risk of suffering a hip fracture over a three year period among people not taking any osteoporotic drug is 10%; another way of expressing this risk would be: 100 of 1000 people not taking any osteoporotic drug will suffer a hip fracture over a three year period. "10%" represents a probability while "100 of 1000" represents a frequency.

Summary:

Health professionals and consumers may change their choices when the same risks and risk reductions are presented using alternative statistical formats. Based on the results of 35 studies reporting 83 comparisons, we found the risk of a health outcome is better understood when it is presented as a natural frequency rather than a probability. On average, people perceive risk reductions to be larger and are more persuaded to adopt a health intervention when its effect is presented in relative terms (eg using relative risk reduction which represents a proportional reduction) rather than in absolute terms (eg using absolute risk reduction which represents a simple difference). We found no differences between health professionals and consumers. The implications for clinical and public health practice are limited by the lack of research on how these alternative presentations affect actual behaviour. However, there are strong logical arguments for not reporting relative values alone, as they do not allow a fair comparison of benefits and harms as absolute values do.

 

[Michael Scally MD]

[For other salient work by Ioannidis, see: https://thinksteroids.com/community/threads/134297485 ]

Comparison of Effect Sizes Associated With Biomarkers Reported in Highly Cited Individual Articles

Many new biomarkers are continuously proposed as potential determinants of disease risk, prognosis, or response to treatment. The plethora of statistically significant associations increases expectations for improvements in risk appraisal. However, many markers get evaluated only in 1 or a few studies. Among those evaluated more extensively, few reach clinical practice.

This translational attrition requires better study. Are the effect sizes proposed in the literature accurate or overestimated? It is interesting to address this question in particular for biomarker studies that are highly cited. Many of these risk factors are also evaluated in meta-analyses that allow overviews of the evidence. However, some meta-analyses may suffer bias from selective reporting, especially among small data sets; then large studies may provide more unbiased evidence.

Here, researchers examined biomarkers that had been evaluated in at least 1 highly cited study and for which at least 1 meta-analysis had been performed for that same association. They aimed to compare the effect size of these associations in the most highly cited studies vs what was observed in the largest studies and the corresponding meta-analyses.

This empirical evaluation of 35 top-cited biomarker studies suggests that many of these highlighted associations are exaggerated. In some cases, these markers may have no predictive ability, if one trusts the subsequent replication record, in particular the results of the largest studies on the same associations. Less than half of these biomarkers have shown nominally significant results in the largest studies that have been conducted on them, and only 1 in 5 has shown an RR greater than 1.37. There are several true associations, but they correspond predominantly to small or modest effects with uncommon exceptions. Such effects, even if genuine, may have only incremental translational value for clinical use.


Ioannidis JPA, Panagiotou OA. Comparison of Effect Sizes Associated With Biomarkers Reported in Highly Cited Individual Articles and in Subsequent Meta-analyses. JAMA: The Journal of the American Medical Association 2011;305(21):2200-10. Comparison of Effect Sizes Associated With Biomarkers Reported in Highly Cited Individual Articles and in Subsequent Meta-analyses, June 1, 2011, Ioannidis and Panagiotou 305 (21): 2200 — JAMA

Context Many biomarkers are proposed in highly cited studies as determinants of disease risk, prognosis, or response to treatment, but few eventually transform clinical practice.

Objective To examine whether the magnitude of the effect sizes of biomarkers proposed in highly cited studies is accurate or overestimated.

Data Sources We searched ISI Web of Science and MEDLINE until December 2010.

Study Selection We included biomarker studies that had a relative risk presented in their abstract. Eligible articles were those that had received more than 400 citations in the ISI Web of Science and that had been published in any of 24 highly cited biomedical journals. We also searched MEDLINE for subsequent meta-analyses on the same associations (same biomarker and same outcome).Data Extraction In the highly cited studies, data extraction was focused on the disease/outcome, biomarker under study, and first reported relative risk in the abstract. From each meta-analysis, we extracted the overall relative risk and the relative risk in the largest study. Data extraction was performed independently by 2 investigators.

Results We evaluated 35 highly cited associations. For 30 of the 35 (86%), the highly cited studies had a stronger effect estimate than the largest study; for 3 the largest study was also the highly cited study; and only twice was the effect size estimate stronger in the largest than in the highly cited study. For 29 of the 35 (83%) highly cited studies, the corresponding meta-analysis found a smaller effect estimate. Only 15 of the associations were nominally statistically significant based on the largest studies, and of those only 7 had a relative risk point estimate greater than 1.37.

Conclusion Highly cited biomarker studies often report larger effect estimates for postulated associations than are reported in subsequent meta-analyses evaluating the same associations.

 

[Michael Scally MD]

Diverse Roles for Sex Hormone Binding Globulin in Reproduction

The sex steroids, testosterone and estradiol, control various aspects of sexual differentiation, gonadal development, and the growth and functional maturation of reproductive tissues. They also influence the maturation of other organ systems during early development, including the lung and kidney. The prenatal effects of androgens exert life-long effects on the expression of genes in the liver, and have been associated with risk for the metabolic syndrome and cardiovascular disease in later life. In addition, androgens and estrogens modulate sexual behaviors that are critical determinants of reproductive success.

As classical hormones, sex steroids or their immediate precursors are produced in the steroidogenic cells of the gonads, adrenal glands and placenta, and are transported in the blood to their target tissues by several steroid-binding proteins. The most abundant plasma protein, albumin, binds all classes of steroids non-specifically and with low affinity, and functions as a reservoir that enhances the solubility of lipophylic molecules and prolongs their biological half-life.

By contrast, a plasma glycoprotein, known as sex hormone-binding globulin (SHBG), binds biologically active androgens and estrogens specifically, with four to five orders of magnitude greater affinity than that of albumin, and is found in the blood of all classes of vertebrates with the exception of birds. Because of its very high ligand-binding affinity, plasma SHBG is the major plasma transport protein for biologically active androgens and estrogens, and changes in the blood levels of SHBG influence their plasma distribution and access to target tissues and cells.

The steroid-binding specificity of SHBG varies between species, but androgens are generally the preferred ligand of SHBG in mammals. In the past, SHBG has therefore also been widely referred to as the androgen-binding protein (ABP) by reproductive biologists, who have studied its production in the testis and how it might influence sperm maturation in male reproductive tract. The cloning of the human SHBG and rat Abp cDNAs and their genes, however, revealed that these proteins are orthologs, and the products of a single gene, which is expressed at low levels in several tissues in addition to the liver and testis. Recently, a second SHBG-related gene encoding an ancient paralog of SHBG has been identified in the Salmonidae order of teleosts, and it is referred to as salmonid shbgb. Unlike the evolutionarily conserved shbg gene, the salmonid shbgb gene is expressed primarily in the ovary, gill and muscle, and is not expressed in the liver or testis.

This review compares the expression and regulation of SHBG genes in different species, and evaluates the diverse effects this may have on their reproductive strategies and fitness.


Hammond GL. Diverse Roles for Sex Hormone-Binding Globulin in Reproduction. Biol Reprod. http://www.biolreprod.org/content/early/2011/05/24/biolreprod.111.092593.full.pdf

Sex hormone-binding globulin (SHBG) transports androgens and estrogens in blood and regulates their access to target tissues. Hepatic production of SHBG fluctuates throughout the life cycle and is influenced by primarily by metabolic and hormonal factors. Genetic differences also contribute to inter-individual variations in plasma SHBG levels. In addition to controlling the plasma distribution, metabolic clearance and bioavailability of sex steroids, SHBG accumulates in the extravascular compartments of some tissues, and in the cytoplasm of specific epithelial cells, where it exerts novel effects on androgen and estrogen action. In mammals, the gene encoding SHBG is expressed primarily in the liver, but is also expressed at low levels in other tissues including the testis. In sub-primate species, Shbg expression in Sertoli cells is under the control of follicle stimulating hormone, and produces the androgen-binding protein that influences androgen actions in the seminiferous tubules and epididymis. In humans, the SHBG gene is not expressed in Sertoli cells but its expression in germ cells produces an SHBG isoform that accumulates in the acrosome. In fish, SHBG is produced by the liver but has a unique function in the gill as a portal for natural steroids and xenobiotics, including synthetic steroids. However, salmon have retained a second poorly-conserved Shbg gene that is expressed only in ovary, muscle and gill, and likely exerts specialized functions in these tissues. This review compares the production and functions of SHBG in different species, and evaluates the diverse effects this has on reproduction.

 

[Michael Scally MD]

Bupropion In Primary Lifelong Delayed Ejaculation

Bupropion is an atypical antidepressant belongs to the chemical class of aminoketones. It is not only the least antidepressant associated with sexual side effects but also it is one of the drugs of choice for the treatment of antidepressant induced sexual dysfunction according to survey of psychiatrists. In addition, it is used in the treatment of female orgasmic disorder. Modell et al. treated 10 men complaining of orgasmic delay or inhibition with bupropion. [Modell JG, May RS, Katholi CR. Effect of bupropion-SR on orgasmic dysfunction in nondepressed subjects: A pilot study. J Sex Marital Ther 2000;26:231–40. http://www.ncbi.nlm.nih.gov/pubmed/10929571] The authors reported significant improvements in the overall sexual satisfaction and orgasmic function in the majority of patients. It is thought that bupropion enhances activity in central dopaminergic and noradrenergic neurotransmitter systems, which are associated with regulation of the sexual response in animals and humans.


Abdel-Hamid IA, Saleh E-S. Primary Lifelong Delayed Ejaculation: Characteristics and Response to Bupropion. The Journal of Sexual Medicine 2011;8(6):1772-9. Primary Lifelong Delayed Ejaculation: Characteristics and Response to Bupropion - Abdel-Hamid - 2010 - The Journal of Sexual Medicine - Wiley Online Library

Introduction. In contrast to premature ejaculation and secondary delayed ejaculation (DE), primary lifelong DE has not been studied extensively. In addition, there is no approved drug treatment.

Aims. To explore the clinical and laboratory characteristics of a series of men complaining of lifelong DE and to report the response to bupropion.

Methods. Nineteen consecutive men with primary lifelong DE were prospectively enrolled in this study. Study group was compared with an age-matched group of 19 healthy men. Both groups underwent history taking, physical examination, International Index of Erectile Function (IIEF), anxiety, and depression scores, ejaculation latency time (IELT) using stop watch and measurement of serum prolactin (PRL) and serum total testosterone (T). Patients received open-label bupropion-SR 150 mg/day for 2 months.

Main Outcome Measures. Stopwatch-measured IELT values, global efficacy question, IIEF, anxiety, and depression scores.

Results. The mean age was 30.8 +/- 5.5 year (range 25–42 years). Men with DE exhibited significantly higher masturbatory activity during marital period, lower night emissions, longer IELT, lower orgasmic, and intercourse satisfaction domains of IIEF, higher anxiety and depression scores compared with the controls (all P < 0.05). Both serum T and PRL levels did not differ significantly between patients and controls (all P < 0.05). Four DE patients (21%) showed history of infertility. The percentage of DE men rating control over ejaculation as “fair to good” increased from 0 to 21.1% after bupropion therapy. The fold decreases of the geometric mean IELT was 0.74 after treatment. The intercourse satisfaction and the orgasmic domains of IIEF and depression score were significantly improved from baseline in the bupropion group (all P < 0.05).

Conclusions. Lifelong DE is mainly associated with higher and idiosyncratic masturbatory activity, lower night emissions, infertility, longer IELT, lower orgasmic, and intercourse satisfaction domains of IIEF, higher anxiety and depression scores. Bupropion-SR in a daily dosage of 150 mg seemed to be of limited benefit in lifelong DE.

 

[Michael Scally MD]

Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men

The central role of GnRH (LHRH) in regulating reproduction by stimulating the secretion of pituitary gonadotropins (LH and FSH) is well established. Kisspeptin, a hypothalamic neuropeptide encoded by the KISS1 gene, has recently emerged as a key central regulator of GnRH secretion. Kisspeptin signaling is obligatory for normal pubertal maturation, as evidenced by absent or advanced pubertal development in individuals with mutations in genes encoding kisspeptin and its receptor [KISS1R; also known as G protein-coupled receptor (GPR) 54]. Administration of exogenous kisspeptin stimulates LH secretion in both men and women.

Human studies of kisspeptin have hitherto used the 54-amino acid peptide, kisspeptin-54. Kisspeptin-54 is cleaved from the 145-amino acid precursor polypeptide encoded by KISS1 and is further processed to 14, 13, and 10 amino acid (kisspeptin-10) sequences, all sharing the same C-terminal decapeptide RFAmide (arginine-amidated phenylalanine) sequence. Although kisspeptin-10 has intrinsic bioactivity similar to the longer kisspeptin fragments, it is also characterized by a shorter half-life and more rapid onset of action after iv administration in rodents. Kisspeptin-10 also has greater potential for pharmaceutical development because both agonists and antagonists have been developed based on its decapeptide sequence. However, there have been no studies on the activity of kisspeptin-10 in humans.

Alterations in GnRH pulsatility and thus LH secretion are a feature of a number of reproductive disorders. Individuals with some forms of male hypogonadism and hypothalamic amenorrhea show decreased pulse frequency, whereas women with polycystic ovarian syndrome show an increase. However, neuroendocrine mechanisms underpinning GnRH pulse generation are yet to be fully delineated. Experimental animals exposed to kisspeptin antagonists demonstrate decreased LH pulsatile secretion, suggesting that kisspeptin modulates GnRH pulse frequency. Although administration of kisspeptin-54 acutely stimulates LH secretion in men and women, it is unclear whether this is mediated by a change in LH pulse frequency, which would indicate an underlying stimulatory effect on GnRH pulse frequency.

In these first-in-human studies of kisspeptin-10, researchers aimed to establish the dose dependency and time course of stimulation of LH secretion after iv bolus doses of kisspeptin-10 and to compare the magnitude of this stimulated LH secretion with that after a maximally stimulatory dose of GnRH. Having established that kisspeptin-10 is an effective LH secretagogue, they further investigated the effects of infusion of kisspeptin-10 on LH pulsatility. They also examined whether high-dose continuous infusion of kisspeptin-10 induces tachyphylaxis of LH response, as previously suggested in a male primate model.

They demonstrated that iv administration of kisspeptin-10 boluses result in potent and dose-dependent stimulation of LH secretion in healthy men. Doses of kisspeptin-10 as low as 0.03 mcg/kg (23 pmol/kg) elicited a significant rise in LH when compared with vehicle, demonstrating the high potency of kisspeptin-10.

Stimulatory effects of kisspeptin-10 on LH, FSH, and testosterone established in this study could inform future studies using kisspeptin as a diagnostic or therapeutic agent. Potent kisspeptin agonists and antagonists currently being tested in animal models are amino acid substitutions of the decapeptide sequence of kisspeptin-10. Dose responsiveness and time course of LH stimulation demonstrated in this study could underpin their translation into clinical studies. Moreover, they have also demonstrated that GnRH responsiveness is preserved in subjects receiving kisspeptin-10 infusion and that maximal LH responses seen with kisspeptin-10 are considerably lower than that achieved with GnRH. Therefore, kisspeptin-10 might provide a more physiological stimulation of the human reproductive axis.


George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men. Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2011/05/26/jc.2011-0089.abstract (Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men)

Context: Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man.

Objective: We investigated our hypothesis that kisspeptin-10 increases GnRH and thus LH pulse frequency.

Design and Participants: The dose response of kisspeptin-10 was investigated by administering iv bolus doses (0.01–3.0 ?g/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of kisspeptin-10 for up to 22.5 h.

Results: Intravenous bolus kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 ?g/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 ?g/kg elicited a reduced response vs. 1 ?g/kg (P < 0.05). Infusion of kisspeptin-10 at 4 ?g/kg • h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and serum testosterone increased from 16.6 ± 2.4 to 24.0 ± 2.5 nmol/liter (P < 0.001). LH pulses were obscured at this high rate of secretion, but a lower dose infusion of kisspeptin-10 (1.5 ?g/kg • h) increased mean LH from 5.2 ± 0.8 to 14.1 ± 1.7 IU/liter (n = 4; P < 0.01) and increased LH pulse frequency from 0.7 ± 0.1 to 1.0 ± 0.2 pulses/h (P < 0.05) and secretory burst mass from 3.9 ± 0.4 to 12.8 ± 2.6 IU/liter (P < 0.05).

Conclusions: Kisspeptin-10 boluses potently evoke LH secretion in men, and continuous infusion increases testosterone, LH pulse frequency, and pulse size. Kisspeptin analogues have therapeutic potential as regulators of LH and thus testosterone secretion.

 

[Michael Scally MD]

Evaluating a CME Program on Erectile Dysfunction as a Cardiovascular Risk Factor

There is a growing consensus among specialists that ED represents an important and early marker for cardiovascular disease (CVD) and other pathologies. Not only do ED and CVD share all major risk factors (including age, inactivity, smoking, obesity, hypertension, dyslipidemia, diabetes, and depression), but studies have shown that ED is a sentinel for CVD even in asymptomatic men. Given the high prevalence of both ED and CVD particularly among men over 40, it seems clear that detecting ED and its potential comorbidities at an early stage could not only contribute to better sexual health for men and their partners but also to longer and healthier lives.

Yet, the condition has not lost its stigma; one 2003 study reported that 82% of men who admitted suffering from ED would have preferred their GP to raise the subject, and 74% were too embarrassed to mention the problem to their urologist. More recent studies have observed similar patterns; in Italy, the ED Evaluation Network (EDEN) found in 2008 that one in five men waited a year or more before seeking treatment, reflecting a clear discomfort in speaking about the issue with their doctor. [De Berardis G, Pellegrini F, Franciosi M, Pamparana F, Morelli P, Tognoni G, Nicolucci A, EDEN Study Group. Management of erectile dysfunction in general practice. J Sex Med 2009;6:1127–34. Management of erectile dysfunction in general prac... [J Sex Med. 2009] - PubMed result ] The same study reported shortcomings in GP knowledge on ED. Less than 10% of physicians said that they routinely asked men over 40 about ED, and few routinely prescribed oral treatment for men with heart disease, despite established evidence pointing to its safety.

Thus, ED emerges as an excellent candidate for a topic of Continuous Medical Education (CME) intervention among primary care practitioners, a cornerstone of maintaining quality care in modern healthcare practice. Because not all CME courses have the same effectiveness, it is important to monitor the results achieved using different CME methodology.


Mas M, García-Giralda L, Rey JR, Martínez-Salamanca JI, Guirao L, Turbí C. Evaluating a Continuous Medical Education Program to Improve General Practitioners Awareness and Practice on Erectile Dysfunction as a Cardiovascular Risk Factor. The Journal of Sexual Medicine 2011;8(6):1585-93. Evaluating a Continuous Medical Education Program to Improve General Practitioners Awareness and Practice on Erectile Dysfunction as a Cardiovascular Risk Factor - Mas - 2011 - The Journal of Sexual Medicine - Wiley Online Library

Introduction. The clear link between erectile dysfunction (ED) and cardiovascular disease (CVD) together with the increased potential for effectively treating ED with oral pharmacological agents make the primary care setting the ideal place to detect and treat ED and its potential comorbidities. Given the observed shortcomings in knowledge related to ED among primary care physicians, continuous medical education (CME) on this topic stands out as a potentially effective way to improve patient care.

Aim. To assess general practitioners' (GPs) knowledge, attitudes, and self-confidence about ED management and the relationship between ED and CVD and to test whether these can be improved by means of a brief training program.

Methods. Eighty GPs completed two similar questionnaires on ED issues, one prior to a CME intervention and one following it. The CME program consisted of reading an annotated set of four review articles and six research articles followed by a live half-day seminar conducted by a GP, a urologist, and a cardiologist.

Main Outcome Measures. Changes in the answers to the two questionnaires were? evaluated by tests for matched pairs using both statistical significance and effect size estimates, and assessment of different predictors were evaluated by multivariate analysis.

Results. A marked improvement was observed in physician knowledge, attitudes, and self-confidence with regard to diagnosing and treating ED following the CME training intervention.

Conclusions. The present study shows that a relatively simple educational procedure can substantially improve the awareness of primary care physicians about the cardiovascular implications of ED and their self confidence in the management of these patients.

 

[Michael Scally MD]

Effect of Sleep Restriction on Testosterone Levels

Leproult R, Van Cauter E. Effect of 1 Week of Sleep Restriction on Testosterone Levels in Young Healthy Men. JAMA: The Journal of the American Medical Association 2011;305(21):2173-4. Effect of 1 Week of Sleep Restriction on Testosterone Levels in Young Healthy Men, June 1, 2011, Leproult and Van Cauter 305 (21): 2173 — JAMA

To the Editor: Chronic sleep curtailment is endemic in modern societies. The majority of the daily testosterone release in men occurs during sleep. Sleep fragmentation and obstructive sleep apnea are associated with reduced testosterone levels. In older men, morning testosterone levels are partly predicted by total sleep time. Testosterone is critical in male sexual behavior and reproduction, but also has important beneficial effects on muscle mass and strength, adiposity, bone density, and vigor and well-being. We investigated the effect of 1 week of sleep restriction on testosterone levels in young healthy men.

Daytime testosterone levels were decreased by 10% to 15% in this small convenience sample of young healthy men who underwent 1 week of sleep restriction to 5 hours per night, a condition experienced by at least 15% of the US working population. By comparison, normal aging is associated with a decrease of testosterone levels by 1% to 2% per year. This testosterone decline was associated with lower vigor scores but not with increased levels of cortisol, a stress-responsive hormone that can inhibit gonadal function. Symptoms and signs of androgen deficiency include low energy, reduced libido, poor concentration, and increased sleepiness, all of which may be produced by sleep deprivation in healthy individuals. Additional investigations of the links between sleep and testosterone are needed to determine whether sleep duration should be integrated in the evaluation of androgen deficiency.

 

[Michael Scally MD]

The Link Between Erectile Function and Cardiovascular Health

The identification of nitric oxide (NO) as the long-sought vascular endothelium– derived relaxing factor resulted in the awarding of a Nobel Prize and a continuing explosion of research in vascular pathophysiology and treatment. The enzyme responsible for NO production, NO synthase (NOS), exists as an endothelial enzyme, endothelial NOS (eNOS), and as a neuronal enzyme, neuronal NOS (nNOS), allowing NO to function as an autocrine and paracrine signal and as a neurotransmitter.

The discovery of NO led to experiments that defined the role of NO in relaxation of smooth muscle of human corpus cavernosum tissue caused by electrical stimulation of nonadrenergic, noncholinergic nerves. Because NO was shown to cause penile smooth muscle relaxation by stimulating cyclic guanosine monophosphate, and the effect was enhanced by a phosphodiesterase-5 (PDE-5) inhibitor of cyclic guanosine monophosphate degradation, this work led to the development of sildenafil, tadalafil, and vardenafil as highly effective treatments for men with erectile dysfunction (ED).

PDE-5 inhibitors, however, primarily shore up cyclic guanosine monophosphate levels rather than correcting the inadequate NO production causing poor erectile and vascular function. NO supports vascular health by inhibiting platelet aggregation and the adhesion of platelets and inflammatory cells to the endothelium, opposing vascular smooth muscle proliferation, maintaining low vascular muscle tone, and preventing atherosclerosis by acting as an anti-inflammatory agent and by reducing oxidative stress and endothelial cell senescence.

ED is an important marker of endothelial dysfunction, which is a pathophysiologic mechanism for progressive vascular disease. Motivating patients to change well-established, long-term poor lifestyle habits is extremely difficult. Preventing cardiovascular sequelae such as myocardial infarction or stroke are relatively distant benefits, whereas barbecued ribs, cheesecake, or a favorite television program promises almost instant gratification. Prevention or improvement of ED should be a more immediate motivator that physicians can use to improve their patients’ lifestyle and in turn their overall cardiovascular health.

Meldrum DR, Gambone JC, Morris MA, Meldrum DA, Esposito K, Ignarro LJ. The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine. Am J Cardiol. The Link Between Erectile and Cardiovascular Healt... [Am J Cardiol. 2011] - PubMed result

Lifestyle and nutrition have been increasingly recognized as central factors influencing vascular nitric oxide (NO) production and erectile function. This review underscores the importance of NO as the principal mediator influencing cardiovascular health and erectile function. Erectile dysfunction (ED) is associated with smoking, excessive alcohol intake, physical inactivity, abdominal obesity, diabetes, hypertension, and decreased antioxidant defenses, all of which reduce NO production. Better lifestyle choices; physical exercise; improved nutrition and weight control; adequate intake of or supplementation with omega-3 fatty acids, antioxidants, calcium, and folic acid; and replacement of any testosterone deficiency will all improve vascular and erectile function and the response to phosphodiesterase-5 inhibitors, which also increase vascular NO production. More frequent penile-specific exercise improves local endothelial NO production. Excessive intake of vitamin E, calcium, l-arginine, or l-citrulline may impart significant cardiovascular risks. Interventions discussed also lower blood pressure or prevent hypertension. Certain angiotensin II receptor blockers improve erectile function and reduce oxidative stress. In men aged <60 years and in men with diabetes or hypertension, erectile dysfunction can be a critical warning sign for existing or impending cardiovascular disease and risk for death. The antiarrhythmic effect of omega-3 fatty acids may be particularly crucial for these men at greatest risk for sudden death.

In conclusion, by better understanding the complex factors influencing erectile and overall vascular health, physicians can help their patients prevent vascular disease and improve erectile function, which provides more immediate motivation for men to improve their lifestyle habits and cardiovascular health.

 

[Michael Scally MD]

Digit Ratio (2D:4D) And Rowing Ergometer Performance

[For further reading, go to: https://thinksteroids.com/community/threads/134293918 & https://thinksteroids.com/community/threads/134294113 ]

Since Baker’s (1888) initial investigation into the sexually dimorphic nature of digit ratio (2D:4D), much work has been performed to explain the phenomena. [Baker F. Anthropological notes on the human hand. Am Anthropol 1888;1:51–76. ANTHROPOLOGICAL NOTES ON THE HUMAN HAND - Baker - 2009 - American Anthropologist - Wiley Online Library ] Although evidence for a link between prenatal androgenization and digit growth is indirect due to the complexities associated with obtaining direct data, various studies have compiled persuasive evidence that such a link exists (see below). In turn, digit ratio is increasingly used as a proxy for fetal hormonal environment, to investigate early life predictors of later phenotype, and sex differences therein. Researchers briefly summarize the evidence for the fetal origins of digit ratio variability, its association with later phenotypic traits, and the use of sport as a valuable arena for testing evolutionary hypotheses regarding digit ratio and intrasexual competition.

The results revealed statistically significant positive correlations between right hand and left 2D:4D and 2,000 m rowing time among males, i.e., low (more masculine) digit ratio is related to better performance. In contrast, no meaningful relationships were found between digit ratio and ergometer performance in female participants. These findings have implications for our understanding of the development of phenotypic characteristics associated with intrasexual competition.


Longman D, Stock JT, Wells JCK. Digit ratio (2D:4D) and rowing ergometer performance in males and females. American Journal of Physical Anthropology 2011;144(3):337-41. Digit ratio (2D:4D) and rowing ergometer performan... [Am J Phys Anthropol. 2011] - PubMed result

Fetal and adult testosterone may be vital in the establishment and maintenance of sex-dependent abilities associated with male physical competitiveness. It has been shown that digit ratio (2D:4D) is negatively associated with prenatal testosterone, and it is also negatively associated with ability in sports such as football, skiing, middle distance running, and endurance running, which are dependent upon an efficient cardiovascular system. The relationship between digit ratio and sports requiring high power (physical strength) output in addition to well-developed cardiovascular systems has not been defined. This study investigated this association in male and female young adult rowers. Participants (77 male and 70 female) were student rowers encompassing a range of abilities from the University of Cambridge. Bilateral digit measurements were taken blind from each subject using Mitutoyo vernier calipers. Rowing performance over 2,000 m was assessed using the Concept 2 rowing ergometer. Significant negative correlations were observed between 2,000 m ergometer performance and male digit ratios, which persisted following adjustment for rowing experience and height. However, no such significant association was found in females despite a comparable sample size.

Our data indicate that digit ratio is a predictor of ability in rowing, a sport which requires both cardiovascular efficiency and high power output, in males but not females. This in turn suggests that fetal testosterone exposure has long-term effects on traits associated with physical power in males but not females, suggesting a sex-difference in the capacity to respond to such exposures.

 

[Michael Scally MD]

[Registration is Free for Endo 2011: Welcome to Endo 2011: The 93rd Annual Meeting & Expo ]

Surgery-Related Weight Loss in Men Reverses Testosterone Deficiency, Study Finds
Surgery-related weight loss in men reverses testosterone deficiency, study finds

ScienceDaily (June 4, 2011) — Low testosterone levels and symptoms of male sexual dysfunction due to obesity may be reversible with weight loss after bariatric surgery, a new study finds.

The results were presented at The Endocrine Society's 93rd Annual Meeting in Boston.

"Morbidly obese men have a high prevalence of hypotestosteronenemia, or low testosterone, and of sexual dysfunction," said study co-author Jean-Paul Thissen, MD, PhD, a professor at the University of Louvain in Brussels. "It is reassuring that these problems are potentially curable by weight loss."

This study included 75 obese men who were patients at an obesity clinic between 2007 and 2010. The men had hormone testing, measurements of body fat and assessment by questionnaire of signs of androgen, or male hormone, deficiency. Signs assessed included erectile dysfunction and low sex drive. Among these patients, 17 underwent gastric bypass surgery and were reassessed three and 12 months later.

Initial assessment of the 75 patients showed that 54 had signs and symptoms of androgen deficiency, and 27 had low testosterone levels. The higher the men's body mass index, waist circumference and body fat, the lower their testosterone levels were. "This correlation suggests a potential causal relationship between obesity and low testosterone," Thissen said.

The 17 men who had weight-loss surgery lost an average of 90.2 pounds. One year after surgery, their testosterone levels increased significantly and were within the normal range, showing a reversal of testosterone deficiency, Thissen reported.

Low testosterone levels were not strongly associated with complaints of sexual dysfunction before surgery. However, Thissen said men did not complain of sexual dysfunction after surgery-related weight loss.


[P1-468] Hypogonadism among a Population of Obese Men: Prevalence, Risk Factors, Mechanisms and Reversibility after Weight Loss Induced by Gastric Bypass Surgery http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-468

V Ippersiel, A Lepot, D Gruson, J Jamart, D Maiter, J-P Thissen. Mont-Godinne Academic Hospital, University of Louvain, Yvoir, Belgium; Saint-Luc Academic Hospital, University of Louvain, Brussels, Belgium; Mont-Godinne Academic Hospital, University of Louvain, Yvoir, Belgium.

Context: Obesity in men is frequently associated with low levels of testosterone, loss of libido and/or erectile dysfunction. Several mechanisms have been proposed to explain this hypogonadism.

Objective: To estimate the prevalence of hypotestosteronemia among a population of obese men, to determine the risk factors and the mechanisms for this condition, and to study its reversibility after significant weight loss obtained by gastric bypass surgery.

Design: A prospective study including 75 consecutive patients between 2007 and 2010.
Setting: Obesity clinic in a teaching academic hospital.

Patients: 75 men aged 43±11 yr with a body mass index (BMI) 41.3±7.3 kg/m² were studied at baseline. Fasting levels of total (TT) and free (FT) testosterone, sex hormone binding globulin (SHBG), LH and FSH, estrone (E1), estradiol (E2), prolactin, IGF-1, lipid profile and HbA1c were measured in the morning. 75-g oral glucose tolerance and HOMA tests were also performed. Body composition was assessed by bioelectrical impedance and ADAM (Androgen Deficiency in Aging Males) questionnaire was recorded. Among these patients, 17 underwent bariatric surgery and were re-evaluated after 3 and 12 months.

Results: At baseline, 39% of obese men had hypotestosteronemia, while the ADAM questionnaire was positive in 93%. Mean levels of TT and FT were 10.9±2.4 and 0.195±0.052 nmol/L, respectively. TT and FT were inversely related to BMI (p<0.05), while TT also correlated negatively with waist circumference (p= 0.012) and body fat mass (p=0.022). No significant correlation was found between testosterone and glucose, HbA1c or HOMA-S. SHBG and LH correlated positively with BMI (p<0.05), but not E1 and E2 levels. After bypass surgery, weight loss (-40.6±16.3 kg) was associated with an increase in TT (+3.97±2.24 nmol/L, p=0.001) but not FT. Erectile function was also improved. A significant decrease was also observed for E2 (p<0.05) and the ratio E2/TT, reflecting reduction in aromatase activity. There were no changes in SHBG, LH and E1 levels.

Conclusion: Low testosterone levels are frequently observed among obese men and correlated with the degree of abdominal adiposity, but not strongly associated with sexual dysfunction. Weight loss induced by gastric bypass surgery leads to normalized TT and to decreased E2 and E2/TT ratio, suggesting a role of excessive aromatization in the hypotestosteronemia associated with obesity.

 

[Michael Scally MD]

The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[This will a separate thread for a limited time. Afterwards, the thread will be merged with OnLine first.]

ENDO 2011 scientific sessions cover the full spectrum of endocrinology, from basic and translational research to clinical research and practice. Welcome to Endo 2011: The 93rd Annual Meeting & Expo

Registration is Free. Abstracts2View™ Program - View abstract content with the ability to bookmark items. In order to obtain this information, you will need to set up a username and password to enter the program and then proceed by searching on desired abstract information. Abstracts are searchable by Session, Author, Title, Category, & Keyword. http://www.abstracts2view.com/endo/

If there is an abstract of interest, please feel free to post. Please adhere to the posting format that follows. Thanks in advance.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-468] Hypogonadism among a Population of Obese Men: Prevalence, Risk Factors, Mechanisms and Reversibility after Weight Loss Induced by Gastric Bypass Surgery http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-468

V Ippersiel, A Lepot, D Gruson, J Jamart, D Maiter, J-P Thissen. Mont-Godinne Academic Hospital, University of Louvain, Yvoir, Belgium; Saint-Luc Academic Hospital, University of Louvain, Brussels, Belgium; Mont-Godinne Academic Hospital, University of Louvain, Yvoir, Belgium.

Context: Obesity in men is frequently associated with low levels of testosterone, loss of libido and/or erectile dysfunction. Several mechanisms have been proposed to explain this hypogonadism.

Objective: To estimate the prevalence of hypotestosteronemia among a population of obese men, to determine the risk factors and the mechanisms for this condition, and to study its reversibility after significant weight loss obtained by gastric bypass surgery.

Design: A prospective study including 75 consecutive patients between 2007 and 2010.

Setting: Obesity clinic in a teaching academic hospital.

Patients: 75 men aged 43±11 yr with a body mass index (BMI) 41.3±7.3 kg/m² were studied at baseline. Fasting levels of total (TT) and free (FT) testosterone, sex hormone binding globulin (SHBG), LH and FSH, estrone (E1), estradiol (E2), prolactin, IGF-1, lipid profile and HbA1c were measured in the morning. 75-g oral glucose tolerance and HOMA tests were also performed. Body composition was assessed by bioelectrical impedance and ADAM (Androgen Deficiency in Aging Males) questionnaire was recorded. Among these patients, 17 underwent bariatric surgery and were re-evaluated after 3 and 12 months.

Results: At baseline, 39% of obese men had hypotestosteronemia, while the ADAM questionnaire was positive in 93%. Mean levels of TT and FT were 10.9±2.4 and 0.195±0.052 nmol/L, respectively. TT and FT were inversely related to BMI (p<0.05), while TT also correlated negatively with waist circumference (p= 0.012) and body fat mass (p=0.022). No significant correlation was found between testosterone and glucose, HbA1c or HOMA-S. SHBG and LH correlated positively with BMI (p<0.05), but not E1 and E2 levels. After bypass surgery, weight loss (-40.6±16.3 kg) was associated with an increase in TT (+3.97±2.24 nmol/L, p=0.001) but not FT. Erectile function was also improved. A significant decrease was also observed for E2 (p<0.05) and the ratio E2/TT, reflecting reduction in aromatase activity. There were no changes in SHBG, LH and E1 levels.

Conclusion: Low testosterone levels are frequently observed among obese men and correlated with the degree of abdominal adiposity, but not strongly associated with sexual dysfunction. Weight loss induced by gastric bypass surgery leads to normalized TT and to decreased E2 and E2/TT ratio, suggesting a role of excessive aromatization in the hypotestosteronemia associated with obesity.


[OR44-5] Fracture Risk after Bariatric Surgery http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_OR44-5

KM Nakamura, EGC Haglind, JA Clowes, SJ Achenbach, EJ Atkinson, LJ Melton, KA Kennel. Mayo Clinic, Rochester, MN; Mayo Clinic, Rochester, MN; Mayo Clinic, Rochester, MN; Guthrie Clinic, Sayre, PA; HealthEast Care System, St Paul, MN.

Introduction: Bariatric surgery is an increasingly common treatment for medically complicated obesity. Adverse changes in multiple parameters of bone health after bariatric surgery have been reported, but the clinical importance of these observations remains unknown. We hypothesized that bariatric surgery patients are at increased risk of fracture.

Methods: Utilizing the resources of the Rochester Epidemiology Project, we conducted a retrospective study of fracture incidence in the 277 SE Minnesota residents who underwent a first bariatric surgery between 1985-2004 at Mayo Clinic Rochester. Fracture data were expressed as standardized incidence ratios (SIR), comparing the number of observed fractures to the number of expected by skeletal site. Expected numbers of fractures were derived by applying age- and sex-specific incidence rates from the local population to the age- and sex-specific person-years of follow-up. Potential risk factors were evaluated by hazard ratios (HR) from regression models.

Results: The mean (± SD) age at bariatric surgery was 43.7 + 9.9 yrs with 83% (229) females. Gastric bypass surgery was performed in 94% of cases. Following bariatric surgery, 82 subjects experienced 138 fractures. Mean time to first fracture was 5.9 years (range, 0.2 to 18.6) with mean duration of follow-up of 9 years (range, 0.02 to 25.2). The SIR for any fracture was 2.1 (CI, 1.7 to 2.7). The SIR for a first fracture at hip, wrist, spine or humerus was 1.9 (CI, 1.2 to 2.8) and was 2.3 (CI, 1.8 to 2.9) for a first fracture at all other sites; notable were fractures of the foot (SIR, 3.0; CI, 2.0 to 4.3), leg (SIR, 2.2; CI, 1.3 to 3.4), and hand (SIR, 3.1; CI, 1.8 to 4.9) fractures. After adjustment for age, better activity status before surgery was associated with a lower risk (HR, 0.43; CI, 0.23 to 0.81), but history of fracture prior to bariatric surgery was not associated with subsequent fracture risk.

Conclusion: This study demonstrates an increased rate of fracture following bariatric surgery which suggests that structural and biochemical changes in bone observed after bariatric surgery are clinically important. Clinicians should discuss bone health with patients who have undergone or are considering bariatric surgery. Further prospective studies are needed to identify strategies that optimize bone health in these patients.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-336] Population-Based Reference Ranges for Testosterone in Men Derived Using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and Validated in Three Geographically Distinct Cohorts http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-336

S Bhasin, MM Pencina, GK Jasuja, TG Travison, AD Coviello, EM Orwoll, PY Wang, CM Nielson, FM Wu, AM Tajar, HM Vesper, AM Zhang, JM Ulloor, RM Singh, RM D'Agostino, RS Vasan. Boston University School of Medicine, Boston, MA; Boston University School of Public Health, Boston, MA; Oregon Health Sciences University, Portland, OR; University of Manchester, Manchester, MA; Centers for Disease Control, Atlanta, GA; Mayo Clinic, Rochester, MN; Boston University School of Medicine, Boston, MA.

Androgen deficiency in men is characterized by a constellation of symptoms and signs and low circulating testosterone (T) levels. Rigorously established reference ranges are essential for identifying whether T levels are normal or low. Population-based reference ranges for T using reliable assays are not available.

Objective: To generate reference limits for total (TT) and free testosterone (FT) concentrations in a community-based sample of healthy young men in the Framingham Heart Study (FHS) Generation 3 cohort.

Methods: TT was measured using liquid chromatography tandem mass spectrometry (LC-MS/MS), SHBG by an immunofluorometric assay, and FT was calculated. TT and FT values below the 2.5th percentile were deemed low.

For validation, we applied these reference limits to three geographically distinct cohorts of community-dwelling men: FHS generations 2 and 3, the European Male Aging Study (EMAS), and the Osteoporotic Fractures in Men Study (MrOS). We determined whether men in these 3 cohorts with low TT or FT by the proposed reference limits had a higher prevalence of 3 conditions that have been consistently associated with low T levels: physical dysfunction, sexual symptoms, and diabetes. We used thresholds based on a healthy young reference sample (T-score approach) because in exploratory analyses, the T-score approach and age-adjusted thresholds (Z-score approach) yielded concordant results for most outcomes. Spline plots of T levels against outcomes in the FHS sample did not yield clear inflection points.

Results: In the reference sample of 456 men, mean(SD), median(quartile), and 2.5th percentile values were 724(221), 699(297), and 348ng/dL for TT and 142(45), 134(60), and 70pg/mL for FT, respectively. In validation samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty, and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels.

Conclusion: Population-based reference ranges provide a rational basis for categorizing T levels as “low” or “normal”. Men with low TT or FT levels by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in prospective randomized trials.