Testosterone Series - Article One

Testosterone was once considered just the male sex hormone, that is until it was brought to the limelight by the use of testosterone and related anabolic steroids by bodybuilders and both power and to a lesser extent endurance athletes.


The effects of testosterone in increasing muscle mass, strength, and performance are undeniable. In order to increase these effects, bodybuilders, and power and endurance athletes, whether recreational or competitive, use exogenous testosterone and anabolic steroids in supraphysiological levels. Sometimes the levels used, especially in some professional bodybuilders and power athletes, may be hundreds of times the levels found in young healthy adult males.


Testosterone is often the key to body composition and athletic success but it can be a convoluted one, and one needing a deep knowledge of first the reasons behind and meaning of endogenous fluctuations, and the effects of the interaction of testosterone with other factors, both endogenous and exogenous. For example, the effects of testosterone can be affected by nutrition, training, receptor status, and other hormones and growth factors.


Because the amount of information I would like to provide to you is so large, I will be breaking it up into a series of five articles to make it more user friendly and easier to assimilate.


Regulation of Testosterone Production and Secretion


The regulation and metabolism of testosterone is complex. However, it is important to know some of the basics so you can put the information in this article and the following ones in context. So here is a brief synopsis off the production and secretion of testosterone in males.


Much of this information comes from a book I wrote in 1984 (Drug Use and Detection in Amateur Sports, MGD Press, 1984) as the basics haven’t changed much. And we’ll be covering the newer and relevant information in the articles that make up the rest of this series. It’ll help to refer to Figure 1 as you read the info below, keeping in mind that the actual interactions that occur to regulate serum testosterone levels are more complex than is represented in this figure and the description below.


The endocrine system and the nervous system are the two major controlling systems of the body. They allow adaptation to change in the internal and the external environment. The endocrine system uses hormones by way of the circulatory system to effect changes, while the nervous system uses direct contact by nerve endings to affect its target tissue. Most exogenous androgenic hormones mimic the effects of endogenous hormones by binding to receptors for endogenous hormones. The exogenous hormone may, of may not, be chemically identical to the endogenous hormone.


The Hypothalamus


The extrahypothalamic nervous system provides input to the hypothalamus, and thus exerts some control over hypothalamic functions. The hypothalamus in turn regulates the activity of the pituitary gland. Various releasing and inhibitory hormones are produced in the hypothalamus, and these regulate the production of pituitary hormones. Some of the pituitary hormones regulate various endocrine glands in the body.


As an example, hypothalamic gonadotropin releasing hormone (GnRH) stimulates production of pituitary luteinizing and follicle stimulating hormones (LH and FSH).Luteinizing hormone in turn stimulates the production of testosterone in the Leydig cells of the testicles. As the level of testosterone rises, it inhibits the hypophyseal-pituitary release of LH, FSH, and GnRH. Testosterone administration slows LH pulse frequency in man, by an effect on the hypothalamic GnRH pulse generator; however it also decreases gonadotropin secretion by a direct action on the pituitary. Extra-hypothalamic factors may inhibit or stimulate GnRH production. Also, LH and FSH may influence GnRH by way of a short feedback loop.


FSH, growth hormone (GH), and prolactin (PRL) synergize with LH to increase testosterone production and secretion, possibly by altering the number of LH receptors of the Leydig cells. Testosterone secretion is regulated by the pituitary LH. Conversely, testosterone alters the sensitivity of the pituitary to GnRH, and is the prime regulator of LH secretion and may also help regulate GnRH secretion. the LH secretion is very sensitive to the level of the circulating testosterone even at physiological levels. Both LH and testosterone levels vary throughout the day, being about 15% higher in the morning than during the rest of the day.


Testosterone administration inhibits gonadotropin secretion by an effect directly on all parts of the HPTA and indirectly by aromatization to estrogen that also affects the HPTA to decrease endogenous testosterone production.



Figure 1 - Hypothalamic-Pituitary-Testicular Axis



What Affects Testosterone Levels in the Body?


Testosterone levels are finicky.


They can be decreased by many factors that may affect one or more of the components of the HPTA, including:



They can also be raised by many factors, some of which seem odd including:



Keep in mind that in some cases a factor may decrease serum testosterone levels and in others lower it. For example, metformin lowers testosterone in healthy men but raises it in men with some disorders (see abstracts below).


Also, the results of some studies need to be validated further. For example, the abstract below shows BPA increases serum testosterone, while other studies have found that it lowers it. Keeping in mind that BPA acts as an anti-androgen, it’s possible that the body may be increasing testosterone levels to overcome the blocking of the normal action of testosterone in the body by BPA.



Abstracts and Info FYI


I’ve copied some selected abstracts and information pieces below from Pub Med and other sources (all cited) in case you’re interested in following up any of them.


Abstracts on Factors Lowering Testosterone Levels


J Endocrinol. 2011 Jun 8. [Epub ahead of print]

Differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia.

Ducsay C, Myers D.


C Ducsay, Center for Perinatal Biology, Loma Linda University, Loma Linda, 92354, United States.


Nitric oxide (NO) plays a role in a wide range of physiological processes. Aside from its widely studied function in the regulation of vascular function, NO has been shown to impact steroidogenesis in a number of different tissues. The goal of this review is to explore the effects of NO on steroid production and further, to discern its source(s) and mechanism of action. Attention will be given to the regulation of NO synthases in specific endocrine tissues including ovaries, testes and adrenal glands. The effects of hypoxia on generation of NO and subsequent effects on steroid biosynthesis will also be examined. Finally, a potential model for the interaction of hypoxia on NO synthesis and steroid production is proposed.


Full paper at




Toxicol Appl Pharmacol. 2000 Dec 15;169(3):222-30.

Decreased steroid hormone synthesis from inorganic nitrite and nitrate: studies in vitro and in vivo.

Panesar NS, Chan KW.

Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, SAR China.


Nitrites and nitrates are consumed nonchalantly in diet. Organic nitrates are also used as vasodilators in angina pectoris, but the therapy is associated with tolerance whose mechanism remains elusive. Previously, we found inorganic nitrate inhibited steroidogenesis in vitro. Because adrenocorticoids regulate water and electrolyte metabolism, tolerance may ensue from steroid deficiency. We have studied the effects of nitrite and nitrate on in vitro synthesis and in vivo blood levels of steroid hormones. In vitro, nitrite was more potent than nitrate in inhibiting human chorionic gonadotropin (hCG)-stimulated androgen synthesis by Mouse Leydig Tumor cells. At concentrations above 42 mM, nitrite completely inhibited androgen synthesis, and, unlike nitrate, the inhibition was irreversible by increasing hCG concentration. The cAMP production remained intact but reduced with both ions. The nitric oxide (NO) scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (c-PTIO) significantly increased hCG- or cAMP-stimulated androgen synthesis in all buffers, suggesting that NO is a chemical species directly involved in the nitrite/nitrate-induced inhibition. This is further supported by c-PTIO countering the inhibitory action of methylene blue on androgen synthesis. Rats given distilled water containing 50 mg/L NaNO(2) or NaNO(3) for 4 weeks drank significantly less daily. At the end, their blood corticosterone and testosterone levels were significantly decreased. The adrenocortical histology showed bigger lipid droplets, which are pathogonomic of impaired steroidogenesis. Nitrite and nitrate are metabolized to NO, which binds heme in cytochrome P450 enzymes, thereby inhibiting steroidogenesis. Therapeutic nitrates likewise may decrease adrenal (and gonadal) steroidogenesis. Cortisol deficiency would impair water excretion causing volume expansion, and aldosterone deficiency would cause sodium loss and raised renin. Paradoxically, volume expansion without sodium retention and raised renin has all been reported in tolerance.




Aging Cell. 2010 Apr;9(2):236-42. Epub 2010 Jan 20.

Long-term effects of calorie restriction on serum sex-hormone concentrations in men.

Cangemi R, Friedmann AJ, Holloszy JO, Fontana L.


Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA.


Calorie restriction (CR) slows aging and consistently reduces circulating sex hormones in laboratory animals. However, nothing is known regarding the long-term effects of CR with adequate nutrition on serum sex-hormone concentration in lean healthy humans. In this study, we measured body composition, and serum total testosterone, total 17-beta-estradiol, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEA-S) concentrations in 24 men (mean age 51.5 +/- 13 years), who had been practicing CR with adequate nutrition for an average of 7.4 +/- 4.5 years, in 24 age- and body fat-matched endurance runners (EX), and 24 age-matched sedentary controls eating Western diets (WD). We found that both the CR and EX volunteers had significantly lower body fat than the WD volunteers (total body fat, 8.7 +/- 4.2%; 10.5 +/- 4.4%; 23.2 +/- 6.1%, respectively; P = 0.0001). Serum total testosterone and the free androgen index were significantly lower, and SHBG was higher in the CR group than in the EX and WD groups (P < or = 0.001). Serum 17beta-estradiol and the estradiol:SHBG ratio were both significantly lower in the CR and EX groups than in the WD group (P < or = 0.005). Serum DHEA-S concentrations were not different between the three groups. These findings demonstrate that, as in long-lived CR rodents, long-term severe CR reduces serum total and free testosterone and increases SHBG concentrations in humans, independently of adiposity. More studies are needed to understand the role of this CR-mediated reduction in sex hormones in modulating the pathogenesis of age-associated chronic diseases such as cancer and the aging process itself.




Testosterone Decreases after Ingestion of Sugar (Glucose)

Testosterone Decreases after Ingestion of Sugar (Glucose)
Released: 6/11/2009 4:00 PM EDT
Source: Endocrine Society


Men with low testosterone should have their hormone levels retested after they fast overnight because eating may transiently lower testosterone levels, a new study concludes. The results were presented at The Endocrine Society’s 91st Annual Meeting in Washington, D.C.

“Both the incidence of low testosterone, or hypogonadism, in men and the annual number of testosterone prescriptions are increasing, likely as a result of the obesity epidemic and our aging population,” said study co-author Frances Hayes, MD, an endocrinologist at St. Vincent’s University Hospital in Dublin, Ireland, who did the research at Massachusetts General Hospital, Boston. “The decision to prescribe testosterone therapy is based on the result of a blood sample, so obtaining an accurate measurement of testosterone is key to making a correct diagnosis of hypogonadism.”

In current guidelines for evaluating men with hypogonadism, The Endocrine Society recommends measuring blood levels of testosterone—the major male sex hormone—on two or more occasions in the morning, when testosterone is highest. However, no guidelines exist on when to draw a testosterone sample in relation to food intake, Hayes said.

Past research shows that a high level of insulin, the hormone primarily secreted after eating, is related to low testosterone levels. Like eating, glucose intake causes blood glucose (sugar) levels to rise, which stimulates secretion of insulin. Hayes and her colleagues examined the impact of a standard dose of glucose on testosterone levels in 74 men. The researchers administered the oral glucose tolerance test, a screening test for diabetes that involves drinking a sugary solution (75 grams of pure glucose) and then measuring blood sugar levels.

Of the 74 men, 42 had normal glucose tolerance on the test, 23 had impaired glucose tolerance (also called prediabetes) and 9 had newly diagnosed type 2 diabetes.

The authors found that the glucose solution decreased blood levels of testosterone by as much as 25 percent, regardless of whether the men had diabetes, prediabetes or normal glucose tolerance.

Two hours after glucose administration, the testosterone level remained much lower than before the test in 73 of the 74 men, a statistically significant difference, the authors reported. Of the 66 men who had normal testosterone levels before the test, 10 (15 percent) became hypogonadal at one or more time points during the test.

The results did not differ by changes in insulin levels, according to the abstract. Other hormones that could change testosterone measurements also did not appear to affect results. Hayes said more research is needed to find the factor or factors responsible for this drop in testosterone.

Because glucose intake, and likely food, decreases testosterone, she said, “This research supports the notion that men found to have low testosterone levels should be reevaluated in the fasting state.”




Wei Sheng Yan Jiu. 2010 Jan;39(1):53-5.

[Effect of fluoride on human hypothalamus-hypophysis-testis axis hormones].

[Article in Chinese]

Hao P, Ma X, Cheng X, Ba Y, Zhu J, Cui L.


Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.



To study of endocrine disturbing effect of fluoride on human hypothalamus-hypophysis-testis axis hormones.


Sunying County, Kaifeng City was selected as polluted district which the fluoride in drinking water was 3.89 mg/L, and Shenlilou county was selected as control district which the fluoride was less than 1.0 mg/L. 150 individual lived there more than 5 years were srlected randomly. And investigated by medical examination, then blood and urine sample were collected, and the serum level of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), testosterone (T) and estradiol (E2) were measured by RIA method, and the urine level of fluoride were measured. Other than that, the concentration of fluoride in the water, food, soil and air were detected by the standard methods.


The concentrations of fluoride in the water, food and soil of the fluoride polluted district were significantly higher than those of control district (P < 0.05), and the concentration fluoride in the air of two district were not found. There was no significant difference of serum level of GnRH between fluoride polluted district and control district (P > 0.05). The serum level of LH in men of fluoride polluted district was significantly higher than that of control group (P < 0.05), and the serum level of T in men of fluoride polluted district was significantly less than that of control group (P < 0.05). There was no significant difference of serum level of LH between fluoride polluted district and control district (P > 0.05), and the serum level of T in women of fluoride polluted district was significantly higher than that of control group (P < 0.05). There was no significant difference of serum level of E2 between fluoride polluted district and control district (P > 0.05).


Fluoride could effect hormone levels of each layer of the hypothalamus-hypophysis-testis axis, and show the reproductive endocrine disturbing effects. The reproductive endocrine disturbing effects of male maybe more severe than those of female.




J Androl. 2007 Mar-Apr;28(2):252-8. Epub 2006 Oct 4.

Effects of 3-methyl-4-nitrophenol in diesel exhaust particles on the regulation of testicular function in immature male rats.

Li C, Taneda S, Suzuki AK, Furuta C, Watanabe G, Taya K.


Department of Basic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.


We investigated the effects of 3-methyl-4-nitrophenol (4-nitro-m-cresol, PNMC) isolated from diesel exhaust particles (DEP) on the reproductive functions of male rats. Twenty-eight-day-old rats were injected subcutaneously with PNMC (1, 10, or 100 mg/kg) daily for 5 days. The weights of the epididymis, seminal vesicle, and Cowper gland were significantly decreased in rats treated with 10 mg/kg PNMC. The plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were significantly increased by PNMC at 100 mg/kg. However, the plasma concentrations of testosterone and immunoreactive (ir)-inhibin were significantly decreased by PNMC at 100 mg/kg. The testosterone content of the testicles was significantly decreased in the group treated with 100 mg/kg PNMC compared with the control group. Furthermore, testicular concentration of ir-inhibin was significantly decreased by PNMC at 1 mg/kg or 100 mg/kg. To investigate the direct effects of PNMC on the secretion of LH and FSH from the anterior pituitary gland, and on the secretion of testosterone from the testes, we exposed cultured anterior pituitary and interstitial Leydig cells to PNMC (10(-6), 10(-5), 10(-4) M) with or without gonadotropin-releasing hormone (GnRH; 10 nM) (for the LH and FSH tests) and human chorionic gonadotropin (hCG; 0.1 IU/mL) (for the testosterone test) for 24 hours. PNMC did not change either the basal or GnRH-stimulated levels of FSH and LH secretion. However, PNMC significantly inhibited both basal and hCG-stimulated testosterone production. These findings suggest that PNMC has a direct effect on the testes of immature male rats, causing a reduction in testosterone secretion.




J Clin Endocrinol Metab. 2003 Jul;88(7):3160-6.

Middle-aged men secrete less testosterone at night than young healthy men.

Luboshitzky R, Shen-Orr Z, Herer P.


Endocrine Institute, Haemek Medical Center (R.L.), Afula 18101, Israel.


Aging men largely maintain their testicular androgen production. Cross-sectional studies have demonstrated that after the age of 40 yr a 0.2-2% annual decline is observed in morning total testosterone. In elderly males, the coordinate release of LH and testosterone became asynchronous despite normal serum levels of these hormones. The aim of this study was to test the reproductive hormone rhythm at night in middle-aged men. We studied seven healthy middle-aged (46.6 +/- 6.7 yr) and six healthy young (23.9 +/- 2.4 yr) men by determining their serum levels of LH and testosterone levels every 15 min from 1900-0700 h with simultaneous sleep recordings. The nocturnal rise in testosterone occurred earlier in young men (2235 +/- 0022 h) and at 2331 +/- 0057 h in middle-aged men (P < 0.04). In young men, the mean testosterone level at night (5.0 +/- 1.3 ng/ml; 17.4 +/- 4.4 nmol/liter) and the integrated nocturnal secretion [area under the curve (AUC); 60.6 +/- 8.9 ng/ml.h; 210 +/- 31 nmol/liter.h] were significantly higher compared with the values (3.6 +/- 1.1 and 31.1 +/- 7.2 ng/ml.h; 12.6 +/- 3.8 and 108 +/- 24.8 nmol/liter.h, respectively) observed in middle-aged men (P < 0.04 and P < 0.01, respectively). The mean (3.5 +/- 0.3 mIU/ml; 3.5 +/- 0.3 IU/liter) and AUC (43.4 +/- 8.3 mIU/ml.h; 43.4 +/- 8.3 IU/liter.h) LH values in middle-aged men were significantly higher than the values observed in young men (2.0 +/- 0.7 and 30.8 +/- 6.1 mIU/ml.h; 2.0 +/- 0.7 and 30.8 +/- 6.1 IU/liter.h; P < 0.05 and P < 0.01, respectively). Young men had significantly more testosterone pulses at night (6.7 +/- 1.6/12 vs. 3.8 +/- 1.1/12 h in middle-aged men; P < 0.005) of shorter interpulse interval (88.5 +/- 23.6 vs. 137.4 +/- 46.4 min; P < 0.02). LH pulse characteristics and sleep quality were similar in both groups. However, the first rapid eye movement (REM) sleep episode occurred earlier in middle-aged men (2303 +/- 0034 h) vs. young men (0010 +/- 0054 h; P < 0.04). As a consequence, the testosterone rise antedated the first REM episode by 90 min in young men. The link between testosterone rise and REM sleep episode was not observed in middle-aged men. Linear regression analysis revealed that the LH AUC was significantly related to age (P < 0.02). Analysis of covariance revealed that the two groups differed significantly in testosterone AUC (P < 0.04). Comparison of LH and testosterone concentrations showed significant and positive cross-correlations between LH and testosterone only in young men, with the testosterone rise lagging 60 min after the rise in LH. Our findings suggest that in middle-aged men, less pulsatile testosterone and more LH are secreted at night than in young men, with disruption of the association between testosterone rhythm and REM sleep. The decline in nocturnal testosterone secretion appears to involve a combination of testicular and pituitary hypogonadism.


Full text PDF available at




Sleep. 2007 Apr;30(4):427-32.

Association between sleep and morning testosterone levels in older men.

Penev PD.


Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.



The circulating testosterone levels of healthy men decline with advancing age. This process is characterized by considerable inter-individual variability, the causes of which are of significant biological and clinical interest but remain poorly understood. Since sleep quantity and quality decrease with age, and experimentally-induced sleep loss in young adults results in hormonal changes similar to those that occur spontaneously in the course of aging, this study examined whether some of the variability in circulating testosterone levels of older men can be related to objective differences in their sleep.


Observational study.


General community and university clinical research center.


Twelve healthy men ages 64 to 74 years.


Three morning blood samples were pooled for the measurement of total and free testosterone. In addition to overnight laboratory polysomnography, wrist activity monitoring for 6-9 days was used to determine the amount of nighttime sleep of the participants in everyday life settings.


The main outcome measures were total sleep time and morning testosterone levels. Sleep time in the laboratory was correlated with the usual amount of nighttime sleep at home (Pearson's r = 0.842; P = 0.001). Bivariate correlation and multiple linear regression analyses revealed that the amount of nighttime sleep measured by polysomnography was an independent predictor of the morning total (Beta 0.792, P = 0.017) and free (Beta 0.741, P = 0.029) testosterone levels of the subjects.


Objectively measured differences in the amount of nighttime sleep are associated with a significant part of the variability in the morning testosterone levels of healthy older men.




J Clin Oncol. 2010 Dec 1;28(34):5054-60. Epub 2010 Oct 25.

Testosterone levels and quality of life in diverse male patients with cancers unrelated to androgens.

Fleishman SB, Khan H, Homel P, Suhail MF, Strebel-Amrhein R, Mohammad F, Mahajan D, Rosenwald V, Guarino MJ, Mirzoyev T, Wozniak TF, Suppiah K.


Continuum Cancer Centers of New York, Beth Israel Medical Center and St Luke's-Roosevelt Hospital, New York, NY, USA.



Symptoms secondary to hormonal changes significantly impact quality of life (QoL) in patients with cancer. This cross-sectional study examines prevalence of hypogonadism and its correlation with QoL and sexual dysfunction.


We collected blood and medical histories from 428 male patients with non-testosterone-related cancer at three cancer centers. Serum was analyzed for total testosterone (TT), free testosterone (FT), bioavailable testosterone (BAT), and sex hormone binding globulin (SHBG). The Functional Assessment of Cancer Therapy-Prostate (FACT-P) QoL questionnaire measured physical, social, emotional, and functional domains as well as sexual function. Exclusion criteria were prostate, testicular, or male breast cancer; known hypogonadism; and HIV.


Mean and median TTs were 337.46 and 310 ng/dL, respectively. The mean age of patients was 62.05 years. The crude prevalence of hypogonadism (ie, TT < 300 ng/dL) was 48%, and mean TT in hypogonadal patients was 176 ng/dL. The prevalences that were based on FT (ie, hypogonadal < 52 pg/dL) and BAT (ie, hypogonadal < 95 ng/dL) were 78% and 66%, respectively. The mean FT and BAT values in hypogonadal patients were 25 pg/dL and 45 ng/dL, respectively. Hypogonadal patients had decreased total QoL scores on FACT-P (P = .01) and decreased three-item sexual function subset (P = .003).


The prevalence of hypogonadism was unexpectedly high. Measurement of FT or BAT detected a higher prevalence than TT alone, which confirmed previous studies. Correlation of T with FACT-P showed significant reduction of both overall QoL and sexual function for hypogonadal men. BAT and FT levels showed a stronger correlation than TT with overall FACT-P and subscales. The prevalence of symptomatic hypogonadism in male patients with cancer exceeds that found in comparable studies in noncancer populations.




Mol Pain. 2010 Oct 26;6:69.

Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats.

Aloisi AM, Ceccarelli I, Fiorenzani P, Maddalena M, Rossi A, Tomei V, Sorda G, Danielli B, Rovini M, Cappelli A, Anzini M, Giordano A.


Department of Physiology, Neuroscience and Applied Physiology Unit, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.



The steroid hormone testosterone has been found to be greatly reduced by opioids in different experimental and clinical conditions. The purpose of this study on male rats was to determine the effects of a single injection of morphine (5 mg/Kg) on persistent pain (formalin test) and the single or combined effects on p450-aromatase and 5-alpha reductase type 1 mRNA expression in the brain, liver and testis. Testosterone was determined in the plasma and in the brain, morphine was assayed in the plasma.


In the morphine-treated rats, there were increases of 5-alpha reductase mRNA expression in the liver and aromatase mRNA expression in the brain and gonads. Morphine was detected in the blood of all morphine-treated rats even though there were no clear analgesic affects in the formalin-treated animals three hours after treatment. Testosterone was greatly reduced in the plasma and brain in morphine-treated subjects.


It appears that morphine administration can induce long-lasting genomic effects in different body areas which contribute to the strong central and peripheral testosterone levels. These changes were not always accompanied by behavioral modifications.

Study shows a single shot of morphine has long lasting effects on testosterone levels

November 4th, 2010 in Medicine & Health / Research

A single injection of morphine to fight persistent pain in male rats is able to strongly reduce the hormone testosterone in the brain and plasma, according to a new paper published in Molecular Pain. The study, led by Anna Maria Aloisi, M.D., of the Department of Physiology – Section of Neuroscience and Applied Physiology at the University of Siena, Italy, Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia, University of Siena, and the Human Health Foundation in Spoleto, Italy, showed that opioids had "long lasting genomic effects in body areas which contribute to strong central and peripheral testosterone levels" including the brain, the liver and the testis.

The study showed increases in aromatase, an enzyme that is responsible for a key step in the biosynthesis of estrogen. The findings are particularly important since testosterone is the main substrate of aromatase, which is involved in the formation of estradiol. Both testosterone and estradiol are important hormones, engaged in cognitive functions as well as in mood, motor control and in many other functions, such as bone structure remodeling.

"Our lab became interested in gonadal hormones several years ago when it became clear that there were many differences in pain syndromes between the sexes," says Dr. Aloisi. "In looking at differences, it was immediately apparent that these changes were introduced by different treatments, opioids in particular."

"The research findings are very relevant to the management of patients with chronic pain," said Marco Pappagallo, M.D., professor and director of pain research and development, Department of Anesthesiology, Mount Sinai School of Medicine, New York, NY. "Today, primary care physicians, pain specialists, and a variety of health care professionals are asked not only to treat pain but how to manage side effects of drugs and to strive for the best possible comprehensive care and wellness of patients who experience chronic pain. Opioid induced hypogonadism can cause health complications to which patients with pain can be overly susceptible, including chronic fatigue, loss of stamina, emotional and sexual disturbances, as well painful skeletal and muscular complications."

It has been known that patients treated with opioids for short or long periods show low levels of gonadal hormones. Hypogonadism was already described in opioid users and applied to pain patients as OPIAD (opioid induced androgen deficiency). It is also known that patients treated with opioids, including newer drugs (fentalyl, tramadol) have a high probability to be hypogonadic, with menopausal symptoms occurring in women and andropausal symptoms in men.

"The use of opioids puts a 'physiological' block on the reproductive system and can induce a long lasting absence of these essential hormones from the blood and the brain," says Dr. Aloisi. "The normal effect of opioids to restrict reproduction in stressed subjects is multiplied by the higher levels/ long duration of opioids in the body."

"Until a few years ago this condition was completely unrecognized by physicians although some reports clearly showed it in many kinds of patients," notes Dr. Aloisi. "Today there remains some ignorance on this condition but gonadal hormones are more commonly cited as responsible for many chronic degenerative pathologies."

Despite the side effects of opioids, Antonio Giordano, M.D., Ph.D., Director of the Sbarro Institute for Cancer Research and Molecular Medicine, warns that the study's message is not meant to limit the use of opioids for pain. Instead, he suggests that doctors should "take into consideration this side effect, since it is very easy to find hormone replacement therapies. Using HRTs, patients can get relief from their pain, and improve their quality of life."

Provided by Sbarro Health Research Organization

"Study shows a single shot of morphine has long lasting effects on testosterone levels." November 4th, 2010.




Leproult R, Van Cauter E. Effect of 1 week of sleep restriction on testosterone levels in young healthy men. JAMA. 2011 Jun 1;305(21):2173-4.


Sleep loss lowers testosterone in healthy young men

Cutting back on sleep drastically reduces a healthy young man's testosterone levels, according to a study published in the June 1 issue of the Journal of the American Medical Association (JAMA). Eve Van Cauter, PhD, professor in medicine and director of the study, found that men who slept less than five hours a night for one week in a laboratory had significantly lower levels of testosterone than when they had a full night's sleep. Low testosterone has a host of negative consequences for young men, and not just in sexual behavior and reproduction. It is critical in building strength and muscle mass, and bone density.


"Low testosterone levels are associated with reduced well being and vigor, which may also occur as a consequence of sleep loss" said Van Cauter. At least 15% of the adult working population in the US gets less than 5 hours of sleep a night, and suffers many adverse health effects because of it. This study found that skipping sleep reduces a young man's testosterone levels by the same amount as aging 10 to 15 years.


"As research progresses, low sleep duration and poor sleep quality are increasingly recognized as endocrine disruptors," Van Cauter said.


The ten young men in the study were recruited from around the University of Chicago campus. They passed a rigorous battery of tests to screen for endocrine or psychiatric disorders and sleep problems. They were an average of 24 years old, lean and in good health.


For the study, they spent three nights in the laboratory sleeping for up to ten hours, and then eight nights sleeping less than five hours. Their blood was sampled every 15 to 30 minutes for 24 hours during the last day of the ten-hour sleep phase and the last day of the five-hour sleep phase.


The effects of sleep loss on testosterone levels were apparent after just one week of short sleep. Five hours of sleep decreased their testosterone levels by 10% to 15%. The young men had the lowest testosterone levels in the afternoons on their sleep restricted days, between 2 pm and 10 pm. The young men also self-reported their mood and vigor levels throughout the study. They reported a decline in their sense of well-being as their blood testosterone levels declined. Their mood and vigor fell more every day as the sleep restriction part of the study progressed.


Testosterone levels in men decline by 1% to 2% a year as they age. Testosterone deficiency is associated with low energy, reduced libido, poor concentration, and fatigue.


Provided by University of Chicago Medical Center


"Sleep loss lowers testosterone in healthy young men." May 31st, 2011.




Saudi Med J. 2002 Aug;23(8):934-7.

Effects of short term metformin administration on androgens in normal men.

Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM.

National Center for Diabetes Endocrinology and Genetics, Jordan University Hospital, Amman, Jordan.


OBJECTIVE: To study the effect of metformin on androgens in normal men.

METHODS: A total of 12 healthy males volunteered to participate in the study. A blood sample was obtained from each of them and analyzed for the following: Testosterone (total and free), sex hormone binding globulin dehydroepiandrosterone sulphate, 17-hydroxyprogesterone, luteinizing hormone, and follicle stimulating hormone. In addition, each participant was subjected to a glucose tolerance test and his insulin level was measured. Metformin 850 mg twice daily for 2-weeks was given to each subject after which the above tests were repeated. A paired t-test was used to assess the statistical significance of any observed differences before and after metformin.

RESULTS: After metformin administration, there was a significant reduction in serum level of total testosterone (p=0.0001), free testosterone (P=0.002), and 17 hydroxyprogesterone (p=0.0001). There was also a significant increase in serum level of sex hormone binding globulin (p=0.009) and dehydroepiandrosterone sulphate (P=0.0008). Serum levels of luteinizing hormone and follicle stimulating hormone showed no significant changes. Similarly, there were no changes in fasting plasma glucose, fasting serum insulin, weight, or blood pressure.

CONCLUSION: Metformin administration was associated with a reduction in total testosterone, free testosterone, and 17-hydroxyprogesterone and an increase in sex hormone binding globulin and dehydroepiandrosterone sulphate in normal males. The clinical significance of these findings needs further investigation.




Obes Res. 2001 Nov;9(11):662-7.

The effects of metformin and diet on plasma testosterone and leptin levels in obese men.

Ozata M, Oktenli C, Bingol N, Ozdemir IC.

Department of Endocrinology and Metabolism, Gulhane School of Medicine, Etlik-Ankara, Turkey.


OBJECTIVE: The aim of this study was to investigate the effects of combined hypocaloric diet and metformin on circulating testosterone and leptin levels in obese men with or without type 2 diabetes.

RESEARCH METHODS AND PROCEDURES: Twenty obese men with type 2 diabetes (mean body mass index [BMI]: 35.5 +/- 1.1 kg/m(2)) and 20 nondiabetic obese men were enrolled in the study. We measured serum follicle-stimulating hormone, luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), sex-hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and plasma leptin levels before and 3 months after metformin treatment. Both groups were placed on a hypocaloric diet and 850 mg of metformin taken orally twice daily for 3 months.

RESULTS: Metformin and hypocaloric diets led to decreases in BMI and waist and hip circumferences in both groups. A significant decrease in TT levels in the diabetic group and FT levels in the control group was found, whereas follicle-stimulating hormone, LH, and DHEAS levels were not changed significantly. A significant increase in SHBG levels was observed in the control group but not in the patient group. Leptin levels also decreased after treatment in both groups. Decreased testosterone levels were not correlated to changes in waist and hip circumference, waist-to-hip ratio, BMI, and levels of fasting blood glucose, leptin, SHBG, or DHEAS in the diabetic group. However, a decrease in FT was correlated to changes in the levels of SHBG (r = -0.71, p = 0.001) and LH (r = 0.80, p = 0.001) but not to other parameters.

DISCUSSION: We conclude that metformin treatment combined with a hypocaloric diet leads to reduced FT levels in obese nondiabetic men and to reduced TT levels in obese men with type 2 diabetes. Increased SHBG levels may account for the decrease in FT levels in the former group.




Abstracts on Factors Raising Testosterone Levels


Life Sci. 1996;59(2):97-104.

Involvement of D-aspartic acid in the synthesis of testosterone in rat testes.

D'Aniello A, Di Cosmo A, Di Cristo C, Annunziato L, Petrucelli L, Fisher G.


Department of Biochemistry, Zoological Station of Naples, Italy.


D-Aspartic acid (D-Asp) is an endogenous amino acid which occurs in many marine and terrestrial animals. In fetal and young rats, this amino acid occurs prevalently in nervous tissue, whereas at sexual maturity it occurs in endocrine glands and above all in pituitary and testes. Here, we have studied if a relationship exists between the presence of D-Asp and the hormonal activity. The following results were obtained: 1) Both D-Asp and testosterone are synthesized in rat testes in two periods of the animal's life: before birth, about the 17th day after fertilization and, after birth, at sexual maturity. 2) Immunocytochemical studies have demonstrated that this enantiomer is localized in Leydig and Sertoli cells. 3) In vivo experiments, consisting of i.p. injection of D-Asp to adult male rats, demonstrated that this amino acid accumulates in pituitary and testis (after 5 h, the accumulation was of 12 and 4-fold over basal values, respectively); simultaneously, luteinizing hormone, testosterone and progesterone significantly increased in the blood (1.6-fold, p < 0.05; 3.0-fold, p < 0.01 and 2.9-fold, p < 0.01, respectively). 4) Finally, in vitro experiments, consisting of the incubation of D-Asp with isolated testes also demonstrated that this amino acid induces the synthesis of testosterone. These results suggest that free D-Asp is involved in the steroidogenesis.




Reprod Biol Endocrinol. 2009 Oct 27;7:120.

The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats.

Topo E, Soricelli A, D'Aniello A, Ronsini S, D'Aniello G.


1Stazione Zoologica Anton Dohrn, 80121, Villa Comunale, 80121, Napoli, Italy.



D-aspartic acid is an amino acid present in neuroendocrine tissues of invertebrates and vertebrates, including rats and humans. Here we investigated the effect of this amino acid on the release of LH and testosterone in the serum of humans and rats. Furthermore, we investigated the role of D-aspartate in the synthesis of LH and testosterone in the pituitary and testes of rats, and the molecular mechanisms by which this amino acid triggers its action.


For humans: A group of 23 men were given a daily dose of D-aspartate (DADAVIT) for 12 days, whereas another group of 20 men were given a placebo. For rats: A group of 10 rats drank a solution of either 20 mM D-aspartate or a placebo for 12 days. Then LH and testosterone accumulation was determined in the serum and D-aspartate accumulation in tissues. The effects of D-aspartate on the synthesis of LH and testosterone were gauged on isolated rat pituitary and Leydig cells. Tissues were incubated with D-aspartate, and then the concentration (synthesis) of LH and cGMP in the pituitary and of testosterone and cAMP in the Leydig cells was determined.


In humans and rats, sodium D-aspartate induces an enhancement of LH and testosterone release. In the rat pituitary, sodium D-aspartate increases the release and synthesis of LH through the involvement of cGMP as a second messenger, whereas in rat testis Leydig cells, it increases the synthesis and release of testosterone and cAMP is implicated as second messenger. In the pituitary and in testes D-Asp is synthesized by a D-aspartate racemase which convert L-Asp into D-Asp. The pituitary and testes possesses a high capacity to trapping circulating D-Asp from hexogen or endogen sources.


D-aspartic acid is a physiological amino acid occurring principally in the pituitary gland and testes and has a role in the regulation of the release and synthesis of LH and testosterone in humans and rats.




Biol Trace Elem Res. 2009 Summer;129(1-3):65-9. Epub 2008 Dec 20.

Testosterone levels in athletes at rest and exhaustion: effects of calcium supplementation.

Cinar V, Baltaci AK, Mogulkoc R, Kilic M.


Karaman High School of Physical Education and Sport, Selcuk University, Karaman, Turkey.


The effects of 4 weeks of calcium supplementation on free- and total testosterone levels were established in active and sedentary adult males at rest and exhaustion. Thirty healthy male athletes were equally divided into three study groups, as follows: Group 1-non-exercising subjects receiving 35 mg calcium/kg body weight; Group 2-subjects receiving 35 mg calcium/kg body weight undergoing training routines for 90 min/day, 5 days a week and Group 3-subjects undergoing training routines for 90 min/day, 5 days a week. The testosterone levels were determined before and after supplementation, at rest and following a hard training routine. The plasma free- and total testosterone levels increased at exhaustion before and after supplementation relative to resting values (p < 0.05). This was also true when active subjects were compared to inactive subjects (p < 0.05). Our results show that training results in increased testosterone levels in athletes and that the increase is greater if accompanied by calcium supplementation, which may be useful for increasing overall athletic performance.




Clin Endocrinol (Oxf). 2010 Aug;73(2):243-8. Epub 2009 Dec 29.

Association of vitamin D status with serum androgen levels in men.

Wehr E, Pilz S, Boehm BO, März W, Obermayer-Pietsch B.

Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University Graz, Graz, Austria.

Comment in:

·                     Nat Rev Urol. 2010 Oct;7(10):532.


OBJECTIVE: Studies in rodents indicate a role of vitamin D in male reproduction, but the relationship between vitamin D and androgen levels in men is largely unexplored. We aimed to investigate the association of 25-hydroxyvitamin D [25(OH)D] levels with testosterone, free androgen index (FAI) and SHBG. Moreover, we examined whether androgen levels show a similar seasonal variation to 25(OH)D.

DESIGN: In this cross-sectional study, 25(OH)D, testosterone and SHBG levels were assessed by immunoassay in 2299 men who were routinely referred for coronary angiography (1997-2000).

MEASUREMENTS: Main outcome measures were associations of 25(OH)D levels with testosterone, SHBG and FAI. FAI was calculated as testosterone (nmol/l)/SHBG (nmol/l) x 100.

RESULTS: Men with sufficient 25(OH)D levels (> or =30 microg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20-29.9 microg/l) and 25(OH)D-deficient (<20 microg/l) men (P < 0.05 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels (P < 0.05 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (12.2 microg/l, 15.9 nmol/l and 40.8, respectively) and peak levels in August (23.4 microg/l, 18.7 nmol/l and 49.7, respectively) (P < 0.05 for all).

CONCLUSION: Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal variation. Randomized controlled trials are warranted to evaluate the effect of vitamin D supplementation on androgen levels




Horm Metab Res. 2010 Dec 10. [Epub ahead of print]

Effect of Vitamin D Supplementation on Testosterone Levels in Men.

Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, Wehr E, Zittermann A.

Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria.


The male reproductive tract has been identified as a target tissue for vitamin D, and previous data suggest an association of 25-hydroxyvitamin D [25(OH)D] with testosterone levels in men. We therefore aimed to evaluate whether vitamin D supplementation influences testosterone levels in men. Healthy overweight men undergoing a weight reduction program who participated in a randomized controlled trial were analyzed for testosterone levels. The entire study included 200 nondiabetic subjects, of whom 165 participants (54 men) completed the trial. Participants received either 83 μg (3 332 IU) vitamin D daily for 1 year (n=31) or placebo (n=23). Initial 25(OH)D concentrations were in the deficiency range (<50 nmol/l) and testosterone values were at the lower end of the reference range (9.09-55.28 nmol/l for males aged 20-49 years) in both groups. Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group, but remained almost constant in the placebo group. Compared to baseline values, a significant increase in total testosterone levels (from 10.7±3.9 nmol/l to 13.4±4.7 nmol/l; p<0.001), bioactive testosterone (from 5.21±1.87 nmol/l to 6.25±2.01 nmol/l; p=0.001), and free testosterone levels (from 0.222±0.080 nmol/l to 0.267±0.087 nmol/l; p=0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group. Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.




Endocr Regul. 2010 Jan;44(1):3-8.

Changes of metabolic profile in men treated for androgenetic alopecia with 1 mg finasteride.

Duskova M, Hill M, Starka L.


Institute of Endocrinology, Prague, Czech Republic.



Androgenetic alopecia is recognized as a risk factor for cardiovascular diseases, glucose metabolism disorders, and benign prostate hyperplasia and/or carcinoma. Finasteride, used for treatment of androgenetic alopecia at a dose of 1mg/day, is an effective inhibitor of type II 5alpha-reductase, the enzyme responsible for the reduction of testosterone to dihydrotestosterone. Recent studies reported that dihydrotestosterone, among other activities, might play some role in visceral fat metabolism. It thus seemed reasonable to examine whether finasteride treatment of androgenetic alopecia ameliorates some features of metabolic syndrome frequently seen associated with this condition.


We examined 12 men with premature balding (defined as frontoparietal and vertex hair loss before age 30 with alopecia defined as grade 3 vertex or more on the Norwood-modified Hamilton alopecia classification). Hormonal levels and metabolic parameters were determined and insulin tolerance tests performed for all individuals. Finasteride (1 mg/day) was administrated for 12 months. The hormonal profile and lipid spectrum were monitored after 4, 8 and 12 months of treatment and insulin tolerance tests were repeated after 12 months of the treatment.


After treatment with finasteride the expected changes in the steroid spectrum were seen, namely a decrease in dihydrotestosterone and increase in testosterone, androstenedione and free testosterone index. We observed an initial increase in total cholesterol and HDL- and LDL-cholesterol, which stabilized with prolonged treatment. We founded a significant decrease in glycated hemoglobin HbA1c and insulin resistance measured using rate constant for plasma glucose disappearance (kITT) showed only a borderline decrease.


Finasteride is an efficient 5alpha-reductase inhibitor even at low doses of 1 mg/day. In men treated with this dose for 12 months, we observed mild differences in metabolic profile with slight amelioration of glucose metabolism regulation.




Psychol Sci. 2010 Feb 1;21(2):276-83. Epub 2009 Dec 22.

Scent of a woman: men's testosterone responses to olfactory ovulation cues.

Miller SL, Maner JK.


Department of Psychology, Florida State University, Tallahassee, FL 32306-4301, USA.


Adaptationist models of human mating provide a useful framework for identifying subtle, biologically based mechanisms influencing cross-gender social interaction. In line with this framework, the current studies examined the extent to which olfactory cues to female ovulation--scents of women at the peak of their reproductive fertility--influence endocrinological responses in men. Men in the current studies smelled T-shirts worn by women near ovulation or far from ovulation (Studies 1 and 2) or control T-shirts not worn by anyone (Study 2). Men exposed to the scent of an ovulating woman subsequently displayed higher levels of testosterone than did men exposed to the scent of a nonovulating woman or a control scent. Hence, olfactory cues signaling women's levels of reproductive fertility were associated with specific endocrinological responses in men--responses that have been linked to sexual behavior and the initiation of romantic courtship.




Eur Arch Psychiatry Clin Neurosci. 2010 Nov;260 Suppl 2:S100-5. Epub 2010 Oct 12.

Fascination violence: on mind and brain of man hunters.

Elbert T, Weierstall R, Schauer M.


Clinical Psychology & Neuropsychology, University of Konstanz, Konstanz, Germany.


Why are savagery and violence so omnipresent among humans? We suggest that hunting behaviour is fascinating and attractive, a desire that makes temporary deprivation from physical needs, pain, sweat, blood and, ultimately, the willingness to kill tolerable and even appetitive. Evolutionary development into the "perversion" of the urge to hunt humans, that is to say the transfer of this hunt to members of one's own species, has been nurtured by the resultant advantage of personal and social power and dominance. While a breakdown of the inhibition towards intra-specific killing would endanger any animal species, controlled inhibition was enabled in humans in that higher regulatory systems, such as frontal lobe-based executive functions, prevent the involuntary derailment of hunting behaviour. If this control--such as in child soldiers for example--is not learnt, then brutality towards humans remains fascinating and appealing. Blood must flow in order to kill. It is hence an appetitive cue as is the struggling of the victim. Hunting for men, more rarely for women, is fascinating and emotionally arousing with the parallel release of testosterone, serotonin and endorphins, which can produce feelings of euphoria and alleviate pain. Bonding and social rites (e.g. initiation) set up the constraints for both hunting and violent disputes. Children learn which conditions legitimate aggressive behaviour and which not. Big game hunting as well as attack of other communities is more successful in groups--men also perceive it as more pleasurable. This may explain the fascination with gladiatorial combat, violent computer games but as well ritualized forms like football.




Nutr Cancer. 2000;38(2):163-7.

Relationships between types of fat consumed and serum estrogen and androgen concentrations in Japanese men.

Nagata C, Takatsuka N, Kawakami N, Shimizu H.

Department of Public Health, Gifu University School of Medicine, Japan.


The relationships between types of fat consumed and serum concentrations of estrone, estradiol, total and free testosterone, dihydrotestosterone, and sex hormone-binding globulin were examined in 69 Japanese men aged 43-88 years. Diet was assessed by a semiquantitative food frequency questionnaire. Intake of saturated, monounsaturated, and polyunsaturated fats was inversely correlated with serum total testosterone after controlling for age, total energy, body mass index, alcohol intake, and smoking status, but the correlation was statistically significant only for polyunsaturated fat (r = -0.29, p = 0.02). Intakes of eicosapentanoic and docosahexaenoic acids, n-3 fatty acids from fish, were significantly inversely correlated with total testosterone (r = -0.25, p = 0.04 and r = -0.32, p = 0.01, respectively). Serum estrone, estradiol, and free testosterone were not significantly correlated with any type of fat studied. The correlations of total testosterone with n-3 fatty acids from fish remained significant after additional adjustment for the other categories of fat (r = -0.27, p = 0. 03 for eicosapentanoic acid and r = -0.32, p = 0.01 for docosahexaenoic acid), while the correlations with saturated and monounsaturated fats became nearly null after the adjustment.




Int J Sports Med. 2007 Dec;28(12):1070-6. Epub 2007 May 11.

Dietary intake, serum hormones, muscle mass and strength during strength training in 49 - 73-year-old men.

Sallinen J, Pakarinen A, Fogelholm M, Alen M, Volek JS, Kraemer WJ, Häkkinen K.

Department of Biology of Physical Activity and Neuromuscular Research Center, University of Jyväskylä, Jyväskylä, Finland.


Effects of dietary intake on serum hormones, muscle cross-sectional area (CSA) and strength during strength training were studied in two groups of men: 1) strength training + nutritional counseling (n = 22, 59.1 +/- 6.1 yrs), and 2) strength training (n = 23, 58.5 +/- 7.1 yrs). Both groups performed strength training twice a week for 21 weeks. Counseling increased carbohydrate (p < 0.01) and fiber intake (p < 0.001) and polyunsaturated/saturated fat-ratio (p < 0.05) and decreased fat intake (p < 0.01). Muscle strength and CSA increased by 16 - 20 % and by 5.4 - 5.9 % in both groups (p < 0.001). Changes in protein content of diet correlated with the changes in the acute postexercise concentrations of total (r = 0.64, p < 0.01) and free testosterone (r = 0.54, p < 0.05) after training in the counseling group. Moreover, changes in the free testosterone responses to heavy-resistance exercise correlated with the increases in the muscle CSA (r = 0.52, p < 0.05) in the counseling group. Serum basal testosterone/sex hormone-binding globulin-ratios correlated with the body mass normalized energy (kJ/kg: r = 0.54, p < 0.001), protein (g/kg: r = 0.42, p < 0.01) and fat (g/kg: r = 0.51, p < 0.01) intake in all participants during the training. The data indicate that protein and fat intake may influence serum testosterone concentrations and that the changes in exercise-induced testosterone responses may contribute to muscle mass development during strength training.




Minerva Endocrinol. 2010 Sep;35(3):145-51.

Effects of metformin and short-term lifestyle modification on the improvement of male hypogonadism associated with metabolic syndrome.

Casulari LA, Caldas AD, Domingues Casulari Motta L, Lofrano-Porto A.

Section of Endocrinology, University Hospital of Brasília, Faculty of Medicine, University of Brasília, Brasília, DF, Brazil.


AIM: The metabolic syndrome is associated with male hypogonadism, but specific studies about the mechanisms and treatment of the testosterone deficit are scanty. The aim of this study was to evaluate the effects of metformin combined with diet and physical activity on the testicular function of men with metabolic syndrome.

METHODS: Thirty-five men (40.4 ± 13.3 years old) with metabolic syndrome were evaluated before and after a four-month period of therapy with metformin 850 mg twice daily, associated with a balanced normocaloric diet and subtle improvement in physical activity. The subjects were divided in two groups: 21 males with normal plasma testosterone levels (≥ 300 ng/dL) and 14 males with low plasma testosterone levels (< 300 ng/dL).

RESULTS: There was a significant decrease in fasting insulin levels and HOMA-IR after treatment (P = 0.01 and P = 0.06), which was more pronounced in the hypogonadic group (for the effect of absence or presence of hypogonadism, P = 0.04). The mean total and free testosterone levels increased significantly after treatment in both groups, similarly. The increase in FSH levels was more pronounced in the hypogonadic group than in the eugonadic group.

CONCLUSION: In this series of males with metabolic syndrome, treatment with metformin associated with healthy dietary modifications and a mild physical activity increment resulted in significant improvement of insulin sensitivity and increase in total and free testosterone levels, regardless of the presence of hypogonadism.




Am J Clin Nutr. 1996 Dec;64(6):850-5.

Effects of dietary fat and fiber on plasma and urine androgens and estrogens in men: a controlled feeding study.

Dorgan JF, Judd JT, Longcope C, Brown C, Schatzkin A, Clevidence BA, Campbell WS, Nair PP, Franz C, Kahle L, Taylor PR.

Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, MD 20892-7326, USA.


We conducted a controlled feeding study to evaluate the effects of fat and fiber consumption on plasma and urine sex hormones in men. The study had a crossover design and included 43 healthy men aged 19-56 y. Men were initially randomly assigned to either a low-fat, high-fiber or high-fat, low-fiber diet for 10 wk and after a 2-wk washout period crossed over to the other diet. The energy content of diets was varied to maintain constant body weight but averaged approximately 13.3 MJ (3170 kcal)/d on both diets. The low-fat diet provided 18.8% of energy from fat with a ratio of polyunsaturated to saturated fat (P:S) of 1.3, whereas the high-fat diet provided 41.0% of energy from fat with a P:S of 0.6. Total dietary fiber consumption from the low- and high-fat diets averaged 4.6 and 2.0 g.MJ-1.d-1, respectively. Mean plasma concentrations of total and sex-hormone-binding-globulin (SHBG)-bound testosterone were 13% and 15% higher, respectively, on the high-fat, low-fiber diet and the difference from the low-fat, high-fiber diet was significant for the SHBG-bound fraction (P = 0.04). Men's daily urinary excretion of testosterone also was 13% higher with the high-fat, low-fiber diet than with the low-fat, high-fiber diet (P = 0.01). Conversely, their urinary excretion of estradiol and estrone and their 2-hydroxy metabolites were 12-28% lower with the high-fat, low-fiber diet (P < or = 0.01). Results of this study suggest that diet may alter endogenous sex hormone metabolism in men.




Am J Physiol Endocrinol Metab. 2010 Oct;299(4):E544-50. Epub 2010 Jul 27.

Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway.

Andric SA, Janjic MM, Stojkov NJ, Kostic TS.


Reproductive Endocrinology and Signaling Group, Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.


Sildenafil citrate (Viagra), a cGMP-selective phosphodiesterase (PDE) inhibitor, is widely used to treat erectile dysfunction and pulmonary arterial hypertension. In contrast to its well established action on erectile dysfunction, little is known on the action of sildenafil on cGMP/cAMP signaling and testicular steroidogenesis. This study was designed to assess the effects of prolonged sildenafil treatment on NO synthase-dependent signaling and steroidogenic function of rat Leydig cells. Male adult rats were treated with Viagra (1.25 mg/kg body wt) daily for 30 days. In our studies, serum testosterone and ex vivo testosterone production significantly increased in sildenafil-treated animals. Human chorionic gonadotropin-stimulated testosterone production and cAMP accumulation were also significantly higher in Leydig cells obtained from sildenafil-treated rats. The expression of soluble guanylyl cyclase (GUCY1) subunits (Gucy1a1, Gucy1b1) significantly increased; cAMP-specific Pde4a, cGMP-specific Pde6c, and dual Pde1c and Nos2 were inhibited and expression of Nos3, protein kinase G1 (Pkg1), and Pde5 remained unchanged. Treatment of purified Leydig cells with NO donor caused a dose-dependent increase in both testosterone and cGMP production. Testosterone and cGMP production was significantly higher in Leydig cells obtained from sildenafil-treated animals. The stimulatory effect of NO donor was significantly enhanced by saturating concentrations of hCG in both Leydig cells obtained from control and sildenafil-treated animals. Occurrence of mature steroidogenic acute regulatory protein also increased in sildenafil treated animals in accord with increased cAMP and cGMP production. In summary, inhibition of PDE activity during prolonged sildenafil treatment increased serum testosterone level and Leydig cells' steroidogenic capacity by coordinated stimulatory action on cAMP and cGMP signaling pathway.




Int J Exp Pathol. 2009 Aug;90(4):454-62.

Chronic treatment with sildenafil stimulates Leydig cell and testosterone secretion.

Saraiva KL, Silva AK, Wanderley MI, De Araújo AA, De Souza JR, Peixoto CA.


Laboratório de Ultraestrutura do Centro de Pesquisas Aggeu Magalhães (FIOCRUZ), Recife, CEP 50670-420, Brazil.


The phosphodiesterase type 5 (PDE5) inhibitor, Sildenafil, is a novel, oral treatment approach for pulmonary hypertension. As Leydig cells present PDE5, this study was conducted to investigate the effects of the chronic treatment with Sildenafil (25 mg/kg) on male Swiss Webster mice steroidogenesis. After a 4-week long experimental design, Leydig cells were analysed by morphological and immunocytochemical procedures. Serum testosterone was assayed by radioimmunoassay. Leydig cells presented noteworthy ultrastructural alterations, such as a vesicular smooth endoplasmic reticulum, large vacuoles scattered through the cytoplasm, enlarged mitochondria with discontinue cristaes and whorle membranes with vesicles at the periphery, which are typical characteristics of an activated steroid-secreting cell. Important immunocytochemical labelling for steroidogenic acute regulatory protein, cytochrome P450 side-chain cleavage enzyme and testosterone were detected in isolated Leydig cells. In addition, Sildenafil-treated mice showed significant increased levels of total testosterone. The results obtained in the present study are consistent with the hypothesis that the accumulation of cyclic guanosine monophosphate by PDE5 inhibition could be involved in the androgen biosynthesis stimulation. Important clinical implications of hormonal disorders should be taken into account for patients with pulmonary hypertension.




Cent Eur J Public Health. 2011 Mar;19(1):54-9.

Smoking practices in Jordanian people and their impact on semen quality and hormonal levels among adult men.

Al-Matubsi HY, Kanaan RA, Hamdan F, Salim M, Oriquat GA, Al Hanbali OA.


Faculty of Pharmacy, Applied Science University, Amman, Jordan.


Despite worldwide anti-smoking campaigns, cigarette smoking prevalence is increasing in the third-world countries. It is now regarded as the most important public health issue. Here, we study the current smoking situation and investigate the impact of cigarette smoking on semen quality and hormonal levels among adult people. Furthermore, we suggest various strategies to reduce smoking consumption among young individuals. Across-sectional data from 804 adult smoker subjects (male n = 530 and female n = 274) aged between 15 and 45 years were analyzed. One hundred and eleven males were agreed for further evaluation of their semen quality and hormones compared with 93 age-matched non-smoking males. This study showed that the majorfactors initiating smoking among women were friends' influence (49%), life pressures (16%) and parental imitation (14%). The major reasons in men was friends' influence (65%). Furthermore, 61% ofwomen and 89% of men smoke in public implying social acceptance oreven encouragement of this habit. This study also found that low-income Jordanians consume more tobacco materials than those in the middle- and higher income. Furthermore, smokers had significantly lower (p < 0.001) sperm concentration and motility values and higher (p < 0.001) serum testosterone and luteinizing hormone (LH) levels than non-smokers.




Environ Health Perspect. 2010 Nov;118(11):1603-8.

Daily bisphenol A excretion and associations with sex hormone concentrations: results from the InCHIANTI adult population study.

Galloway T, Cipelli R, Guralnik J, Ferrucci L, Bandinelli S, Corsi AM, Money C, McCormack P, Melzer D.


School of Biosciences, University of Exeter, Exeter, United Kingdom.



Bisphenol A (BPA) is a high production volume chemical widely used in packaging for food and beverages. Numerous studies have demonstrated that BPA can alter endocrine function in animals, yet human studies remain limited.


We estimated daily excretion of BPA among adults and examined hypothesized associations with serum estrogen and testosterone concentrations.


We conducted cross-sectional analyses using data from the InCHIANTI Study, a prospective population-based study of Italian adults. Our study included 715 adults between 20 and 74 years old. BPA concentrations were measured by liquid chromatography-mass spectrometry in 24-hr urine samples. The main outcome measures were serum concentrations of total testosterone and 17beta-estradiol.


Geometric mean urinary BPA concentration was 3.59 ng/mL [95% confidence interval (CI), 3.42-3.77 ng/mL], and mean excretion was 5.63 microg/day (5th population percentile, 2.1 microg/day; 95th percentile, 16.4 microg/day). We found higher excretion rates among men, younger respondents, and those with increasing waist circumference (p = 0.013) and weight (p = 0.003). Higher daily BPA excretion was associated with higher total testosterone concentrations in men, in models adjusted for age and study site (p = 0.044), and in models additionally adjusted for smoking, measures of obesity, and urinary creatinine concentrations (beta = 0.046; 95% CI, 0.015-0.076; p = 0.004). We found no associations with the other serum measures. We also found no associations with the primary outcomes among women, but we did find an association between BPA and SHBG concentrations in the 60 premenopausal women.


Higher BPA exposure may be associated with endocrine changes in men. The mechanisms involved in the observed cross-sectional association with total testosterone concentrations need to be clarified.




Andrologia. 2011 Mar 28. doi: 10.1111/j.1439-0272.2010.01075.x. [Epub ahead of print]

Impact of cell phone use on men's semen parameters.

Gutschi T, Mohamad Al-Ali B, Shamloul R, Pummer K, Trummer H.


Queen's University, Kingston, ON, Canada. Medical University of Graz, Graz, Austria  


1119). Significant difference was observed in sperm morphology between the two groups. In the patients of group A, 68.0% of the spermatozoa featured a pathological morphology compared to only 58.1% in the subjects of group B. Patients with cell phone usage showed significantly higher T and lower LH levels than those who did not use cell phone. No significant difference between the two groups was observed regarding FSH and PRL values. Our results showed that cell phone use negatively affects sperm quality in men. Further studies with a careful design are needed to determine the effect of cell phone use on male fertility. = 991); group B: no use (n = The objective of the present retrospective study was to report our experience concerning the effects of cell phone usage on semen parameters. We examined 2110 men attending our infertility clinic from 1993 to October 2007. Semen analysis was performed in all patients. Serum free testosterone (T), follicle stimulating hormone (FSH), luteinising hormone (LH) and prolactin (PRL) were collected from all patients. The information on cell phone use of the patients was recorded and the subjects were divided into two groups according to their cell phone use: group A: cell phone use (n = 1119). Significant difference was observed in sperm morphology between the two groups. In the patients of group A, 68.0% of the spermatozoa featured a pathological morphology compared to only 58.1% in the subjects of group B. Patients with cell phone usage showed significantly higher T and lower LH levels than those who did not use cell phone. No significant difference between the two groups was observed regarding FSH and PRL values. Our results showed that cell phone use negatively affects sperm quality in men. Further studies with a careful design are needed to determine the effect of cell phone use on male fertility.



Cell Phone Use May Reduce Male Fertility, Austrian-Canadian Study Suggests

ScienceDaily (May 19, 2011) — Men who have been diagnosed with poor sperm quality and who are trying to have children should limit their cell phone use, a new study suggests. Researchers in Austria and Canada have found that while cell phone use appears to increase the level of testosterone circulating in the body, it may also lead to low sperm quality and a decrease in fertility.

"Our findings were a little bit puzzling," says Rany Shamloul, a postdoctoral fellow in the Department of Pharmacology and Toxicology at Queen's University in Canada and a co-author of the study. "We were expecting to find different results, but the results we did find suggest that there could be some intriguing mechanisms at work."

The research team at Queen's and at the Medical University of Graz, Austria, discovered that men who reported cell phone use had higher levels of circulating testosterone but they also had lower levels of luteinizing hormone (LH), an important reproductive hormone that is secreted by the pituitary gland in the brain.

The researchers hypothesize that electromagnetic waves (EMW) emitted by cell phones may have a dual action on male hormone levels and fertility. EMW may increase the number of cells in the testes that produce testosterone; however, by lowering the levels of LH excreted by the pituitary gland, EMW may also block the conversion of this basic circulating type of testosterone to the more active, potent form of testosterone associated with sperm production and fertility.

More in-depth research is needed to determine the exact ways in which EMW affects male fertility.

Results of the research appear in the journal Andrologia, published by Wiley-Blackwell. In addition to Shamloul at Queen's, authors include T. Gutschi, B. Mohamad Al-Ali, K. Pummer, and H. Trummer at the Medical University of Graz.

Provided by Queen's University

"Cell phone use may reduce male fertility." May 19th, 2011.



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