Hormone Therapies for Men

Testosterone is not just a hormone responsible for sexual function in male physiology. It has significant effects on muscle protein synthesis, maintenance of muscle and bone mass, erythropoiesis, fat distribution, energy levels, libido, and overall physical performance. Testosterone levels can gradually decrease with age; however, the degree of this decrease varies considerably from person to person and can also be affected by obesity, insulin resistance, sleep disorders, chronic diseases, certain medications, severe calorie restriction, and changes in hypothalamo-pituitary function. Therefore, when low testosterone is detected, it is important not only to increase the number but also to understand why it is low. 

Testosterone, Muscle Mass, and Healthy Aging

Muscle tissue is not merely a mechanical structure that enables movement. Today, we increasingly understand that skeletal muscle is one of the most important organs for metabolic health. Muscle tissue plays a vital role in glucose utilization, supports physical capacity and independent living, and forms a significant protective reserve against falls, fragility, and loss of function as we age. Therefore, maintaining muscle mass and strength, especially in middle and old age, should be a fundamental goal for long-term health. Rapid muscle loss in older men has been associated with higher mortality; furthermore, in very large cohorts, low muscle strength is also considered a strong predictor of mortality and loss of function [1,2]. In short, it can be said that people with less muscle mass live shorter lives and have to struggle with more chronic diseases. This is true not only for men but also for women.

Testosterone is an important hormonal factor in this equation. It has long been known that testosterone replacement can increase muscle protein synthesis in men with low testosterone [3]. Randomized studies have shown that testosterone treatment can increase lean body mass and improve muscle strength and physical performance, especially in men with low baseline testosterone [4,5]. 

There is an important distinction here: muscle mass and muscle strength are not the same thing. More muscle does not always mean more function. Therefore, resistance training, adequate protein and energy intake, sleep quality, and metabolic health must be considered together with testosterone optimization. In other words, testosterone is an important anabolic signal for muscle health; however, just as exercise cannot replace good hormone levels, testosterone therapy cannot replace resistance training. The two are like pieces of a puzzle that complement each other.

One of the most important aspects of hormone therapy in men is that age and life plans directly influence the choice of treatment. For example, it is not appropriate to apply the same hormonal approach to a 60-year-old man who does not plan to have children, has consistently low testosterone levels, and experiences muscle loss, decreased libido, low energy, or significant changes in body composition, as it is to a 30-year-old man who is active in sports and wants to have children in the future.

Classical endocrinology guidelines recommend that low testosterone be evaluated together with concordant symptoms or findings for the diagnosis of testosterone deficiency [6]. However, in a broader approach to healthy aging, it may not be necessary to wait for the onset of severe symptoms. In a scenario where testosterone is significantly low or has regressed considerably from the person's previous physiological levels, it is more meaningful to evaluate body composition, muscle mass, metabolic health, sexual function, and overall physical capacity together.

The goal here is not to create supraphysiological testosterone levels. The aim is to maintain or recreate the physiological hormonal environment in the appropriate patient and to prevent, as much as possible, losses in muscle, bone, sexual function, or quality of life that may occur due to hormonal deficiency.

Testosterone Replacement Therapy

For suitable men with true testosterone deficiency who do not have a compelling need to preserve fertility, testosterone replacement therapy (TRT) is the most direct treatment option. Treatment can be administered via injections, transdermal gels, or other testosterone preparations. The choice of treatment should be individualized based on the person's age, lifestyle, hormone profile, hematocrit response, symptoms, and treatment preferences.

I prefer transdermal testosterone gels for many patients. One of the most important reasons for this is that daily application can create a more physiological and predictable testosterone profile. With regular daily use, transdermal gels can keep testosterone relatively stable within the normal physiological range, and the dose can be easily increased or decreased in small increments as needed [20,21]. In contrast, short-acting intramuscular testosterone esters, in particular, can produce higher testosterone peaks after application, and levels may decrease as the next injection approaches. These peak-trough fluctuations can lead to fluctuations in energy, libido, or mood in some patients, and may also increase the likelihood of side effects such as increased hematocrit due to suprapsychological peaks [21,22].

Although pellet treatments can provide longer-lasting testosterone release, their main disadvantage in my view is that the dose cannot be changed quickly once treatment has started. The effect of the pellet lasts for several months after placement; therefore, it is not possible to adjust the dose the next day as with gels if the dose is too high or too low. In addition, pellet placement requires a minor surgical procedure and pellet extrusion, hematoma or local complications can rarely occur [23].

With daily gel use, treatment can be personalized in a much more dynamic way. Treatment can begin with a low dose, and small dose adjustments can be made after evaluating clinical response and testosterone levels. This feature is particularly consistent with the "start low, progress slowly, and adjust according to the individual's clinical response" approach in hormone optimization.

Gels also have disadvantages. Absorption can vary from person to person, daily application is required, and proper usage guidelines must be followed to prevent the transfer of testosterone from the application area to other people.

Randomized clinical trials show that testosterone therapy can improve sexual desire and activity in men with low testosterone, increase lean mass and support muscle performance in some men. In a three-year controlled study, older men who received testosterone showed significant improvements in muscle mass, muscle strength and stair climbing ability compared to placebo [5]. 

Cardiovascular safety has also been the subject of significant debate in the past. One of the largest randomized safety trials to date in this regard is... TRAVERSETestosterone treatment in hypogonadal men at high risk of cardiovascular disease has shown that it is no worse than placebo in terms of major cardiovascular events [7]. This result does not mean that testosterone is risk-free for everyone, but it is important because it shows that some of the previous fears are not supported when used under appropriate patient selection and follow-up. 

Why Don't We Always Give Testosterone to Young Men?

One of the most important questions, especially in young men, is fertility. External testosterone administration increases testosterone in the blood while increasing negative feedback on the hypothalamus and pituitary gland. As a result, LH and FSH may be suppressed, testosterone concentration in the testes may decrease, and sperm production may be severely reduced. In some men, this can progress to severe oligospermia or azoospermia. Therefore, direct TRT is often not the first choice for men who want to preserve their fertility in the short or medium term [6,8]. 

In this group, the goal might be to increase the body's own testosterone production rather than administering testosterone externally. We can do this in a few ways:

1- Human chorionic gonadotropin (hCG), It stimulates testosterone production from Leydig cells by activating the LH receptor. Therefore, it is a very valuable option, especially in secondary hypogonadism and in men where fertility preservation is important. One of the most important advantages of hCG is that it directly stimulates the testes. Therefore, it can help preserve testicular function while increasing serum testosterone. Gonadotropin therapies have been among the standard approaches for male infertility due to hypogonadotropic hypogonadism for many years [9]. 

A randomized study has shown that both hCG and clomiphene can significantly increase testosterone levels in hypogonadal men [10]. 

2- Clomiphene and EnclomipheneClomiphene citrate (Clomid) is not a classic testosterone replacement drug for use in men. It is a selective estrogen receptor modulator, and its use in men is mostly off-label.

It can increase GnRH, LH, and FSH signaling by reducing estrogen feedback at the hypothalamic level. This gives it the advantage of increasing the testes' own testosterone production while preventing the suppression of spermatogenesis.

This is a very sensible strategy, especially in younger men who are thought to have secondary or functional hypogonadism and who want to preserve their fertility potential. Systematic reviews show that clomiphene can increase testosterone levels and improve clinical symptoms in some men [11]. 

Enclomiphene, is the trans isomer of clomiphene and has been investigated as a more selective SERM approach for male hypogonadism. Recent randomized trial meta-analyses support the fact that clomiphene/enclomiphene treatment can increase total testosterone, LH and FSH [12]. 

3- Peptide Therapies for Muscle Mass It is important not to confuse peptides with testosterone therapy.

CJC-1295, ipamorelin, and similar growth hormone secretagogues/GHRH analogs are not drugs that directly increase testosterone. Their primary effects are on the growth hormone and IGF-1 axis.

Human studies with CJC-1295 in healthy adults have shown a significant and long-lasting increase in GH and IGF-1 levels [13]. Ipamorelin has also shown selective GH-releasing properties in human studies [14]. 

Increasing the GH/IGF-1 axis may have effects on body composition. For example, long-term randomized studies with MK-677, an oral ghrelin mimete, have shown an increase in lean body mass [15]. 

Therefore, the idea of supporting muscle mass, recovery, and anabolic activity through a different hormonal axis is biologically interesting, especially in young, athletic men for whom initiating testosterone replacement is unnecessary or undesirable from a fertility perspective.

However, it is important to clearly define the scientific limits here. There is no strong randomized clinical evidence that CJC-1295 or ipamoreline increases muscle mass in young athletes, resulting in clinically significant increases in testosterone. It would not be accurate to present peptide therapies as a proven alternative to testosterone replacement.

These should be considered primarily as experimental or complementary therapies targeting body composition via the GH/IGF-1 axis in selected patients.

Nutraceutical Approach for Men Who Do Not Want Testosterone Therapy

In men with mild or borderline testosterone deficiency, especially those with lifestyle-modifiable factors, some nutraceutical approaches may be considered before resorting directly to drug therapy.

However, it's important to set expectations correctly: no supplement consistently achieves the testosterone boost that TRT can provide in true hypogonadism. It should be considered more for supporting endogenous production, reducing stress factors, or optimizing mildly low testosterone.

Tongkat Ali

One of the most interesting options in this area is Tongkat Ali (Eurycoma longifolia). In a randomized, double-blind, placebo-controlled study, standardized Eurycoma longifolia extract was used in men aged 50-70 years with testosterone below 300 ng/dL and an increase in total testosterone was shown, especially in the 200 mg/day group [16]. 

A systematic review and meta-analysis of clinical studies also suggests that Tongkat Ali may increase total testosterone in men, with the effect being more pronounced in hypogonadal men [17]. However, the number of studies and sample sizes are still not comparable to the TRT literature. 

Therefore, it wouldn't be accurate to describe Tongkat Ali as "natural testosterone"; however, it could be considered a reasonable supplement for some men with low to normal testosterone levels, especially those who are not yet willing to undergo pharmacological treatment.

Ashwagandha

Ashwagandha (Withania somnifera) için de ilginç insan verileri bulunmaktadır. Overweight, yaşlanmakta olan erkeklerde yapılan randomize, çift kör, crossover bir çalışmada sekiz haftalık ashwagandha kullanımı plaseboya kıyasla testosteronda yaklaşık %14.7 daha fazla artış, DHEA-S’de ise yaklaşık %18 daha fazla artış ile ilişkili bulunmuştur [18]. 

Other studies conducted on men who perform resistance training also show that ashwagandha may have positive effects on muscle mass, muscle strength and testosterone [19]. 

The effect size should not be compared to TRT, but it may be a significant starting point for treatment, particularly in men with high stress levels, poor sleep quality, or borderline testosterone levels.

When a man has low testosterone, the first step shouldn't be simply giving him hormones or adding supplements. Visceral obesity, insulin resistance, severe calorie restriction, insufficient sleep, obstructive sleep apnea, excessive alcohol consumption, opioids, and certain other medications can negatively impact the hypothalamo-pituitary-testicular axis. Correcting these factors can significantly restore testosterone production in some men. It's particularly important to investigate the underlying cause of low testosterone in young men, rather than immediately attributing it to aging or "andropause."

What tests should be done before treatment?

I don't limit the initial assessment in men to just total testosterone measurement. Total testosterone measurements taken in the morning, preferably on different days, form the basis of the assessment. In addition, SHBG and free or calculated free testosterone are quite valuable, especially if total testosterone does not match the clinical picture.

Measurement of LH and FSH helps to determine whether low testosterone is due to primary hypogonadism of testicular origin or secondary hypogonadism originating from the hypothalamus/pituitary gland. Prolactin, estradiol, and DHEA-S can also be added to the evaluation in appropriate patients. In a broader baseline panel, the following parameters are quite valuable:

Total testosterone, free testosterone, SHBG, LH, FSH, estradiol, prolactin, DHEA-S; TSH, fT4 and, if necessary, fT3; complete blood count, especially hemoglobin/hematocrit; fasting glucose, insulin, HOMA-IR and HbA1c; extended lipid profile, ApoB and Lp(a); liver and kidney function tests. PSA and prostate evaluation should also be performed according to age and individual risk profile.

Monitoring hematocrit is particularly important in testosterone therapy because erythrocytosis can develop in some men. Current guidelines also recommend evaluating testosterone, hematocrit and prostate risk in the appropriate age group before and during treatment [6,8]. 

I don't limit hormonal assessment in men to just total or free testosterone measurement. How hormones are metabolized in the body is quite important, especially in terms of estrogen-androgen balance, aromatization tendency, DHT formation, and which metabolic pathways steroid hormones are directed to via the liver.

Therefore, utilizing comprehensive urinary hormone metabolite profiles in patients can provide additional information not shown by serum tests. Such panels can evaluate not only testosterone but also total estrogen load, estrone (E1), estradiol (E2), estriol (E3), 2-hydroxyestrone, 4-hydroxyestrone, 16α-hydroxyestrone, and methoxy-estrogen metabolites. Indicators related to androgen metabolism, such as DHT, androsterone, etiocholanolone, DHEA-S, and 5α-reductase activity, can also be observed. 

This approach is particularly helpful in understanding the existing hormonal balance in men with suspected estrogen dominance or a high tendency towards aromatization before initiating testosterone therapy. Two men with the same serum testosterone level may convert testosterone to DHT or estrogen at significantly different rates. These differences will affect the response to treatment, symptoms, and which method or dose is most appropriate.

Therefore, I consider the hormone metabolite profile not only a diagnostic test but also a baseline for personalizing treatment, better assessing initial risks, and observing how metabolic trends change after treatment. Especially during testosterone therapy, I believe it's crucial to look not only at "has testosterone increased?" but also at where the testosterone goes and how it is metabolized in the body. In the sample report You can view these parameters.

The goal of treatment is not to chase a single number. In men, as in women, hormone therapy should not be reduced to a mere laboratory figure. Testosterone levels should be monitored after treatment begins; however, the success of treatment is not solely determined by an increase in testosterone from 400 to 700 ng/dL. Muscle mass and strength, energy levels, libido, erectile function, sleep, body composition, mental performance, exercise capacity, and overall quality of life should all be considered together.

Simultaneously, hematocrit, estradiol, PSA, and necessary metabolic parameters should be monitored, and treatment should be adjusted according to individual response. Especially in hormone optimization, the fundamental principle is to support physiological levels and not to administer more than is necessary.

***

All information presented here is for general informational and educational purposes only. This content is not intended to diagnose any disease, provide personalized medical assessments, or initiate, modify, or discontinue any treatment.

The information provided does not replace a doctor's examination, personal medical evaluation, or professional healthcare. Because health conditions and treatment needs vary from person to person, it is recommended that you consult your own doctor or relevant healthcare professional before starting any medication, supplement, treatment, or medical practice, or making any changes to your current treatment.

Because medical information and scientific data can change over time, the information presented here should not be assumed to be applicable to every individual or every clinical situation.

I wish you healthy days,

Dr. Ahmet Özyiğit, MD, MSc, PgDip, FAAMM, ABAARM
Longevity Physician

Elite Research and Surgical Hospital

 

References:

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