Testosterone Research versus Testosterone Myths

Testosterone spikes at day 7 after ejaculationCOMMENTS: We wrote this article to highlight possible mechanisms behind the benefits of rebooting. Below I address the most common misconceptions related to testosterone, abstinence and ejaculation. The preponderance of human and animal research points to neither abstinence nor ejaculation having any significant long-term effects on blood testosterone levels - other than a spike around day 7 of abstinence. That said, there's been no study examining the effects of porn addiction on hormone levels. It is not unreasonable to assume that hormones are altered by brain changes associated with porn addiction (i.e. in the hypothalamus). I caution readers (especially r/nofap) to not conflate the effects of ejaculation with the effects of a severe porn addiction.

  1. As stated, the preponderance of animal & human studies suggest that neither abstinence nor “too much ejaculation” have any effect on blood testosterone levels. However, there's evidence that ejaculation to the point of sexual satiation triggers multiple brain changes - including a decline in androgen receptors. and increases in estrogen receptors and dopamine-blocking opioids in several brain regions. Full recovery takes about 15 days and is quite apart from addiction-related brain changes. More below.
  2. There is no consistent correlation between sexual activity, or abstinence, and plasma testosterone levels – other than a one-day transient spike (46% above baseline) following seven days of abstinence. Wide fluctuations in male testosterone levels (10-40%) are normal.  
  3. There is no evidence for abstinence raising testosterone levels. Only two studies have measured T levels during a long-term abstinence (16 & 21 days), and both found no change:
    1.  The "famous" Chinese study measured testosterone levels every day for 16 days, and found little change until around day 7, when a spike occurred. After the one day spike Testosterone returned to baseline or slightly lower from day 8 through day 16 when the experiment ended.
    2. The study in #4
  4. This abstract - Endocrine response to masturbation-induced orgasm in healthy men following a 3-week sexual abstinence, where subjects didn't ejaculate for 3 weeks, is often cited as evidence that abstinence leads to increased testosterone. It doesn't. This sentence from the abstract is poorly worded and misleading: "although plasma testosterone was unaltered by orgasm, higher testosterone concentrations were observed following the period of abstinence". In the full study, testosterone levels are the same in both groups. Examine the testosterone graph C on page 379. Notice testosterone levels at the start of the film (10-minute mark) were identical in both groups. End of story. The confusing language in the abstract refers to testosterone differences while masturbating. While watching the erotic film and masturbating, T-levels dropped for the pre-abstinence masturbation session. After 21 days of abstinence, T-levels stayed closer to the 10 minute baseline during masturbation. The statement - "higher testosterone concentrations were observed following the period of abstinence" - means that testosterone levels did not fall as much during the stimulus: masturbation & porn viewing. The authors suggest anticipation of watching a porno (perhaps augmented by the anticipation of finally masturbating) caused testosterone to remain elevated throughout the viewing.
  5. Rodent studies consistently find that ejaculation to "sexual exhaustion" has no effect on testosterone levels. These studies follow the animals for up to 15 days. However, they do find multiple changes within the limbic system, including a decline in androgen receptors, and increase in estrogen receptors & opioids (which block dopamine), and alterations in gene expression.
  6. Long-term studies on primates have shown no reliable correlation between ejaculation and blood testosterone levels.
  7. Many studies report similar testosterone levels in healthy men and men with chronic ED (1, 2, 3, 4). From these studies alone we can conclude that 1) low testosterone is rarely a cause of ED, 2) frequency of ejaculation has no effect on T levels.
  8. In fact, the authors of these two ED studies (study1, study2) suggest that abstinence may lead to chronically low testosterone levels. This 2014 ED study found higher testosterone/DHT after penile implant surgery led to increased sexual activity.
  9. Many men with porn-induced erectile dysfunction have seen doctors. Virtually all have reported normal testosterone levels.
  10. Many human and animal studies show that low testosterone has no effect on erections achieved through stimulation. See this discussion by a professor of reproductive endocrinology - Hypogonadal men and erections and Testosterone and Erectile Dysfunction
  11. This single study from 1976 reported less sexual activity correlating with higher testosterone - for some subjects, but not all. However, the study also found that higher levels of testosterone were associated with periods of sexual activity. A bit contradictory. Let's place this study in context: It has never been replicated and contains countless uncontrolled variables. All other animal and human studies examining testosterone and high ejaculation frequency, abstinence, various levels of sexual activity, along with erectile dysfunction refute its findings.
  12. The evidence points to addiction processes or sexual conditioning as the primary cause of porn-induced ED, porn-induced loss of libido, or what is euphemistically called “sexual exhaustion”.
  13. Some men with porn-induced ED have tried testosterone supplementation, with no success. When these same men rebooted, their ED was cured.
  14. By the way, most studies that involve porn viewing report it has little or no effect on testosterone levels. For example, The endocrine effects of visual erotic stimuli in normal men. (but some do)
  15. Reward circuitry dopamine is behind sexual desire, motivation, and erections. In short, the many improvements guys see in libido and confidence as they reboot are probably coming from changes in their brains, not their testosterone levels.

Men experience myriad benefits as they unhook from porn and compulsive masturbation. It's natural to assume positive changes such as more confidence, better mood, less anxiety, and greater motivation must have something to do with blood testosterone levels. However, neither human or animal research supports the testosterone hypothesis. While a few men have reported abstinence associated with higher T, the vast majority of men who are tested (before & during) report no significant change. Since many factors (stress, exercise, diet) can affect T levels and lab results, we need to be cautious with an occasional anecdote. On the other hand, it is quite possible that brain changes associated with porn addiction can affect hormones via the hypothalamus. Examples include: alteration in the autonomic nervous system and the HPA axis (CRF, cortisol, norepinephrine), along with any number of steroid hormones derived from the gonads or adrenal glands. Longitudinal research on porn addicts and "rebooted" porn addicts would help clarify the mechanisms behind claimed physical benefits such as, deeper voice, better response to exercise, hair growth, clearer skin, etc. 

For the science behind the benefits guys experience see - Porn, Masturbation and Mojo: A Neuroscience Perspective - Ex-porn users usually get their mojo back. Why?

 


STUDIES


 

LOWER T RELATED TO ABSTINENCE. HIGHER T WITH RESUMED SEXUAL ACTIVITY:

Sexual inactivity results in reversible reduction of LH bioavailability.

Int J Impot Res. 2002 Apr;14(2):93-9; discussion 100.

Carosa E, Benvenga S, Trimarchi F, Lenzi A, Pepe M, Simonelli C, Jannini EA.

Abstract

We have recently documented significantly reduced serum testosterone (T) levels in patients with erectile dysfunction (ED). To understand the mechanism of this hypotestosteronemia, which was independent of the etiology of ED, and its reversibility only in patients in whom a variety of nonhormonal therapies restored sexual activity, we measured serum luteinizing hormone (LH) in the same cohort of ED patients (n=83; 70% organic, 30% nonorganic). Both immunoreactive LH (I-LH) and bioactive LH (B-LH) were measured at entry and 3 months after therapy. Based on outcome (ie number of successful attempts of intercourse per month), patients were categorized as full responders (namely, at least eight attempts; n=51), partial responders (at least one attempt; n=20) and non-responders (n=16). Compared to 30 healthy men with no ED, baseline B-LH (mean+/-s.d.) in the 83 patients was decreased (13.6+/-5.5 vs 31.7+/-6.9 IU/L, P<0.001), in the face of a slightly increased, but in the normal range, I-LH (5.3+/-1.8 vs 3.4+/-0.9 IU/L, P<0.001); consequently, the B/I LH ratio was decreased (3.6+/-3.9 vs 9.7+/-3.3, P<0.001).

Similar to our previous observation for serum T, the three outcome groups did not differ significantly for any of these three parameters at baseline. However, outcome groups differed after therapy. Bioactivity of LH increased markedly in full responders (pre-therapy=13.7+/-5.3, post-therapy=22.6+/-5.4, P<0.001), modestly in partial responders (14.8+/-6.9 vs 17.2+/-7.0, P<0.05) but remained unchanged in non-responders (11.2+/-2.2 vs 12.2+/-5.1). The corresponding changes went in the opposite direction for I-LH (5.2+/-1.7 vs 2.6+/-5.4, P<0.001; 5.4+/-2.2 vs 4.0+/-1.7, P<0.05; 5.6+/-1.2 vs 5.0+/-1.2, respectively), and in the same direction as B-LH for the B/I ratio (3.7+/-4.1 vs 11.8+/-7.8, P<0.001; 4.2+/-4.3 vs 5.8+/-4.2, P<0.05; 2.1+/-0.7 vs 2.6+/-1.3, respectively).

We hypothesize that the hypotestosteronemia of ED patients is due to impaired bioactivity of LH. This reduced bioactivity is reversible, provided that resumption of sexual activity is achieved regardless of the therapeutic modality. Because biopotency of pituitary hormones is controlled by the hypothalamus, LH hypoactivity should be due to the hypothalamic functional damage associated to the psychological disturbances which unavoidably follow sexual inactivity.

COMMENTS: Authors suggest that successful sexual activity increases LH and testosterone in men treated for ED. None of the men were treated with hormones, and low testosterone was not the cause of their ED. If true in healthy men, this suggests that sex/ejaculation may prevent a decline in testosterone levels.

Lack of sexual activity from erectile dysfunction is associated with a reversible reduction in serum testosterone.

Int J Androl. 1999 Dec;22(6):385-92.

Jannini EA, Screponi E, Carosa E, Pepe M, Lo Giudice F, Trimarchi F, Benvenga S.

Abstract

The role of androgenic hormones in human sexuality, in the mechanism of erection and in the pathogenesis of impotence is under debate. While the use of testosterone is common in the clinical therapy of male erectile dysfunction, hypogonadism is a rare cause of impotence. We evaluated serum testosterone levels in men with erectile dysfunction resulting either from organic or non-organic causes before and after non-hormonal impotence therapy. Eighty-three consecutive cases of impotence (70% organic, 30% non-organic, vascular aetiology being the most frequent) were subjected to hormonal screening before and after various psychological, medical (prostaglandin E1, yohimbine) or mechanical therapies (vascular surgery, penile prostheses, vacuum devices).

Thirty age-matched healthy men served as a control group. Compared to controls, patients with impotence resulting from both organic and non-organic causes showed reduced serum levels of both total testosterone (11.1 +/- 2.4 vs. 17.7 +/- 5.5 nmol/L) and free testosterone (56.2 +/- 22.9 vs. 79.4 +/- 27.0 pmol/L) (both p < 0.001). Irrespective of the different aetiologies and of the various impotence therapies, a dramatic increase in serum total and free testosterone levels (15.6 +/- 4.2 nmol/L and 73.8 +/- 22.5 pmol/L, respectively) was observed in patients who achieved normal sexual activity 3 months after commencing therapy (p < 0.001).

On the contrary, serum testosterone levels did not change in patients in whom therapies were ineffective. Since the pre-therapy low testosterone levels were independent of the aetiology of impotence, we hypothesize that this hormonal pattern is related to the loss of sexual activity, as demonstrated by its normalization with the resumption of coital activity after different therapies. The corollary is that sexual activity may feed itself throughout the increase in testosterone levels.

COMMENTS: Authors suggest that lack of sexual activity leads to lower testosterone. In the above study they hypothesize that this may be related to the stress of ED, or may be due to the resumption of sexual activity itself. Hard to sort out as all the subjects suffered from ED, and had lower testosterone.

 

The impact of sexual activity on serum hormone levels after penile prosthesis implantation.

Arch Ital Urol Androl. 2014 Sep 30;86(3):193-6. doi: 10.4081/aiua.2014.3.193.

OBJECTIVES:

Penile prosthesis implantation is the final treatment option for patients who have erectile dysfunction. Most of the patients use their penile prosthesis successfully and frequently for penile-vaginal intercourse. Previous literature showed that decrease in sexual activity resulted in decreased serum testosterone levels and vice versa. The aim of this study was to examine the impact of sexual activity on serum sex hormone levels after penile prosthesis usage.

MATERIAL AND METHODS:

In this study, we examined sixtyseven patients for their sex hormone changes who had penile prosthesis surgery 2.7 ± 1.5 years ago.

RESULTS:

Patients were using their penile prosthesis for sexual activity with a mean of 9.9 ± 5.7 times per month. Dehydroepiandrosterone sulfate was significantly higher compared to pre-surgery results (5.3 ± 2.6 vs 4.5 ± 2.9; p = 0.031). Mean serum total testosterone levels of patients before and after penile prosthesis usage were clinically significant 15.78 ± 4.8 nmol/L and 16.5 ± 6.1 nmol/L, respectively. Mean serum luteinizing hormone levels of patients before and after penile prosthesis usage were 3.98 ± 2.16 IU/L and 5.47 ± 4.76 IU/L, respectively. No statistical significance difference was observed in the mean total and free testosterone, estradiol and luteinizing hormone levels between pre- and post-surgery.

CONCLUSION:

This study results demonstrated that sexual activity changed sex hormone levels positively among those men who were implanted penile prosthesis because of erectile dysfunction.

Comments: Another study reporting higher testosterone and DHT when sexual activity increases or is resumed.


 

LONG-TERM EFFECTS OF ABSTINENCE AND DIFFEREING EJACULATION FREQUENCIES:

A research on the relationship between ejaculation and serum testosterone level in men.

Jiang M, Xin J, Zou Q, Shen JW. J Zhejiang Univ Sci.

2003 Mar-Apr;4(2):236-40

The purpose of this study is to gain understanding of the relationship between ejaculation and serum testosterone level in men. The serum testosterone concentrations of 28 volunteers were investigated daily during abstinence periods after ejaculation for two phases.

The authors found that the fluctuations of testosterone levels from the 2nd to 5th day of abstinence were minimal. On the 7th day of abstinence, however, a clear peak of serum testosterone appeared, reaching 145.7% of the baseline ( P < 0.01). No regular fluctuation was observed following continuous abstinence after the peak.

Ejaculation is the precondition and beginning of the special periodic serum testosterone level variations, which would not occur without ejaculation. The results showed that ejaculation-caused variations were characterized by a peak on the 7th day of abstinence; and that the effective time of an ejaculation is 7 days minimum. These data are the first to document the phenomenon of the periodic change in serum testosterone level; the correlation between ejaculation and periodic change in the serum testosterone level, and the pattern and characteristics of the periodic change.

COMMENT: This is the only study that measured T level everyday, for 3 weeks, and they found no difference before or after the one day spike. This one day peak indicates a cycle initiated by orgasm. The experiment measured testosterone levels every day for 16 days following an ejaculation. Testosterone levels do not slowly rise over 7 days to reach 146% of baseline. Nor do levels slowly decline.  It’s a one day spike—up and back down. During other daily measurements, testosterone levels remain within normal ranges. Plasma testosterone levels are controlled by hormonal signals originating from the hypothalamus. It's common for spikes of hormones to activate other hormones or physiological events. No one yet knows the significance of this plasma-testosterone cycle initiated by ejaculation.

Note: This is one of the most cited studies on forums where men discuss bodybuilding, exercise, sex, health and the like. Please keep in mind the numerous factors that affect daily testosterone fluctuations, including type of activity or exercise, sexual stimulation, social status, mood, pheromones, stress, emotions, season, etc.

 

Orgasmic frequency and plasma testosterone levels in normal human males

, Volume 5, Issue 2, pp 125-132

Twenty males participated in a 2-month study examining the relationship between 8 a.m. plasma testosterone levels and orgasmic frequency. Within subjects, higher levels of testosterone are associated with periods of sexual activity. Over subjects, however, the direction of the relationship is reversed. Mean testosterone levels were higher for sexually less active individuals.

COMMENT: Average testosterone levels were higher in less sexually active men. But—sexual activity increased testosterone levels in individuals—on average. This single study from 1976 reported less sexual activity correlating with higher testosterone - for some subjects, but not all. However, the study also found that higher levels of testosterone were associated with periods of sexual activity. A bit contradictory. Let's place this study in context: It has never been replicated and contains countless uncontrolled variables. All other animal and human studies examining testosterone and 1) high ejaculation frequency, 2) abstinence, 3) various levels of sexual activity, and 4) erectile dysfunction, report n little or no relationship between ejaculation/abstinence and testosterone levels.

 

Endocrine response to masturbation-induced orgasm in healthy men following a 3-week sexual abstinence.

Exton MS, Krüger TH, Bursch N, Haake P, Knapp W, Schedlowski M, Hartmann U.

World J Urol. 2001 Nov;19(5):377-82

This current study examined the effect of a 3-week period of sexual abstinence on the neuroendocrine response to masturbation-induced orgasm. Hormonal and cardiovascular parameters were examined in ten healthy adult men during sexual arousal and masturbation-induced orgasm. Blood was drawn continuously and cardiovascular parameters were constantly monitored. This procedure was conducted for each participant twice, both before and after a 3-week period of sexual abstinence. Plasma was subsequently analysed for concentrations of adrenaline, noradrenaline, cortisol, prolactin, luteinizing hormone and testosterone concentrations. Orgasm increased blood pressure, heart rate, plasma catecholamines and prolactin. These effects were observed both before and after sexual abstinence. In contrast, although plasma testosterone was unaltered by orgasm, higher testosterone concentrations were observed following the period of abstinence. These data demonstrate that acute abstinence does not change the neuroendocrine response to orgasm but does produce elevated levels of testosterone in males.

COMMENT: The wording of the abstract is a mess. The full study completely contradicts what I have bolded. See #4 above


 

SHORT-TERM EFFECTS OF EJACULATION ON TESTOSTERONE

Neuroendocrine and cardiovascular response to sexual arousal and orgasm in men.

Psychoneuroendocrinology. 1998 May;23(4):401-11

Data regarding the neuroendocrine response pattern to sexual arousal and orgasm in man are inconsistent. In this study, ten healthy male volunteers were continuously monitored for their cardiovascular and neuroendocrine response to sexual arousal and orgasm. Blood was continuously drawn before, during and after masturbation-induced orgasm and analyzed for plasma concentrations of adrenaline, noradrenaline, cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, growth hormone (GH), beta-endorphin and testosterone. Orgasm induced transient increases in heart rate, blood pressure and noradrenaline plasma levels. Prolactin plasma levels increased during orgasm and remained elevated 30 min after orgasm. In contrast, none of the other endocrine variables were significantly affected by sexual arousal and orgasm.

COMMENT: Short-term testosterone levels not affected by orgasm—which opposes the following study.

 

Endocrine effects of masturbation in men

Journal of Endocrinology, Vol 70, Issue 3, 439-444 1976 by Society for Endocrinology

The levels of pregnenolone, dehydroepiandrosterone (DHA), androstenedione, testosterone, dihydrotestosterone (DHT), oestrone, oestradiol, cortisol and luteinizing hormone (LH) were measured in the peripheral plasma of a group of young, apparently healthy males before and after masturbation. The same steroids were also determined in a control study, in which the psychological anticipation of masturbation was encouraged, but the physical act was not carried out. The plasma levels of all steroids were significantly increased after masturbation, whereas steroid levels remained unchanged in the control study. The most marked changes after masturbation were observed in pregnenolone and DHA levels. No alterations were observed in the plasma levels of LH. Both before and after masturbation plasma levels of testosterone were significantly correlated to those of DHT and oestradiol, but not to those of the other steroids studied. On the other hand, cortisol levels were significantly correlated to those of pregnenolone, DHA, androstenedione and oestrone. In the same subjects, the levels of pregnenolone, DHA, androstenedione, testosterone and DHT, androstenedione and oestrone. In the same subjects, the levels of pregnenolone, DHA, androstenedione, testosterone and DHT in seminal plasma were also estimated; they were all significantly correlated to the levels of the corresponding steroid in the systemic blood withdrawn both before and after masturbation. As a practical consequence, the results indicate that whenever both blood and semen are analysed, blood sampling must precede semen collection.

COMMENT: Short-term testosterone levels were elevated by orgasm, but less so than other steroids. However, this result is countered by several other studies.

 

Relationship of serum testosterone to sexual activity in healthy elderly men.

J Gerontol. 1982 May;37(3):288-93.

Abstract

There are reports of decreases in both sexual activity and serum testosterone in older men but not of any clear association between the two variables. In healthy participants in the Baltimore Longitudinal Study on Aging, despite the fact that serum testosterone did not decline with age, sexual activity decreased in a highly predictable fashion. In men over 60 years old, those with higher levels of sexual activity (for age) had significantly greater levels of serum testosterone. Although we found an inverse correlation between testosterone and percentage of body fat, there was no relationship between percentage of body fat and sexual activity. We also found no correlation between testosterone or sexual activity and smoking or coronary heart disease. Subjects drinking more than 4 oz. of ethanol per day were more likely to have decreased sexual activity but not diminished testosterone concentration. Our data suggest that, although serum testosterone level and ethanol intake may affect sexual activity in older men to some degree, age itself still appears to be the most influential variable.

COMMENTS:  men over 60 years old, those with higher levels of sexual activity (for age) had significantly greater levels of serum testosterone. This doesn't support the meme that ejaculation uses up testosterone


 

MEN WITH ED HAVE T LEVELS COMPARABLE TO MEN WITHOUT ED

Plasma testosterone levels of sexually functional and dysfunctional men.

Schwartz MF, Kolodny RC, Masters WH. Arch Sex Behav. 1980 Oct;9(5):355-66

Plasma testosterone levels in a group of 341 men with sexual dysfunction were compared to those in 199 men with normal sexual function. All subjects were participants in a 2-week intensive conjoint sex therapy program at the Masters & Johnson Institute. Testosterone determinations were made using radioimmunoassay methods after column chromatography; all blood samples were obtained on the second day of therapy between 8:00 and 9:00 a.m. after an overnight fast. Circulating levels of testosterone in men with normal sexual function (mean 635 ng/dl) were not significantly different from testosterone values in sexually dysfunctional men (mean 629 ng/dl). However, men with primary impotence (N = 13) had significantly higher testosterone levels than men with secondary impotence (N = 180), with mean levels of 710 and 574 ng/dl, respectively (p < 0.001). The mean testosterone level for men with ejaculatory incompetence was 660 ng/dl (N = 15), while for men with premature ejaculation the mean was 622 ng/dl (N = 91). Plasma testosterone concentrations were not related to therapy outcome but were correlated negatively with age of patients.

COMMENTS: As it says—not much difference in testosterone levels between impotent and normal guys. Conclusion should be that many of the impotent men are not having orgasms. Further conclusion is that testosterone levels are not significant players in post-ejaculatory experience—including a post-ejaculatory hangover—since long term differences between ejaculators and non-ejaculators do not occur.

 

Is there a relationship between sex hormones and erectile dysfunction? Results from the Massachusetts Male Aging Study.

J Urol. 2006 Dec;176(6 Pt 1):2584-8.

The prevalence of erectile dysfunction increases as men age. Simultaneously, age related changes occur in male endocrine functioning. We examined the association between erectile dysfunction and total testosterone, bioavailable testosterone, sex hormone-binding globulin and luteinizing hormone.

Data were obtained from the Massachusetts Male Aging Study, a population based cohort study of 1,709 men. Self-reported erectile dysfunction was dichotomized as moderate or severe vs none or mild. Odds ratios and 95% CI were used to assess the association between sex hormone levels and erectile dysfunction. Multiple logistic regression models were used to adjust for potential confounders including age, body mass index, partner availability, phosphodiesterase type 5 inhibitor use, depression, diabetes and heart disease.

Using data from the most recent followup, analyses were conducted on 625 men with complete data. A moderate decrease in erectile dysfunction risk was observed with increasing total testosterone and bioavailable testosterone levels. However, this effect was not apparent after controlling for potential confounders. Increased luteinizing hormone levels (8 IU/l or greater) were associated with a higher risk of erectile dysfunction (adjusted OR 2.91, 95% CI 1.55-5.48) compared to luteinizing hormone levels less than 6 IU/l. A significant interaction between luteinizing hormone and total testosterone levels showed that increased testosterone levels were associated with a decrease in risk of erectile dysfunction among men with luteinizing hormone levels greater than 6 IU/l.

In this large population based cohort of older men we found no association among total testosterone, bioavailable testosterone, sex hormone-binding globulin and erectile dysfunction. Testosterone levels were associated with a decrease in risk of erectile dysfunction only in men with increased luteinizing hormone levels.

 

Pituitary gonadal system function in patients with erectile impotence and premature ejaculation.

Arch Sex Behav. 1979 Jan;8(1):41-8.

The pituitary testicular system was studied in men with psychogenic impotence. Eight patients with primary erectile impotence age 22--36 years, eight men with secondary erectile impotence age 29--55 years, and 16 men with premature ejaculation age 23--43 years were studied. The last group was further divided into two subgroups: E1 (n = 7) patients without and E2 (n = 9) patients with anxiety and avoidance behavior toward coital activity. Sixteen normal adult men age 21--44 served as a control group. Diagnosis was made after psychiatric and physical examinations. Patients complaining primarily of loss of libido were not considered in the study. Ten consecutive blood samples were obtained over a period of 3 hr from each patient. Luteinizing hormone (LH), total testosterone, and free (not protein-bound) testosterone were measured. Statistical analysis revealed no significant differences between patients and normal controls.

 

Plasma testosterone and testosterone binding affinities in men with impotence, oligospermia, azoospermia, and hypogonadism.

Br Med J. 1974 Mar 2;1(5904):349-51.

Mean plasma testosterone levels (+/- S.D.), using Sephadex LH-20 and competitive protein binding, were 629 +/- 160 ng/100 ml for a group of 27 normal adult men, 650 +/- 205 ng/100 ml for 27 impotent men with normal secondary sex characteristics, 644 +/- 178 ng/100 ml for 20 men with oligospermia, and 563 +/- 125 ng/100 ml for 16 azoospermic men. None of these values differ significantly. For 21 men with clinical evidence of hypogonadism the mean plasma testosterone (+/- S.D.), at 177 +/- 122 ng/100 ml, differed significantly (P < 0.001) from that of the normal men.The mean testosterone binding affinities (as measured by the reciprocal of the quantity of plasma needed to bind 50% of (3)H-testosterone tracer) were similar for normal, impotent, and oligospermic men. Though lower for azoospermic men the difference was not significant (P >0.1). For 12 of the 16 hypogonadal males the testosterone binding affinity was normal, but raised binding affinities, similar to those found in normal adult females or prepubertal boys (about twice normal adult male levels), were found in four cases of delayed puberty. These findings help to explain why androgen therapy is usually useless in the treatment of impotence.

 

Effects of testosterone on sexual function in men: results of a meta-analysis.

Clin Endocrinol (Oxf). 2005 Oct;63(4):381-94.

The role of androgen decline in the sexual activity of adult males is controversial. To clarify whether sexual function would benefit from testosterone (T) treatment in men with partially or severely reduced serum T levels, we conducted a systematic review and meta-analysis of placebo-controlled studies published in the past 30 years. The aim of this study was to assess and compare the effects of T on the different domains of sexual life.Guided by prespecified criteria, software-assisted data abstraction and quality assessed by two independent reviewers, a total of 17 randomized placebo-controlled trials were found to be eligible. For each domain of sexual function we calculated the standardized mean difference relative to T and reported the results of pooled estimates of T treatment using the random effect model of meta-analysis. Heterogeneity, reproducibility and consistency of the findings across studies were explored using sensitivity and meta-regression analysis.         

RESULTS:

Overall, 656 subjects were evaluated: 284 were randomized to T, 284 to placebo (P) and 88 treated in cross-over. The median study length was 3 months (range 1-36 months). Our meta-analysis showed that in men with an average T level at baseline below 12 nmol/l, T treatment moderately improved the number of nocturnal erections, sexual thoughts and motivation, number of successful intercourses, scores of erectile function and overall sexual satisfaction, whereas T had no effect on erectile function in eugonadal men compared to placebo. Heterogeneity was explored by grouping studies according to the characteristics of the study population. A cut-off value of 10 nmol/l for the mean T of the study population failed to predict the effect of treatment, whereas the presence of risk factors for vasculogenic erectile dysfunction (ED), comorbidities and shorter evaluation periods were associated with greater treatment effects in the studies performed in hypogonadal, but not in eugonadal, men. Meta-regression analysis showed that the effects of T on erectile function, but not libido, were inversely related to the mean baseline T concentration. The meta-analysis of available studies indicates that T treatment might be useful for improving vasculogenic ED in selected subjects with low or low-normal T levels. The evidence for a beneficial effect of T treatment on erectile function should be tempered with the caveats that the effect tends to decline over time, is progressively smaller with increasing baseline T levels, and long-term safety data are not available. The present meta-analysis highlights the need, and pitfalls, for large-scale, long-term, randomized controlled trials to formally investigate the efficacy of T replacement in symptomatic middle-aged and elderly men with reduced T levels and ED.

 


FLUCTUATIONS IN TESTOSTERONE ARE NORMAL

A cycle of plasma testosterone in the human male.

J Clin Endocrinol Metab. 1975 Mar;40(3):492-500

The object of the study was to assess the lability of testosterone levels in plasma of normal human males over a long period of time and to search for periodicities in changing levels. Blood samples obtained from 20 healthy young men every second day for 2 months were assayed for total testosterone concentration by radioligand saturation analysis with late-pregnancy plasma. The flucturations of plasma testosterone levels over the total time span were substantial for most individuals; the coefficients of variation ranged from 14 to 42% (median 21%). The presence of periodic functions in these fluctuations was tested by 4 different, relatively independent methods. Close agreement among at least 3 analytic methods was found for 12 out of the 20 subjects. These 12 subjects had cycles of plasma testosterone levels with periods ranging between 8-30 days, with a cluster of periods around 20-22 days. The majority of such cycles were significant at least at the 5% level. The mean amplitudes of these cycles ranged from 9 to 28% of the subjects' mean testosterone levels (average 17%).

COMMENTS: "The fluctuations of plasma testosterone levels over the total time span were substantial for most individuals - ranged from 14 to 42% (median 21%)."  Not only that but many other things affects T levels, including type of exercise, mood, social rank, drugs, alcohol, etc.

 


 

STUDIES ON TESTOSTERONE AND PORN VIEWING:

1) The endocrine effects of visual erotic stimuli in normal men.

 Psychoneuroendocrinology. 1990;15(3):207-16.

 Carani C, Bancroft J, Del Rio G, Granata AR, Facchinetti F, Marrama P.

Abstract

Endocrine responses to erotic stimulation in the laboratory were assessed in eight normal subjects. Each subject was tested on two occasions. On one occasion only neutral stimuli were involved. After 15 min baseline, 30 min of films were shown. For the erotic condition on the other occasion, two 10-min erotic films were interspersed with 10 min of neutral film. Fifteen-minute blood samples were taken from the start of each test and continued for 5 hr after the films. Plasma was assayed for testosterone, LH, prolactin, cortisol, ACTH and beta-endorphin. Urine was collected for 4 hr before and 4 hr after the films; this was assayed for adrenaline, noradrenaline and dopamine. Sexual arousal occurred in response to the erotic films in all subjects, as shown by erectile and subjective responses. There were no significant changes in hormone or catecholamine levels following either the erotic or the neutral stimuli, except for a rise in cortisol during the neutral but not the erotic film. These results indicate that in the laboratory, substantial sexual response can occur without accompanying endocrine or biochemical changes.

2) Neuroendocrine and cardiovascular response to sexual arousal and orgasm in men.

Psychoneuroendocrinology. 1998 May;23(4):401-11.

Abstract

Data regarding the neuroendocrine response pattern to sexual arousal and orgasm in man are inconsistent. In this study, ten healthy male volunteers were continuously monitored for their cardiovascular and neuroendocrine response to sexual arousal and orgasm. Blood was continuously drawn before, during and after masturbation-induced orgasm and analyzed for plasma concentrations of adrenaline, noradrenaline, cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, growth hormone (GH), beta-endorphin and testosterone. Orgasm induced transient increases in heart rate, blood pressure and noradrenaline plasma levels. Prolactin plasma levels increased during orgasm and remained elevated 30 min after orgasm. In contrast, none of the other endocrine variables were significantly affected by sexual arousal and orgasm.

COMMENTS: I've seen a few "sciencey" articles claim that porn use increases testosterone levels 100%. The take away is that porn use is a great way to keep your T levels high. However, I have yet to find a study to verify such claims. Several studies report that masturbation to porn has no effects on testosterone levels.

 


 

Pharmacological and physiological aspects of sexual exhaustion in male rats

Scand J Psychol. 2003 Jul;44(3):257-63.

Fernández-Guasti A, Rodríguez-Manzo G.

Departamento de Farmacobiología, Cinvestav, Mexico. jfernand@mail.cinestav.mx

Abstract

The present article reviews the current findings on the interesting phenomenon of sexual satiety. Knut Larsson in 1956 reported on the development of sexual exhaustion in the male rat after repeated copulation. We have studied the process and found the following results.

(1) One day after 4 hours of ad libitum copulation, two-thirds of the population showed complete inhibition of sexual behavior, while the other third displayed a single ejaculatory series from which they did not recover.

(2) Several pharmacological treatments, including 8-OH-DPAT, yohimbine, naloxone and naltrexone, reverse this sexual satiety, indicating that the noradrenergic, serotonergic and opiate systems are involved in this process. Indeed, direct neurochemical determinations showed changes in various neurotransmitters during sexual exhaustion.

(3) Given enough stimulation, by changing the stimulus female, sexual satiety was prevented, suggesting that there are motivational components of the sexual inhibition that characterizes sexual exhaustion.

(4) The GABA antagonist bicuculline, or the electrical stimulation of the medial preoptic area, did not reverse sexual exhaustion. These data suggest, on the one hand, that sexual exhaustion and the postejaculatory interval (which is shortened by bicuculline administration) are not mediated by similar mechanisms and, on the other, that the medial preoptic area does not regulate sexual satiety.

(5) The androgen receptor density in brain areas closely related to the expression of masculine sexual behavior, such as the medial preoptic nucleus, was drastically reduced in sexually exhausted animals. Such reduction was specific to certain brain areas and was not related to changes in the levels of androgens. These results suggest that changes in brain androgen receptors account for the inhibition of sexual behavior present during sexual exhaustion.

(6) The recovery process of sexual satiety after 4 hours of ad libitum copulation reveals that, after 4 days, only 63% of the males are able to show sexual behavior while after 7 days all animals display copulatory activity.

COMMENTS: The part of the brain where the receptor drop occurred tends to be very similar in all mammals. If this drop in testosterone receptors occurs in human males, it could explain why some men feel like their testosterone is low after too frequent ejaculation, and why they feel like their testosterone levels rise with a period of abstinence.

NOTE: This temporary effect is being measured in normal brains. If your brain has changed due to addiction, your dopamine is also dysregulated, quite apart from a temporary decline in testosterone receptors, and you will need longer to return to normal libido.

Also: #4 - Sexual exhaustion was prevented by introducing a novel female (that's what porn does).

 


 

Increased estrogen receptor alpha immunoreactivity in the forebrain of sexually satiated rats.

Horm Behav. 2007 Mar;51(3):328-34. Epub 2007 Jan 19.

Phillips-Farfán BV, Lemus AE, Fernández-Guasti A.

Department of Pharmacobiology, CINVESTAV, México City, México.

Abstract

Estrogen receptor alpha (ERalpha) participates in the neuroendocrine regulation of male sexual behavior, primarily in brain areas located in the limbic system. Males of many species present a long-term inhibition of sexual behavior after several ejaculations, known as sexual satiety. It has been shown that androgen receptor density is reduced 24 h after a single ejaculation or mating to satiety, in the medial preoptic area, nucleus accumbens and ventromedial hypothalamus. The aim of this study was to analyze if the density of ERalpha was also modified 24 h after a single ejaculation or mating to satiety. Sexual satiety was associated with an increased ERalpha density in the anteromedial bed nucleus of the stria terminalis (BSTMA), ventrolateral septum (LSV), posterodorsal medial amygdala (MePD), medial preoptic area (MPA) and nucleus accumbens core (NAc). A single ejaculation was related to an increase in ERalpha density in the BSTMA and MePD. ERalpha density in the arcuate (Arc) and ventromedial hypothalamic nuclei (VMN), and serum estradiol levels remained unchanged 24 h after one ejaculation or mating to satiety. These data suggest a relationship between sexual activity and an increase in the expression of ERalpha in specific brain areas, independently of estradiol levels in systemic circulation.

COMMENTS: Estrogen receptors density increases in several regions following a single ejaculation, and sexual satiety. In the full study they suggest this change lasts longer than 24 hrs.


 

Relationship Between Sexual Satiety And Brain Androgen Receptors.

Romano-Torres M, Phillips-Farfán BV, Chavira R, Rodríguez-Manzo G, Fernández-Guasti A.

Neuroendocrinology. 2007;85(1):16-26. Epub 2007 Jan 8.

Department of Pharmacobiology, Centro de Investigación y Estudios Avanzados, Mexico City, Mexico.

Abstract

Recently we showed that 24 h after copulation to satiety, there is a reduction in androgen receptor density (ARd) in the medial preoptic area (MPOA) and in the ventromedial hypothalamic nucleus (VMH), but not in the bed nucleus of the stria terminalis (BST).

The present study was designed to analyze whether the ARd changes in these and other brain areas, such as the medial amygdala (MeA) and lateral septum, ventral part (LSV), were associated with changes in sexual behavior following sexual satiety.

Males rats were sacrificed 48 h, 72 h or 7 days after sexual satiety (4 h ad libitum copulation) to determine ARd by immunocytochemistry; additionally, testosterone serum levels were measured in independent groups sacrificed at the same intervals. In another experiment, males were tested for recovery of sexual behavior 48 h, 72 h or 7 days after sexual satiety. The results showed that 48 h after sexual satiety 30% of the males displayed a single ejaculation and the remaining 70% showed a complete inhibition of sexual behavior. This reduction in sexual behavior was accompanied by an ARd decrease exclusively in the MPOA-medial part (MPOM). Seventy-two hours after sexual satiety there was a recovery of sexual activity accompanied by an increase in ARd to control levels in the MPOM and an overexpression of ARd in the LSV, BST, VMH and MeA. Serum testosterone levels were unmodified during the post-satiety period. The results are discussed on the basis of the similarities and discrepancies between ARd in specific brain areas and male sexual behavior.

COMMENTS: According to other studies androgen receptors increase on day 4, but have declined once more by day 7

 


 

Sexual behavior correlates with the diurnal plasma testosterone range in intact male rhesus monkeys

Biol Reprod. 1984 Apr;30(3):652-7.

Michael RP, Zumpe D, Bonsall RW.

Abstract

There is evidence that androgens are necessary for the full expression of sexual behavior in male primates, but it has proved difficult to relate sexual activity to circulating androgens levels in comparisons between intact males. In the present study, 4423 behavior tests of 32 pairs of rhesus monkeys were conducted in a constant photoperiod over a 2-year period, and there was no significant relationship between the frequency of ejaculation and plasma testosterone levels in samples collected at 0800, 1600 or 2200 h. However, the magnitude of the diurnal range between the lowest and highest levels correlated negatively with sexual behavior. As the seasonal increase in sexual activity occurred, there was a corresponding decrease in the diurnal range of plasma testosterone. Furthermore, those males with the highest numbers of ejaculations showed the smallest diurnal plasma testosterone ranges. An additional experiment with 32 males revealed that neither behavior testing nor the occurrence of ejaculation influenced the diurnal testosterone range. Consequently, we have concluded that if any causality operated it would be in the direction of a hormonal influence on behavior. These findings suggest that increased nocturnal levels of testosterone do not enhance behavior and that a threshold level maintained throughout the 24 h may be a critical endocrine factor.

COMMENTS: Again, testosterone levels and ejaculation have little correlation


 

The post-orgasmic prolactin increase following intercourse is greater than following masturbation and suggests greater satiety (2006)

Biol Psychol. 2006 Mar;71(3):312-5. Epub 2005 Aug 10.

Brody S, Krüger TH.

Division of Psychology, School of Social Sciences, University of Paisley, Scotland, UK. stuartbrody@hotmail.com

Abstract

Research indicates that prolactin increases following orgasm are involved in a feedback loop that serves to decrease arousal through inhibitory central dopaminergic and probably peripheral processes. The magnitude of post-orgasmic prolactin increase is thus a neurohormonal index of sexual satiety. Using data from three studies of men and women engaging in masturbation or penile-vaginal intercourse to orgasm in the laboratory, we report that for both sexes (adjusted for prolactin changes in a non-sexual control condition), the magnitude of prolactin increase following intercourse is 400% greater than that following masturbation. The results are interpreted as an indication of intercourse being more physiologically satisfying than masturbation, and discussed in light of prior research reporting greater physiological and psychological benefits associated with coitus than with any other sexual activities.

COMMENTS: This may be the only study comparing the hormonal differences between sexual intercourse and masturbation. It concluded that intercourse raised prolactin 400% more than masturbation. Prolactin rises at orgasm, and functions as a sexual satiationmechanisms - it inhibits dopamine.


 

 

Testosterone Graph: Endocrine response to masturbation-induced orgasm in healthy men following a 3-week sexual abstinence

This ABSTRACT - Endocrine response to masturbation-induced orgasm in healthy men following a 3-week sexual abstinence, where subjects didn't ejaculate for 3 weeks, is often cited as evidence that abstinence leads to increased testosterone. It doesn't.

This sentence from the abstract is poorly worded and misleading:

"although plasma testosterone was unaltered by orgasm, higher testosterone concentrations were observed following the period of abstinence".

In the full study, (this graph) testosterone levels are the same in both groups.

  • White squares: Masturbation & porn viewing just prior to the 3-week abstinence.
  • Black squares: Masturbation & porn viewing to end the 21 days of abstinence.
  1. 10 minutes: BASELINE TESTOSTERONE MEASUREMENTS
  2. 20 minutes: Getting ready to to masturbate/watch porn
  3. 30 minutes: Watching porn & masturbating
  4. 40 minutes: Around orgasm
  5. 50 and 60 minutes: Recovery

You can clearly see that testosterone levels were nearly identical at 10 minutes, the first measurement. At 20 minutes, the abstinent group declined just a teeny bit, while the pre-abstinent group experienced a significant decline.

When the abstract says: "higher testosterone concentrations were observed following the period of abstinence" - it is actaully stating that abstinence prevented a drop in testosterone while watching porn and masturbating.

 

 

Treatment of Men for “Low Testosterone”: A Systematic Review (2016)

 

Abstract

Testosterone products are recommended by some prescribers in response to a diagnosis or presumption of “low testosterone” (low-T) for cardiovascular health, sexual function, muscle weakness or wasting, mood and behavior, and cognition. We performed a systematic review of 156 eligible randomized controlled trials in which testosterone was compared to placebo for one or more of these conditions. We included studies in bibliographic databases between January 1, 1950 and April 9, 2016, and excluded studies involving bodybuilding, contraceptive effectiveness, or treatment of any condition in women or children. Studies with multiple relevant endpoints were included in all relevant tables. Testosterone supplementation did not show consistent benefit for cardiovascular risk, sexual function, mood and behavior, or cognition. Studies that examined clinical cardiovascular endpoints have not favored testosterone therapy over placebo. Testosterone is ineffective in treating erectile dysfunction and controlled trials did not show a consistent effect on libido. Testosterone supplementation consistently increased muscle strength but did not have beneficial effects on physical function. Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood. The prescription of testosterone supplementation for low-T for cardiovascular health, sexual function, physical function, mood, or cognitive function is without support from randomized clinical trials.

1. Introduction

Testosterone and methyltestosterone are marketed in the United States for men with congenital or acquired hypogonadism. Some practitioners have used testosterone preparations to treat a variety of symptoms identified as those of “low testosterone” (low-T), a term that has not been uniformly defined. We present a systematic review of randomized controlled trials (RCTs) that evaluated the use of testosterone therapy against placebo or inactive comparator in adult men for cardiovascular health, sexual function, muscle weakness/wasting, mood and behavior, or cognition. We did not include studies of testosterone in men with missing or damaged testicles, or who had Klinefelter syndrome or other genetic anomalies. We did not include studies on the use of testosterone for any indication in women or in children, the use of androgens in contraception, or the use of androgens for bodybuilding or athletic performance.

2. Methods

2.1 Data Search, Synthesis and Analysis

Computerized literature searches were conducted in PubMed, Embase, and APA PsycNET. Searches were limited to human males but were not restricted by language or date. The PubMed search was conducted using the MeSH term “testosterone” and the modifiers “administration and dosage,” “adverse effects,” “deficiency,” “standards,” “therapeutic use,” or “therapy.” The original PubMed search was conducted for studies published between January 1, 1950 and November 26, 2013. The Embase search was conducted using the Emtree key term “testosterone,” modified by “adverse drug reaction,” “androgen deficiency,” “therapy,” “drug dose,” or “clinical trial.” The original Embase search was conducted for studies published between January 1, 1974 and November 26, 2013. The PsycNET search was conducted using the term “testosterone” modified by “addiction,” “drug dependency,” “therapy,” “treatment,” or “deficiency.” The original PsycNET search was conducted for studies published between January 1, 1806 and November 26, 2013. All searches were repeated on April 9, 2016 to identify clinical trials that had been published since the initial search, so the final search included more than four decades of trials from all databases.

2.2 Study Selection

Search results were combined using EndNote and duplicates were deleted. These results were filtered using the key term “clinical trial.” Titles and abstracts were reviewed to identify RCTs and eliminate irrelevant studies. Relevant studies were retrieved.

2.3 Data Extraction

Data were extracted into tables by 4 independent reviewers according to the presence of information on cardiovascular health, sexual function, muscle weakness/wasting, mood and behavior, or cognition. Studies with multiple relevant endpoints were included in all relevant tables. Review articles were identified and retrieved, and their reference lists were searched for primary publications of RCTs.

Some studies that included randomized controlled designs also included open-label continuation phases. We evaluated and summarized the randomized controlled portions of these studies. Although our primary interest was the use of testosterone for the treatment of hypogonadism, however defined by study authors, we included trials of testosterone in eugonadal men. In some studies, eugonadal subjects were randomized to receive testosterone or a comparator (usually placebo), and hypogonadal subjects were treated with testosterone only. We evaluated and summarized only the randomized portions of these studies.

2.4 Quality Assessment

We assessed quality of studies by a 5-point Jadad score. In order to be as inclusive as possible, we included all studies identified regardless of Jadad score. For clinical endpoints only (angina/ischemia, congestive heart failure, and erectile dysfunction) we also included an analysis of studies restricted to Jadad scores of 4 or 5. We accepted whatever criteria were used by individual study authors to define low testosterone.

3. Results

Fig 1 lists the exclusion criteria used to select 226 qualifying papers from 11,417 reviewed abstracts. Although most studies were described by their authors as randomized, not all indicated the nature of the randomization procedures. Some studies included identical numbers of subjects in treatment and exposed conditions, suggesting that allocation was not random. After further examination, 70 papers did not meet our criteria, so the final data set included 156 papers.

Fig 1 
Literature Search and Study Selection.

3.1 Cardiovascular Health

Table 1 summarizes extracted studies that focused on the effect of testosterone on cardiovascular endpoints, including 17 studies on ischemia/angina, 6 on congestive heart failure (CHF), 25 on lipids, and 11 on inflammatory and coagulation markers.

Table 1 
Effects of Testosterone on Cardiovascular Endpoints.

3.1.1 Coronary artery disease

In studies that investigated the effect of testosterone on patients with coronary artery disease (CAD), eligible men generally were identified based on stable angina, angiographic evidence of some degree of coronary artery occlusion, or a history of myocardial infarction (MI). Six studies involved men in whom the study authors reported evidence of hypogonadism either clinically [] or based on plasma testosterone concentration []; the remainder included men without regard to plasma testosterone concentration. All but three of the studies evaluated ST-segment depression on an exercise stress test using a modification of the Bruce protocol. One of the studies not using the Bruce protocol evaluated findings on electrocardiography (ECG) and Holter monitoring, without specification of an exercise protocol.[] Another study added single-photon emission computer tomography (SPECT) to evaluate for deficits in myocardial uptake of a labeled perfusion tracer.[] One study used magnetic resonance imaging (MRI) estimates of myocardial perfusion.[] One study evaluated change in coronary artery calcium score over time, showing no difference between testosterone and placebo.[]

Two studies evaluated brachial artery response to release of occlusion as an indicator of sensitivity to local vasodilators in men with CAD and did not directly address the coronary arteries; both reported results favorable to testosterone therapy.[, ] Two studies in apparently healthy men with bioavailable testosterone <4.44 nM (128 ng/dL) or total testosterone ≤15 nM (432 ng/dL) found no change in brachial artery reactivity in response to transdermal testosterone or dihydrotestosterone therapy.[, ] The study that used MRI showed no effect of 8 weeks of oral testosterone undecanoate therapy on myocardial perfusion, although there was increased perfusion of those segments supplied by an unobstructed coronary artery.[]

Three studies used acute treatments with intravenous (IV) testosterone just prior to exercise testing. Two of the studies showed favorable effects of treatment on time to ST-segment depression.[, ] One study showed no effect on ECG or SPECT evidence of ischemia.[] A year-long study showed benefits of testosterone treatment on ST-segment depression.[] The remaining eight studies evaluated treatments of 2 to 24 weeks in duration.[, , , , ] The 3 studies that looked at time to ST-segment depression found a benefit of testosterone supplementation.[, , ]

Although 2 studies reported improvements in angina symptoms during or after testosterone treatment,[, ] 4 studies showed no effect of treatment on angina.[, , , ] Most studies did not report any measure of angina symptoms. A study on men with leg claudication or trophic ulcers attributed to arteriosclerosis did not show an improvement in subjective symptoms, walking, or plethysmographic estimation of blood flow endpoints after 3 months of testosterone therapy.[]

There was a decreased incidence of silent MI with testosterone treatment in 1 study.[] Another study, designed to determine the effect of testosterone supplementation on lower-extremity strength and physical function in men 65 years of age and older, was stopped early by a Data and Safety Monitoring Board due to an excess of cardiovascular adverse events.[] These adverse events included acute coronary syndrome (ACS), MI, ECG abnormalities, and arrhythmias, among others.

Eleven studies of coronary artery disease scored 4 or 5 on the Jadad scale. Of these, only one of five studies that included angina as an outcome found a benefit. Four of five studies that assessed ST segment depression found a benefit.

3.1.2 Congestive heart failure

Six studies evaluated effects of testosterone treatment on CHF.[] In two papers from the same group,[, ] it is not clear whether treatments were randomly assigned. Administration of testosterone by the buccal route was associated with beneficial effects on cardiac index and systemic vascular index in the acute catheterization setting, consistent with an acute vasodilatory effect.[] Intramuscular (IM) testosterone treatment for 12 weeks improved exercise capacity and reduced heart failure symptom scores without identifiable effects on left ventricular size or ejection fraction (EF).[] Another study of IM testosterone in men with CHF showed an improvement in oxygen consumption, respiratory efficiency (ventilation/carbon dioxide consumption), and distance walked in 10 minutes without changes in EF or left ventricular end-diastolic diameter.[] The improvements in exercise function appeared attributable to the response of men with baseline plasma testosterone concentration <12 ng/mL (~4 nM). A study of a testosterone patch showed improvement in the shuttle walk test.[] Another study showed no effect of IM testosterone enanthate on ejection fraction, although there was an improvement in a Doppler-based myocardial performance index.[]

The only study that scored above a 3 on Jadad found a benefit on CHF measures.[]

3.1.3 Lipids

Serum or plasma concentrations of cholesterol fractions, triglycerides, and lipoproteins have been used as surrogate endpoints for cardiovascular risk, although they should not be mistaken for markers of cardiovascular adverse events. In 25 studies, testosterone treatment was associated with favorable, unfavorable, or no effects on lipids as summarized in Table 1. Favorable effects in 11 studies included 5–11% decreases in total cholesterol concentration and variable and inconsistent decreases in triglycerides and low-density lipoprotein (LDL) cholesterol. One of the studies counted as showing a favorable effect did not demonstrate a change in total or high-density lipoprotein (HDL) cholesterol or triglycerides but reported a 13% reduction in LDL cholesterol.[] This finding was based on averages of several repeated measurements over the course of 1 year rather than a determination of improved lipid measurements at the end of the treatment period.

Unfavorable changes were reported in 2 studies [, ] and included increases in total cholesterol, LDL cholesterol, and triglycerides and decreases in HDL cholesterol in men evaluated as hypogonadal prior to androgen therapy. Most of the studies that did not report favorable effects of testosterone on lipids reported no effects at all. One of these studies[] reported a decrease in lipoprotein-a (LP-a), but this finding was transient and occurred in a study with multiple measurements at multiple time points in multiple patient subgroups without adjustment for multiple comparisons. Nine of the 11 studies that had favorable effects on lipids had Jadad scores of 4 or 5. Nine of the 14 studies that lacked favorable effects on lipids had Jadad scores of 4 or 5.

The discordance between studies on the lipid effects of testosterone treatment did not appear to be route dependent. Seven of the 11 studies showing favorable effects used IM injection of testosterone enanthate, esters, or undecanoate. Five of the 14 studies not showing favorable effects on lipids used IM injection of testosterone esters, cypionate, or undecanoate.

3.1.4 Inflammatory or coagulation markers

Eleven studies were identified in which markers that have been associated with atherosclerotic cardiovascular disease risk were measured in men using testosterone or dihydrotestosterone therapy. Three studies reported favorable effects of testosterone on tumor necrosis factor-α (TNF-α), a marker of inflammation.[, , ] One study in men with CHF showed no effect of testosterone treatment by buccal, IM, or transdermal routes on serum concentration of TNF-α.[] One of the studies asserted that there was a decrease in the inflammatory marker interleukin-1β (IL-1β), but a statistically significant effect was not shown.[] Another study showed a decrease in interleukin-6 (IL-6) and C-reactive protein, additional inflammatory markers.[] Two studies performed in elderly men who were largely without a diagnosis of CAD showed no beneficial effect of testosterone therapy on C-reactive protein[, ] as did two studies of men with type 2 diabetes mellitus.[, ] Transdermal dihydrotestosterone did not affect inflammatory markers in men with low total pretreatment testosterone concentrations.[] No change in fibrinogen, plasminogen activator inhibitor-1, or tissue plasminogen activator was shown in men with CAD who used testosterone patches or oral doses.[, ]

3.2 Sexual Function

The 48 studies that assessed sexual function or libido as a primary or secondary endpoint are summarized in Table 2. Study populations included men identified by study authors as “hypogonadal,” normal men, and men with erectile dysfunction (ED). Studies included men with depression,[] chronic renal disease,[] cirrhosis,[] arterial insufficiency,[] cancer,[] diabetes,[] HIV,[, ] Alzheimer disease,[] and chronic obstructive pulmonary disease (COPD).[] Preparations included IM (n = 16), oral (n = 11), topical gel or solution (n = 14), patch (n = 5), and buccal (n = 1) formulations. Studies used a variety of questionnaires, including the International Index of Erectile Function (IIEF), Frenken sexual experience scales, Derogatis Sexual Performance Scale (DSPS), the Aging Males’ Symptoms (AMS) scale, Male Sexual Health Questionnaire, Psychosexual Daily Questionnaire, and study-specific questionnaires. Study reports used different language for symptoms, so we grouped, for example, “libido,” “sexual interest,” and “sexual desire.”

Table 2 
Effects of Testosterone on Sexual Functioning.

Of 47 studies that assessed sexual function or satisfaction, 23 studies reported beneficial effects of testosterone treatment for at least 1 measure of sexual function or satisfaction,[, , , , , ] and 24 studies did not show testosterone-associated improvements in any sexual function endpoint.[, , , , , , ] Three studies we counted as positive were mixed: Steidle et al found improvement with 100 but not 40 mg of gel, Legros et al[] tested 3 dose levels of orally administered testosterone undecanoate (60 mg, 160 mg, and 240 mg) and found a benefit only for the middle dose, and Hackett et al[] found that testosterone worked in a group with testosterone ≤8.0 nM for intercourse satisfaction but not in a group with testosterone 8.1–12 nM. One study “reported a subjective feeling of increased muscular energy and sexual desire in some subjects”.[] There was no difference between groups by Fischer exact test (performed by us) and we excluded this study from further analysis. Limiting analysis to the 30 studies with Jadad scores of 4 or 5 yielded similar results; 14 were positive and 16 negative.

Of 31 studies that evaluated erectile function, 15 found no improvement with testosterone therapy,[, , , , , , , , , , , , ] and 16 reported a benefit.[, , , , , ] Although the study by Chiang et al[] reported a benefit of both testosterone and placebo compared to baseline; however, our analysis did not show a difference between treatment groups. Limiting analysis to the 17 studies with Jadad scores of 4 or 5 yielded similar results; 9 were positive and 8 were negative.

Twelve studies included men with ED; 8 found no benefit of testosterone over placebo,[, , , , , , , ] and 4 found a benefit.[, , , ] One negative study found that testosterone reduced erectile function when compared to placebo; however, there was no change when each group was compared to its baseline.[]

Of 23 studies that specifically reported changes in libido, 13 found that testosterone treatment increased libido,[, , , , , , , , , , , , ] eight found no effect,[, , , , , , , ] and 1 found an effect after 3 but not 6 months of treatment.[] Hackett et al[] found that testosterone improved sexual desire in a group with initial testosterone ≤8.0 nM but not in a group with initial testosterone 8.1–12 nM.

Eleven studies used the Aging Males’ Symptoms scale, which includes 3 questions on libido and sexual function. Five studies found no difference between testosterone and placebo on total scores,[, , , , ] and 4 studies found a benefit of testosterone.[, , , ] One paper[] reported only sexual subscales but not total AMS scores. On the sexual subscale of the AMS scale, this study reported a benefit, Ho et al[] found no benefit, and Legros et al[] found a benefit of testosterone on the AMS sexual subscale only in the middle (160 mg) of 3 dose levels at 3 of 4 time points. Hackett et al[] found that testosterone improved AMS scores in a group with initial testosterone ≤8.0 nM but not in a group with initial testosterone 8.1–12 nM.

Ten of 13 of the studies on libido or desire with a Jadad score of 4 or 5 found a benefit. Seven of 12 studies on erectile dysfunction with a Jadad score of 4 or 5 found a benefit.

3.3 Muscle Weakness/Wasting

Table 3 summarizes 39 studies that evaluated the effect of testosterone on physical function, muscle strength, or HIV-associated muscle wasting, including 19 in men assessed as having low serum testosterone, 9 on HIV-negative men with normal serum testosterone, 1 on healthy men with normal serum testosterone, and 10 on HIV-positive men. Studies that measured testosterone effects only on body composition (other than in HIV-associated wasting) without measures of physical function or muscle strength were excluded. Subjects included both those defined by the authors as hypogonadal and those considered to have normal testosterone concentrations. Common measures of muscle strength included grip strength dynamometry and the 1-repetition maximum for exercises including the bench press and leg press. Physical function was often measured by the 6-minute walk test, the time and number of steps required to walk 25 feet, and the get-up-and-go test, which evaluates the ability to rise from a chair, walk a short distance, and return to sitting.

Table 3 
Effects of Testosterone on Muscle Weakness/Wasting.

Twenty studies evaluated subjects described as hypogonadal, with 11 of those evaluating healthy subjects. Five studies examined the effects of testosterone supplementation on physical frailty, functional limitations, or a categorization as “sedentary,”[, ] and single studies evaluated subjects with COPD,[] advanced cancer,[] and Parkinson’s disease.[] Ten studies evaluated subjects considered to have normal testosterone concentrations; 1 study included healthy, elderly men, and the remainder included subjects with planned knee replacement surgery,[] stable CHF,[, , ] leg claudication or ulcers,[] long-term glucocorticoid therapy,[] myotonic dystrophy,[] arterial insufficiency,[] COPD,[] or who were planning or undergoing physical rehabilitation.[]

Ten studies evaluated subjects with HIV; 8 of those studies included subjects with HIV-wasting, 1 included subjects with abdominal obesity, and 1 did not use weight criteria. Most of these papers studied older men. Few studies investigated the use of testosterone supplementation in men younger than 60 years.

Twenty-seven studies measured the effects of testosterone treatment on muscle mass, with 22 (81%) of these studies showing a significant increase in muscle mass associated with treatment.[, , , , , , ] Nineteen of 22 (86.3%) of these studies had a Jadad score of 4 or 5. Twenty-five studies assessed the effects of testosterone treatment on fat mass, with 15 (60%) of these studies showing a decrease in fat mass associated with treatment.[, , , , , , , , , , , , , , ] Twelve of these studies had a Jadad score of 4 or 5.

Some studies did not measure muscle and fat mass specifically but used other body composition endpoints. Two studies showed no changes in body weight or BMI,[, ] but another showed an increase in body weight and BMI.[] One study, with a Jadad score of 3, showed no change in weight or estimates of body fat (triceps and scapula skinfold thickness).[] In studies of HIV-positive men with weight loss, 3 of 6 studies (all of which had Jadad scores of 4 or 5) showed an increase in weight with testosterone treatment,[, , ] and all 4 studies that measured muscle mass showed an increase.[, ]

Of the 30 studies that assessed muscle strength as a primary or secondary endpoint, 13 studies (43%) reported an improvement in at least 1 measure of muscle strength.[, , , , , , , , , , , , ] Eleven of 13 of these studies had a Jadad score of 4 or 5. Three of these 12 studies (all with Jadad scores of 4 or 5) reported improvements in fewer than 25% of the measurements.[, , ] In studies of men without HIV, 11 of 24 studies (45.8%) reported an improvement in at least 1 measure of muscle strength. In studies of men with HIV, 2[, ] of 5 studies reported an improvement in at least 1 measure of muscle strength; 3 showed no effect.[, , ]

Twenty-four studies evaluated the effects of testosterone treatment on physical function endpoints and, of these, 5 found an improvement in at least 1 measure of function.[, , , , ] Neither of the 2 studies of HIV patients measuring physical function showed an improvement in function.[, ] Six of these studies had a Jadad score of 4 or 5.[, , , , , ]

In summary, the majority of studies show increased muscle mass but no effect of testosterone on muscle strength or function.

3.4 Mood and Behavior

Forty-five studies evaluating the effect of testosterone on mood and behavior are summarized in Table 4. Twenty-nine of these studies focused on men without psychiatric disorders, and 16 on men with psychiatric disorders.

Table 4 
Effects of Testosterone on Mood and Behavior.

3.4.1 Healthy men

Some studies of mood and behavior were designed to evaluate the potential adverse effects of anabolic steroid abuse. For example, men abusing anabolic steroids have been described as having “Roid Rage.” We did not evaluate steroid abuse studies, but we reviewed studies on testosterone preparations and their association with anger, aggression, and other mood alterations. There was little consistency among the studies we reviewed.

Five studies reported treatment-associated increases in anger, aggression, or hostility.[, ] Only two of these studies had a Jadad score of 4 or 5.[, ] One study,[] with a Jadad score of 3, determined that testosterone gel applied to the skin increased hostility based on evaluations by 2 undergraduate judges of a free-text paragraph written by each subject to describe his mood at the end of treatment. We do not know the reliability of this assessment. Two studies (Jadad score 3 and 5) reported a decrease in anxiety after testosterone treatment.[, ]

Seventeen of 29 studies reported no effect of testosterone treatment on personality, psychological well-being, or mood.[, , , , , , , ] Seven of 17 studies had a Jadad score of 4 or 5. One of these studies could not be evaluated because only a composite score for mood and sexual function was reported.[] The study that used hostility assessments by undergraduate judges found no change in personality as assessed by the Gough and Heilbrun Adjective Check List.[] Another study in this group reported that elevation of testosterone serum concentrations above normal using testosterone gel was associated with an increase in selfishness on a computer game that evaluated the willingness to give away small amounts of money.[] Two additional studies from the same group in non-depressed men with CHF did not show an effect of testosterone on the Beck Depression Inventory (BDI),[, ] although the earlier of these studies concluded otherwise based on a finding that was not statistically significant. A study in non-depressed men with metabolic syndrome reported an improvement in the BDI in testosterone-treated compared to placebo-treated subjects.[] A study found non-depressed men older than 60 years to have a mean 5% decrease in a geriatric depression scale when administered testosterone.[] This study had a Jadad score of 1. Another study [] found that testosterone treatment had no effect on the Hospital Anxiety Depression score (HADS) in men with testosterone ≤8.0 nM but improved the depression subset of the HADS in men with testosterone of 8.1–12 nM. Malkin et al.[] found that 100 mg testosterone every 2 weeks improved the BDI score. This study had a Jadad score of 5.

3.4.2 Men with psychiatric diagnoses

Twelve studies (3 in HIV-positive men) evaluated testosterone supplementation in men with a diagnosis of depression or dysthymia (sometimes also called, “minor depression”), 1 study evaluated the use of testosterone in men with schizophrenia, and 2 studies were conducted in men with Alzheimer disease or cognitive impairment. The study in schizophrenic men used testosterone or placebo gel in addition to whatever treatment the subject was already using.[] There were improvements in the negative symptom scores on a standardized scale but no change in the Calgary Depression Scale for Schizophrenia. The authors used an intention-to-treat (ITT) analysis and implied that better results were seen among subjects who completed the study; however, there were no significant differences in the depression scores between testosterone and placebo among completers. Two studies in men with cognitive impairment or Alzheimer disease (Jadad score 3) found no effect of treatment on neuropsychiatric symptoms, depression, behavior, or quality of life (QoL).[, ] Caregiver-assessed QoL was improved in 1 of these studies.[]

The response of depression and dysthymia to testosterone was mixed and inconsistent. Among HIV-negative men, four studies (all with a Jadad score of 4 or 5) showed testosterone-associated improvements in standard scoring systems for depression and/or in the proportion of subjects who achieved remission of their psychiatric disorder.[, , , ] Four other studies (2 with a Jadad score of 4 or 5) showed no improvement in depression or dysthymia with testosterone compared to placebo.[, , , ] One study (Jadad score 4) showed a transient improvement in depression and melancholia after 3 months of treatment that was no longer apparent after 6 months of treatment.[]

Because it has been noted that HIV-positive men can be depressed and “hypogonadal,” 3 studies administered testosterone to HIV-positive men with depression or dysthymia.[, , ] Two of the studies had a Jadad score of 4[, ] and one study had a Jadad score of 3.[] Testosterone treatment had inconsistent effects on measures of depression; one study showed a 5.8-point improvement in the Beck Depression Inventory (BDI) in men with HIV-associated wasting, although the improvement may have been explained by an increase in weight.[] Another study showed a testosterone-associated improvement in HIV-positive men overall in the Clinical Global Impression (CGI) scale but not among subjects with a depression diagnosis.[] This study also showed improvement in the total and vegetative symptom scores of the Hamilton Rating Scale for Depression (HAM-D) but not in the affective scale, and there was no significant change in BDI scores. A subsequent, larger study by the same group showed no difference in response of depression measured by HAM-D or BDI in men given testosterone compared to placebo.[]

Authors attributed the mixed responses in the literature to the considerable placebo response in most studies and to the possibility of an idiosyncratic response to testosterone, with putative subgroups of responders who were difficult to identify a priori.[, ] The studies, however, did not show consistent responses in subgroups of men who had low serum testosterone concentrations, depression resistant to standard therapy, or men characterized as middle-aged or elderly. In studies in which serum testosterone concentrations were measured on therapy (both with a Jadad score of 5), response of depression or dysthymia was not consistently associated with serum hormone concentration.

3.5 Cognition

Twenty-two studies evaluating the effects of testosterone on cognition are summarized in Table 5. Seventeen focused on men without cognitive impairment and 4 focused on men with cognitive impairment.

Table 5 
Effects of Testosterone on Cognition.

3.5.1 Men described as normal

Ten studies evaluated the effects of testosterone treatment on cognitive endpoints in healthy men. Spatial cognition/memory was reported to be improved with testosterone supplementation in 3 studies,[, , ] unchanged in 2 studies,[, ] and poorer with supplementation in 1 study.[] Although 1 study reported improved working memory[] and 1 study found improved verbal fluency,[] most other studies found no improvement in verbal fluency, memory, or other cognitive endpoints in healthy men given testosterone.[, , , , , , ] Two of 5 studies that showed improvement and 4 of 7 of the studies that showed no improvement had a Jadad score of 4 or 5.

3.5.2 men described as hypogonadal

Hypogonadal men, variously defined, were found in 1 study to have better verbal learning and reversal of digits on number sequencing with testosterone supplementation,[] but no effect on the same domain was found in another study.[] The study showing an advantage used injected testosterone enanthate 200 mg while the negative study used a daily 5 mg patch. Another injection study found no effect of supplementation on memory in hypogonadal men.[] One study reported a possible disadvantage of treatment with dihydrotestosterone compared to placebo in performance on the Modified Mini-Mental State Examination (MMSE),[] but data were not shown and the putative difference could not be evaluated. Another study showed no improvement in visuospatial cognition or MMSE with testosterone treatment for 12 months.[] All studies had Jadad scores of 4 or 5.

3.5.3 Men with cognitive impairment

Treatment of men with suspected or diagnosed Alzheimer disease or cognitive impairment was reported in five studies, two of which had a Jadad score above 3. Although 1 injection study found an improvement on the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-COG),[] another study using testosterone gel found no effect on the same instrument or on other cognitive function tests.[] Spatial and verbal memory were improved after 6 weekly injections of testosterone enanthate in 1 study, but the effect did not persist during a 6-week washout period without treatment.[] A fourth study found no effect of testosterone injections on behavior, activities of daily living (ADLs), or cognition.[] The fifth study found that transdermal testosterone gel was not associated with statistically significant changes in measures of cognition, mood, or quality of life.[]

3.5.4 Proposed explanations for inconsistent results

Because study results have been varied and inconsistent, some authors have proposed that testosterone is not the only factor or even the most important factor in cognitive function. Janowsky et al[] found improved spatial cognition in men treated with scrotal testosterone patches, but there was an imbalance between placebo and testosterone groups in baseline blood concentrations of 17β-estradiol, which these authors attributed to chance. The effect of testosterone and 17β-estradiol on spatial cognition testing was explored using post-hoc testing, and the putative testosterone effect on spatial cognition appeared to be associated with suppression of 17β-estradiol by testosterone supplementation rather than a direct effect of testosterone. This study had a Jadad score of 3.

Most authors with an interest in 17β-estradiol have suggested that the effectiveness of testosterone, when it has shown effectiveness, is due to aromatization to 17β-estradiol. Cherrier et al[] measured testosterone and 17β-estradiol concentrations after injection of testosterone supplements in healthy men and reported that both testosterone and 17β-estradiol concentrations were associated with recall of a test story, but only 17β-estradiol concentrations were associated with performance on the Stroop test. In another study, Cherrier et al reported that only men with an increase in 17β-estradiol concentration after testosterone supplementation showed improvements in verbal memory testing.[] This study used administration of the aromatase inhibitor anastrozole to differentiate between effects attributable to testosterone and those that might be due to 17β-estradiol. Another study without anastrozole found 17β-estradiol serum concentrations after testosterone therapy to be a significant predictor of performance on verbal memory testing.[] All three studies had a Jadad score of 5.

It has also been suggested that testosterone supplementation has produced inconsistent results in cognitive function studies because the blood concentrations achieved by supplementation need to be in an optimum range for effectiveness. Under this hypothesis, over-supplementation is as ineffective as under-supplementation. Cherrier et al[] administered testosterone enanthate IM at 0, 50, 100, or 300 mg weekly and administered tests of verbal and spatial memory. Results were not reported according to treatment group; rather, subjects were divided into those with no, moderate, or large increases in serum testosterone concentrations over baseline. These response categories were defined based on 1 standard deviation above the control response and 1 standard deviation above the response to 100 mg. Subjects with a moderate increase in serum testosterone concentration over baseline (defined as 11–50 nM) performed better on cognitive testing than those with “no increase” (0–10 nM) or a large increase (>51 nM). Seventeen of the 22 men in this moderate-increase group had received testosterone 100 mg/week with the balance evenly divided between the 50 mg and 300 mg doses. The authors explained that they did not use tertiles or quartiles, because using quartiles or tertiles resulted in some placebo patients with significant changes from baseline, raising the question of whether men on placebo with an increase in their serum testosterone concentration were distinguishable on cognitive testing from men who received testosterone supplementation. This study had a Jadad score of 5.

In summary, there is no support for the use of testosterone to enhance cognition in normal or cognitively impaired men.

4. Discussion

This systematic review examined published RCTs of testosterone supplementation for cardiovascular disease or surrogates of cardiovascular disease, sexual function, muscle strength, mood, and cognition. The review was limited to published studies in English and to trials indexed before April 9, 2016. The evidence supporting the use of testosterone for preventing or treating cardiovascular disease is inconsistent and, on balance, unconvincing. Some evidence supported an acute and chronic effect of testosterone therapy on increasing time to ST-segment depression, and there is evidence of improvement in some measures of congestive heart failure. Most studies showed no effect of testosterone therapy on inflammatory markers, and the effects on lipids were inconsistent.

Studies that examined clinical effects have not favored testosterone therapy over placebo. Two of 3 studies that assessed angina showed no effect. Three studies from the same group found a benefit for symptoms associated with CHF. One study was stopped early for cardiovascular adverse effects.

Testosterone supplementation did not demonstrate consistent effectiveness for improving sexual function or satisfaction. Testosterone is ineffective in treating ED. Controlled trials were mixed on libido, with more positive than negative studies.

Substantial evidence supports a favorable effect of testosterone treatment on muscle mass in both healthy men and men with HIV, and a majority of studies showed a decrease in fat mass. Testosterone did not affect most measures of muscle strength. While decreasing frailty and increasing strength in older men might be beneficial, testosterone supplementation does not improve physical function in older men.

Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood. Although 2 studies showed decreased anxiety, treatment of depression showed mixed and inconsistent results. Even if testosterone did benefit mood, social adverse events might ensue; 5 studies noted treatment-related increases in anger, aggression, or hostility. Testosterone did not benefit cognitive impairment or Alzheimer disease; neither did it benefit verbal fluency, memory, or other cognitive endpoints in normal men.

In summary, evidence from RCTs does not support treatment of so-called low-T for improving physical function, sexual function, mood, or cognition. Testosterone increases muscle mass, but not strength, and while some improvement is seen in some surrogate markers of cardiovascular risk, there is little evidence of clinical benefit.

There is conflicting evidence on the association between testosterone supplementation and cardiovascular events. RCTs have reported increased cardiovascular risk with testosterone therapy. One such trial that specifically examined cardiovascular disease and mortality endpoints was stopped early because of an increased risk of cardiovascular events.[] A meta-analysis of 2994 men in 27 randomized controlled trials through 2012 found that testosterone therapy increased the risk of cardiovascular events (OR, 1.54; 95% CI, 1.09–2.18).[]

Observational studies examining the effect of testosterone treatment have shown conflicting results on risk. A Veterans Administration study evaluated men who had undergone coronary angiography and had a total testosterone concentration (presumably plasma) less than 300 ng/dL (10.4 nM).[] Men who were treated with testosterone had an increased risk of all-cause mortality, MI, and stroke compared to men who did not use testosterone (HR, 1.29; 95% CI, 1.05–1.58), based on a mean of 27.5 months of follow-up. Another retrospective cohort study using Veterans Administration data showed a lower rate of all-cause mortality, myocardial infarction, and stroke among testosterone-treated men whose testosterone concentrations “normalized” after treatment.[] Another observational study of men in a large, integrated health care organization found that death rates were reduced over 3 years, but there was no effect on myocardial infarction or stroke.[]

A Medicare-based study identified testosterone exposures and MI outcomes using claims data and matched testosterone-treated with untreated subjects using an empirically derived propensity score and found no increased risk.[] The adjusted HR for testosterone therapy and MI was 0.84 (95% CI 0.69–1.02). Analysis of subjects in the highest quartile propensity score range suggested a protective effect of testosterone treatment, with a HR of 0.69 (95% CI 0.53–0.92). An observational study in men with low testosterone found that treatment was associated with reduced mortality;[] another in diabetics[] reported benefit on all-cause mortality but excluded men who had received testosterone for less than one year and excluded deaths occurring before six months. A large cohort study found that myocardial infarction rates were significantly increased within three months of testosterone treatment initiation; testosterone-treated men over 65 experienced double the rate of myocardial infarctions compared to men who did not received testosterone.[]

Testosterone treatment has been considered for disease prevention because men who are obese, diabetic, hypertensive, or chronically ill have lower plasma concentrations of testosterone.[] However, the direction of causality is unclear; it is possible that obesity or lack of exercise and chronic disease lower testosterone rather than low testosterone concentrations causing disease. It is also possible that another mechanism both lowers testosterone concentrations and increases the risk of some diseases. Observational studies attributing positive health effects to testosterone may be affected by an increased likelihood of healthier men being prescribed testosterone rather than testosterone improving health.

There are parallels between the recommendation of testosterone and of menopausal hormone therapy in women. Physicians prescribed estrogen and estrogen-progestin preparations to menopausal women to prevent cardiovascular disease because observational studies showed that women who took menopausal hormones had less heart disease than women who did not. RCTs, however, showed that menopausal hormone therapy increased the risk of heart attacks and stroke.[] It is likely that healthier women chose to take menopausal hormone therapy, but menopausal hormone administration did not improve health.

In 2012, sales for testosterone therapies exceeded $2 billion, and sales continue to grow in dozens of countries.[] To the extent that this increase in use of testosterone supplementation is based on anticipated improvements in cardiovascular health, sexual function, physical functioning, mood, or cognition, we suggest that it might represent therapy without adequate clinical trial support. We identified no population of normal men for whom the benefits of testosterone use outweigh its risk. Given the known risks of testosterone therapy and the lack of evidence for clinical benefits in normal men, we do not think further trials of testosterone are necessary.

Acknowledgments

We thank Matthew Puretz, Anastassia Reznik, and Nicole Dubowitz for their research assistance in the preparation of this paper.

Funding Statement

There were no funding sources for this study. Dr. Scialli is the sole participant in Scialli Consulting LLC. Scialli Consulting LLC has no employees and did not support this study with either salary or any other funding. Scialli Consulting LLC did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.

Data Availability

This is a systematic review. Studies we reference are available in the public domain.

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