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ANDROPAUSE AWARENESS

Andropause and SARMs

There’s an experience that most healthy, fit men in their 30’s or 40’s will come to share: lagging results in the gym, less vigor in daily life, and decreased libido—even in those who strictly adhere to a healthy diet with appropriate nutritional supplementationThis phenomenon is known as “andropause,” and it was first described in medical literature 80 years ago in the Journal of the American Medical Association [1]It was initially categorized by nervousness, reduced sexual potency, low libido, increased irritability, fatigue, depression, memory disturbances, sleep disturbances, and even hot flushes. Hypogonadism is the scientific term applied to the generalized disorder, and it refers to a clinical syndrome resulting from androgen deficiency, which is now known to adversely affect multiple organs and decrease overall quality of life.

In contrast to menopause which is universal in women and progresses through a well-delineated process associated with absolute gonadal failure, andropause on the other hand is marked by broader onset and slower progression. Many terms have been coined to denote this process, such as male menopause, male climacteric, androgen decline in aging male, aging male syndrome (AMS), and the most recent addition: late onset hypogonadism (LOH). Complete andropause only develops in men who have totally lost testicular function, due to accident or disease, or in men with late-stage prostate cancer requiring surgical castration.

Testosterone levels decrease with age at a rate of about 1% per year, and this decrease is more pronounced in free testosterone levels (ie. bioavailable testosterone) because of alterations in sex hormone binding globulin (SHBG) [2]. The particular decline in testosterone levels in any given man varies naturally and is influenced by chronic diseases, including obesity, adverse emotional stress, and concomitant medication. However, This decline can be slowed by careful management of health and lifestyle factors [3]. Among parameters related to body mass, waist circumference is perhaps the most adaptable modifiable risk factor for developing low testosterone and androgen deficiency.

The testosterone threshold below which symptoms become evident show substantial individual variation, so many men are not overtly symptomatic despite steadily decreasing levels of testosterone. Diminishing testosterone and other anabolic hormones in men (ie. DHEA) from the mid-30’s onward may actually permit or instruct the age-related deteriorations in body function (eg, frailty, obesity, bone mineral loss, cognitive decline, and erectile dysfunction) and testosterone insufficiency in older men has been demonstrated to be associated with higher mortality for a subsequent two decades, independent of other risk factors and pre-existing health issues. However, this association could not be statistically confirmed in the much-heralded Massachusetts Male Aging Study or the New Mexico Aging Study.

For decades now, there has been serious disagreement on how to define the clinical syndrome for statistical and epidemiological purposes. Investigators have generally taken two approaches; the first is purely statistical (ie. lowest 2.5th percentile of testosterone), while the other is clinical (written questionnaire like Androgen Deficiency in the Aging Male. Yet the issue is worsened by the fact that men with biologically significant low T levels may not actually display clinically significant symptoms [4], [5]. Moreover, many relevant symptoms are general in nature and nonspecific.

Late onset low testosterone, a syndrome defined by a biochemical metric, is a common disorder associated with advancing age and characterized by idiosyncratic symptoms and a persistent, non-fluctuating deficiency in serum testosterone level (beneath the threshold for healthy young adult males), but it is often underdiagnosed or left untreated nevertheless. The reported prevalence of low testosterone has been recorded as 3.0–7.5% in men aged 30–70 years, and 20% in men older than 70 years. Meanwhile, prevalence of symptomatic androgen deficiency in men 30–80 years is 6% and it increases substantially with age [6]. On the other hand, data coming from the European Male Aging Study recorded a prevalence of 2% as assessed by low testosterone plus at least three sexual symptoms [7]. Lastly, it is estimated that a mere 5–40% of males with low testosterone actually receive medical treatment to ameliorate symptoms.

To address the growing problem of andropause, physicians turned to Testosterone Replacement Therapy (TRT). While the initial results seemed promising, there are some crucial downsides to this therapeutic approach…

THE PROBLEM WITH TESTOSTERONE REPLACEMENT THERAPY (TRT)

Testosterone vs SARMs

Treating age-related andropause symptoms brought on by low circulating testosterone levels and low libido has traditionally been accomplished using testosterone replacement therapy, yet this choice is controversial. For some men, testosterone therapy initially relieves bothersome signs and symptoms of testosterone deficiency. However, for many men the benefits are not clear, and the associated risks are simply untenable.

For instance, TRT substantially worsens sleep apnea. More importantly, TRT stimulates noncancerous growth of prostate epithelial cells and stimulates the expansion of pre-existing prostate tumors. Testosterone therapy may also increase the risk of heart attack and stroke and contributes to the creation of blood clots in the veins. However, there is still a lack of understanding of the delicate balance of this hormone in human physiology and in particular men’s health, and this creates a hurdle in the path toward effective clinical by the medical community to restore normal physiological levels of testosterone without creating a crippling dependency on injected testosterone supplementation.

One of the major hurdles preventing widespread adoption of TRT is the justifiable worry that artificially elevated testosterone levels can promote the development of prostate cancer [8]. This hypothesis can be traced to evidence from as early as the 1940’s showing that T promotes progression of late-stage prostate cancer [9]. While those early observations were valid, demonstrating that prostate tumors retain function of the androgen receptor and thus testosterone will promote tumor growth and spread, there is scant evidence to support the notion that testosterone alone is carcinogenic and can promote development of prostate cancer. Nevertheless, the severity of this risk has many physicians and patients wary of TRT altogether.

A second major hurdle impeding the clinical utilization of TRT is the mountain of evidence suggesting that testosterone increases cardiovascular disease (CVD) risk, some of which was published in preeminent medical journals including the New England Journal of Medicine [10]–[13]. While this evidence is compelling, it is nonetheless prudent to note that there are some inherent weakness in these studies: some did not use primary outcome measures for CVD endpoints, some were retrospective observational studies instead of cohort studies, and there has been a wide range of testosterone doses used which complicate direct comparisons. 

Nevertheless, after the publication of several published case report studies [14], the U.S. Food and Drug Administration (FDA) issued a warning with regard to the risk of TRT and vascular embolism (ie. blood clots). This warning added yet another hurdle to advancing TRT as a safe option for me. Finally, and most disturbingly, the FDA also suggested that age-related low testosterone does not actually warrant medical treatment unless specific criteria are met [15]. With this determination, the FDA basically announced that there’s nothing wrong with losing youthful vitality and vigor, which is more of a philosophical opinion than medical opinion. Clearly there are important practical issues that remain to be addressed regarding the challenges and opportunities of TRT if there is to be any future for medical testosterone use in the rapidly changing field of men’s health.

However, even when TRT is effective at ameliorating symptoms associated with low testosterone, men who eventually discontinue TRT face a new threat: severe loss of sexual desire.

MALE HYPOACTIVE SEXUAL DESIRE

SARMS for beating low sex drive

One of the major risks in using testosterone creams, patches, gels, injectable formulations is the physiological dependence that soon develops. Ceasing TRT after your body adjusts to it often causes long-term consequences on quality of life, including the dreaded Male Hypoactive Sexual Desire Disorder (MHSDD). This phenomenon is defined as chronic or recurrently deficient sexual/erotic thoughts, desires, and fantasies for sexual activities.

To qualify clinically, these symptoms must persist for a minimum of six months and result in clinically significant distress to wellbeing. The disorder is distinguished by different levels and sub-grouped into lifelong versus acquired, generalized versus situational. In the case of sexual arousal disorder developing secondary to TRT discontinuation, it is an acquired and generalized condition that is difficult to address.

As yet, however, there have been no well-designed studies that assess the risk of long-term dependency on testosterone replacement therapy (TRT) despite published case studies. As the old saying goes, “The absence of evidence is not evidence of absence.” While little has been published in the medical literature regarding this risk, one recent multi-university study of the impact of TRT on fertility cautions that stopping TRT will result not only in the return of baseline serum testosterone levels, but also a significant increase in subjective measures of low testosterone symptoms and a desire to return to higher serum testosterone levels [16]

Meanwhile, reports in the public sector are rife with warnings. For instance, Harry Fisch, MD, the director of the Male Reproductive Center of New York Presbyterian Hospital, wrote that “many men are unaware that TRT shuts down a man’s natural production of the hormone, often causing the testosterone-producing cells to stop working and his testicles to soften and shrink. If a guy suddenly stops taking testosterone after using it for more than a month or so, he’s very likely to feel terrible—he could have low energy, low sex drive, be irritable, and even feel depressed.

These withdrawal symptoms powerfully motivate guys to keep refilling their ‘T’ prescriptions!” Elsewhere, Francois Eid, MD, former director of the Sexual Function Center at New York Presbyterian Hospital, offered his take: “Men often mistake the increased energy and improved mood they experience while using testosterone replacement as proof of its effectiveness. In reality, the steroidal nature of testosterone is what causes these changes. Once the treatment is stopped, men can experience withdrawal and severe depression, as well as the permanent inability to naturally produce testosterone.” 

An article in the Harvard Men’s Health Watch argues that “men get started on testosterone replacement and they feel better, but then it’s hard to come off of it… Men often feel a big difference when they stop therapy, because their body’s testosterone production has not recovered” [17]. In the New York Times, John LaPuma, MD, tells readers that “too many doctors are now writing testosterone prescriptions without even measuring the patient’s hormone levels, much less re-testing for confirmation and adjusting the dose after prescription. Up to a quarter of these prescriptions are dispensed without a blood test. From a psychological perspective, this isn’t helping men. From a medical perspective, it’s devastating. In addition to cardiac risks, prescription testosterone can mean a permanent shut-off in men’s own, albeit diminished, testosterone production. In other words, once you start, you may well be hooked for life.”

Low sexual desire is commonly a presenting clinical sexual complaint for men, who are more likely to present with erectile dysfunction. Cultural norms that often portray men as being continually desirous of sex may make it less likely for men to report low sexual desire to their physicians or their psychologists. Since these are the gatekeepers to medicine, it is impossible to go around them, thus highlighting the importance of research into new compounds such as SARMs which hold great promise for increasing libido and permitting normal sexual arousal.

Most epidemiological studies have not sought to inquire about the full set of diagnostic criteria for male sexual arousal disorders, making it difficult for researchers to determine accurate prevalence rates. Research studies have asked men if they have a lack of interest in sex, but not whether the problem was consistent over a period of 6 months and distressing. However, one European study did examine the prevalence of distressingly low sexual interest in men across a two-month period. In this study, 14% of men in Portugal, Croatia, and Norway reported a distressing lack of sexual desire lasting at least two months long [18]

Men between the ages of 30 and 39 are the most likely to report low sexual interest [19].

Hormonal factors are often implicated in low sexual desire. In men for whom androgen levels have been suppressed due to anabolic steroid use, low testosterone levels have been associated with low levels of sexual interest [20]. For such men, TRT has been shown to increase sexual desire, yet this is not similar for men with normal androgen and AR levels [21]. Hypogonadism, or diminished functional activity of the testis, has been observed in 3-7% of men between the ages of 30 and 70 and in almost a quarter of men aged 70 and older [6]. This condition accounts for the relationship between aging and low libido.

Self-reported prevalence rates of problems with desire range from 5% in the U.S. [19] to 20% in the U.K. [22]The severity of sexual desire problems appears to increase with age once diagnosed if left unaddressed. In a sample of Swedish men, over 40% experienced low sexual desire [23]. Prevalence rates typically decrease when studies examine persistent lack of interest in sexual activity. In a sample of middle-aged men in the U.S., 5% reported an occasional lack of sexual desire, while only 4% reported a frequent lack of sexual desire [19] .

Men in community samples (ie. screened at home instead of seeking out help) are more likely to report desire problems than men in clinical samples. In community samples, reports of desire concerns exceed reports of erectile problems [20]. Men in clinical settings may feel more comfortable talking about erectile problems than desire problems, especially if they consider their problems to be biological rather than psychological in nature.

Lastly, in a study of adult men randomly assigned to either daily application of a testosterone gel or daily application of a placebo, men treated with the testosterone gel had a greater frequency of cardiovascular, respiratory, and dermatologic events compared to men in the control condition [10]. In fact, the incidence of adverse cardiovascular events in the testosterone group was significant enough to stop the trial before the completion of enrollment.

However, there is an alternative to TRT for addressing low libido that is very promising: the coordinated use of SARMs. As of yet, no studies have specifically investigated to benefits of SARM therapy on Male Hypoactive Sexual Desire Disorder despite widespread anecdotal evidence of dramatically increased libido that many SARMs induce, without the unwanted side effects of testosterone replacement therapy (TRT).

THE FUTURE OF SARM THERAPY AS A SUPERIOR ALTERNATIVE FOR PREVENTING ANDROPAUSE AND RESTORING LIBIDO

SARMS for increasing sex drive

Preclinical evidence demonstrates that oral, non-steroidal SARMs can modify sexual behavior in a manner consistent with sexual assertiveness. This phenomenon reflects our understanding that the brain is an important androgen-target tissue because of the role of testosterone in mood, libido and cognition. It is recognized that androgen administration helps to improve libido and mood in both men and women. Therefore, the positive effects of SARMs on libido are an obvious avenue for further research. Furthermore, it is already known that sufficient distribution of SARMs in the central nervous system is important for maintaining libido, and it is well documented that oral SARMs show excellent tissue distribution and can cross the blood-brain barrier.

*The information herein is for educational and informational purposes only. THE PRODUCTS DESCRIBED ARE FOR RESEARCH USE ONLY. For use in animal studies, all research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA). These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

References:

  1. A. A. Werner, “The male climacteric: Report of two hundred and seventy-three cases,” J. Am. Med. Assoc., vol. 132, no. 4, pp. 188–194, Sep. 1946.
  2. A. M. Matsumoto, “Andropause: Clinical implications of the decline in serum testosterone levels with aging in men,” Journals of Gerontology – Series A Biological Sciences and Medical Sciences. 2002.
  3. T. G. Travison, A. B. Araujo, V. Kupelian, A. B. O’Donnell, and J. B. McKinlay, “The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men,” J. Clin. Endocrinol. Metab., 2007.
  4. A. Morales et al., “Adding to the controversy: Pitfalls in the diagnosis of testosterone deficiency syndromes with questionnaires and biochemistry,” Aging Male, 2007.
  5. J. E. Morley et al., “Validation of a screening questionnaire for androgen deficiency in aging males,” Metabolism., 2000.
  6. A. B. Araujo et al., “Prevalence of symptomatic androgen deficiency in men,” J. Clin. Endocrinol. Metab., 2007.
  7. A. Tajar et al., “Characteristics of androgen deficiency in Late-onset hypogonadism: Results from the European Male Aging study (emas),” J. Clin. Endocrinol. Metab., 2012.
  8. J. E. Michaud, K. L. Billups, and A. W. Partin, “Testosterone and prostate cancer: An evidence-based review of pathogenesis and oncologic risk,” Therapeutic Advances in Urology. 2015.
  9. C. Huggins and C. V. Hodges, “The effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate,” Arch. Surg., 1941.
  10. S. Basaria et al., “Adverse events associated with testosterone administration,” N. Engl. J. Med., 2010.
  11. L. Xu, G. Freeman, B. J. Cowling, and C. M. Schooling, “Testosterone therapy and cardiovascular events among men: A systematic review and meta-analysis of placebo-controlled randomized trials,” BMC Med., 2013.
  12. R. Vigen et al., “Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels,” JAMA – J. Am. Med. Assoc., 2013.
  13. W. D. Finkle et al., “Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men,” PLoS One, 2014.
  14. C. J. Glueck and P. Wang, “Testosterone therapy, thrombosis, thrombophilia, cardiovascular events,” Metabolism: Clinical and Experimental. 2014.
  15. C. P. Nguyen, M. S. Hirsch, D. Moeny, S. Kaul, M. Mohamoud, and H. V. Joffe, “Testosterone and ‘age-related hypogonadism’ – FDA concerns,” N. Engl. J. Med., vol. 373, no. 8, pp. 689–691, Aug. 2015.
  16. E. D. Kim, L. Crosnoe, N. Bar-Chama, M. Khera, and L. I. Lipshultz, “The treatment of hypogonadism in men of reproductive age,” Fertil. Steril., 2013.
  17. “Is testosterone therapy safe? Take a breath before you take the plunge – Harvard Health.” [Online]. Available: https://www.health.harvard.edu/mens-health/is-testosterone-therapy-safe-take-a-breath-before-you-take-the-plunge. [Accessed: 16-Apr-2020].
  18. A. Carvalheira, B. Træen, and A. Štulhofer, “Correlates of Men’s Sexual Interest: A Cross-Cultural Study,” J. Sex. Med., 2014.
  19. E. O. Laumann, D. B. Glasser, R. C. S. Neves, and E. D. Moreira, “A population-based survey of sexual activity, sexual problems and associated help-seeking behavior patterns in mature adults in the United States of America,” Int. J. Impot. Res., 2009.
  20. J. Bancroft, “The endocrinology of sexual arousal,” Journal of Endocrinology. 2005.
  21. G. Corona, G. Rastrelli, G. Forti, and M. Maggi, “Update in testosterone therapy for men (CME),” J. Sex. Med., 2011.
  22. J. Bancroft, J. Loftus, and J. S. Long, “Distress about Sex: A National Survey of Women in Heterosexual Relationships,” Archives of Sexual Behavior. 2003.
  23. K. Sjögren Fugl-Meyer and A. R. Fugl-Meyer, “Sexual disabilities are not singularities,” Int. J. Impot. Res., 2002.

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