madman
Super Moderator
Late-Onset Hypogonadism - New Point of View (2012)
Andrzej Gomuła*
The Andropause Institute, Warsaw, Poland
1. Introduction
Long-term testosterone deficiency related to age may adversely affect the health, anatomy, and physiology of man. The implementation of testosterone boost therapy only at the time, when for many years, as the result of testosterone deficiency, irreversible anatomical changes have occurred, is clearly too late. The age-related progressive decrease in testosterone serum concentration levels causes anatomical and functional abnormalities. It is the cause of lipid disorders; it excarberates type-2 diabetes, it is also the common cause of cardiovascular diseases. It contributes to other health problems such as atherosclerosis, hypertension, osteoporosis, and obesity and it manifests itself by decreased libido and potency. There is also a strong relationship between the age-related decrease in testosterone and Parkinson's disease and Alzheimer's disease. Benign prostatic hyperplasia (BPH) and carcinoma of the prostate are closely associated with testosterone deficiency and comedo-carcinoma — the most malignant form of prostate cancer — is directly proportional to the decrease in serum testosterone. Good therapy for increasing testosterone serum levels can reverse the problems associated with aging such as type-2 diabetes, sexual dysfunction, osteoporosis, hyperlipidemia, and ischemic heart disease. It can even reverse symptoms of Parkinson's disease. Using synthetic testosterone is often recommended in the treatment of testosterone deficiency. Unfortunately, synthetic testosterone can cause side effects such as infertility and long-term use of testosterone may also lead to irreversible testicular atrophy. Therefore, patients receiving long-term testosterone therapy are all dependent on adequate doses of synthetic testosterone until the end of their lives. Meanwhile, intramuscular administration of hCG to stimulate endogenous testosterone synthesis has been known since the 1950s. The induction of endogenous testosterone production by hCG has been effective in all age groups while being safe at the same time. In this paper, the author presents problems caused by testosterone deficiency and outlines the possibility of the treatment, which increases the induction of testosterone endosynthesis by hCG. It has not yet been determined how to diagnose testosterone deficiency. The age-related serum testosterone concentration reference range has not been established yet either. The paper presents the first attempt to establish international standards for testosterone serum concentration levels in different age groups.
2. Late-onset hypogonadism
Testosterone exerts influence on multiple life processes such as blood cell production, bone formation, lipid metabolism, protein metabolism, carbohydrate metabolism, liver function, and spermiogenesis (Gooren, 2000). This can affect the structure and function of many organs in the human body. They include skin, hair, muscle, brain, and bones. It also has a significant effect on fertility and sexual behavior. Testosterone plays a very important role in a man's life. At the mitochondrial level of every single cell, it is the catalyst for protein synthesis. It has an effect on the brain's function, and thus determines the physical and sexual condition. It increases libido and improves sexual potency. It stimulates the immune system and affects multiple metabolic processes. It reduces body fat accumulation. It can affect muscle mass and strength. It increases bone mass and accelerates wound healing. Testosterone is responsible for our memory processes. Computer memory circuits are manufactured using metal arranged on silicon. In the process of human memory, proteins are involved. The testosterone that catalyzes the synthesis of various proteins is also a catalyst for storage protein synthesis. Protein synthesis becomes less efficient with age, proteins formed are unstable. Their decay means that an old man remembers what was years ago and cannot remember what just happened. In the literature, there have been isolated reports about the role of testosterone in the etiology of Alzheimer's disease (Hogervorst, 2004).
Testosterone also aids in immune system protein synthesis, which protects us against infection. Hormone intake in pregnant women during the first trimester of pregnancy significantly affects hormone balance in young men. Although hormone therapy allows the woman to keep her pregnancy from failing, it is also essential for organogenesis, and in particular for the reproductive organs of male fetuses. According to the definition in Standards of Endocrinology, “Testosterone deficit disorder manifests itself in a decrease in libido and potency, in constant fatigue, in deterioration of mood and in sleep quality, in nervousness, in hot flushes, in low testosterone, and in elevated serum gonadotropin concentrations” (Zgliczyński & Zgliczyński, 2002).
2.1 Hypogonadism – Primary, secondary, LOH
2.2 Andropause, ADAM, PADAM, LOH, TDS
2.3 Late-onset hypogonadism and age-related testosterone levels
3. Late-onset hypogonadism and other diseases
3.1 Late-onset hypogonadism is not just testosterone deficiency
So far the aging process and clinical and biochemical changes which cause aging have been linked to a reduction in testosterone concentration. This approach is, however, too simplistic. Testosterone is the direct precursor to estradiol, which is the most potent endogenous estrogen, and to many other hormone derivatives which have a significant impact on the normal structure and on the function of the human body. Therefore therapy to increase testosterone is inextricably linked with estradiol supplementation. Here special attention should be paid to the fact that not all preparations of testosterone can be converted to estradiol and to other derivatives, which makes such supplementation seem not to improve, but, sometimes, to make the situation worse. Estrogen affects the skeletal bone and cardiovascular systems in many radical ways. The decline in estrogen is associated with osteoporosis, premature atherosclerosis, a marked risk of myocardial infarction, and loss of bone mass (Gooren & Bunck, 2004).
While testosterone can act directly on cells, it can also be converted to dihydroxytestosterone (DHT) by 5α-reductase. The same chemical reaction occurs which converts estradiol to 4- hydroxyestradiol. In addition to hormonal effects, this compound has the peculiarity of saturation binding for dopamine receptors widely distributed in the brain. If one compares the chemical structure of dopamine with that of 4-hydroxyestradiol, it is possible to find the key to the dopamine receptor − a benzene ring with two hydroxyl groups attached to the ring − which can be seen in Figure 8.
Dopamine receptors saturation in the human brain has some very important implications of many physiological and pathological states. Dopamine deficiency causes Parkinson's disease. Dopamine plays a crucial role in our mental health. Also, male sexual fitness is closely related to hormonal balance and, especially to dopamine and 4-hydroxyestradiol. Outlined below are some of the entities associated with testosterone deficit or with the deficit of testosterone derivatives.
3.2 Late-onset hypogonadism and type 2 diabetes
3.3 Late-onset hypogonadism and hyperlipidemia
3.4 Late-onset hypogonadism and osteoporosis
3.5 Late-onset hypogonadism, chronic prostatitis, BPH, and prostate cancer
3.5.1 Late-onset hypogonadism, BPH, and chronic prostatitis
3.5.2 LOH and prostate cancer
3.6 Late-onset hypogonadism, sexual drive, potency, and libido
For many years, we have been reassured that only androgens have a key role in both stimulating and maintaining sexual function in men. It was believed that testosterone and the existence of a normal level of libido were inseparably connected (Shabsigh, 2003, Morales, et al., 2004). Nevertheless, sexual dysfunction in men is directly associated not only with testosterone but also with estradiol (E-2) and with other neurohormonal factors. Erectile dysfunction was linked to the development of benign prostatic hyperplasia (BPH), without even taking into account the fact that both benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) were often caused by the hormone deficit. The effects of women's hormone replacement therapy on their psychological and sexual functioning are still the subject of the research in the borderline field between medicine and psychology. Female hormone therapy in treating menopause is common around the world. Meanwhile, several years ago it was stated that the effects of this therapy on men were not known. Hormone replacement therapy for men has been lagging for at least 20 years compared with hormone replacement therapy in women (Tenover, 1999). There is a decline in testosterone production in elderly men that can lead to a decrease in sexual desire (Kaufman & T’Sjoen, 2002). Androgen therapy can stop and even reverse this degenerating process (Hajjar, et al., 1997, Morales, et al., 2004). Information on the importance of testosterone in male sexuality is often divergent. It is known that surgical and pharmacological castration leads to impotence. On the other hand, it is recognized that testosterone deficiency is considered to be of little importance in the development of erectile dysfunction or in the life force. (Anderson, 2003, Montorsi et al., 2003).
There was no sexual orientation change in men who underwent surgical castration. Sexual desire was preserved by the majority of the patients, but interest in sex decreased, which was associated with decreased frequency/intensity of orgasms (Zverina, et al., 1990). Testosterone replacement therapy suitable for men with primary testicular failure as a result of surgery conduces to a return to good sexual health and to good psycho-social outcomes (Fossa, et al., 1999). A drop in men’s testosterone levels results in reduced libido and sexual potency. The implementation of hormonal therapy in hypogonadal men at the time when testosterone levels increase significantly, approaching the upper limit for normal, causes regular nocturnal erections. It also increases the number of spontaneous erections and increases sexual activity (Burries, et al., 1992, Tariq, 2002). Other authors also propose that libido is closely tied to testosterone levels and that hormone replacement therapy increases the frequency of sexual thoughts and significantly improves one's libido (Davidson, et al., 1982, Kwan, et al., 1983). Testosterone induces nitric oxide synthesis in vascular endothelium through its influence on arginase activity. This leads to the opening of vascular pathways; facilitates blood flow into the corpora cavernosa, and enhances penile erection. The same mechanism is used in the treatment of erectile dysfunction (ED) with PDE-5 inhibitors. It is currently the primary means of treating ED.
However, such treatment might not be effective when there is a decrease in male libido (the decrease is one of the symptoms of andropause) as a result of a decrease in the level of testosterone which is a hormone produced in a man's testicles. The occurrence of erectile dysfunction causes an increase in depression. Meanwhile, the treatment of depression through the introduction of SSRIs (selective serotonin reuptake inhibitors) affects the deterioration of erectile function in a secondary way (Hsu & Shen, 1995, Keller, et al., 1997). Thus, Andropause Erectile Dysfunction Treatment and male depression treatment are often ineffective. It is worth remembering, however, that andropause can start from any age but generally around age 30, a relatively young age, when a man still has some 40 years of life. Erectile dysfunction, especially in young men, has not yet been linked with their hormonal status.
I have found that during hormone therapy my patients are affected by changes in their sexual health. A thorough analysis of the problem became the subject of the doctoral dissertation of one of my assistants (Czyżowska, 2009).
My research on 88 men aged 20-68 years, (mean age 45), clearly shows an increase in testosterone endosynthesis at the time of hCG Hormone Therapy, on average from 17.93 nmil/L to 40.86 nmol/L. At the same time, a significant increase in E-2 was found in those examined, on average from 168.72 pmol/L to the value of 332.44 pmol/L. The change in hormone levels of those examined resulted in a significant improvement in their sexual performance, libido, and erectile potency, evaluated using the International Index of Erectile Function (IIEF-5) questionnaire. The average value of IIEF-5 before therapy was 13.4 points (SD = 5.0), and during therapy − 19.88 points (SD = 4.3). The data are shown in numbers in Table 7, and graphically in Figures 21÷22.
As noted above, the serum concentration of E-2 plays a dominant role in male sexual health. Low levels of aromatase, which result in extremely low E-2 concentrations, may, nevertheless, be important in male sexual performance without affecting sexual orientation and gender identity (Gomuła, 2006, Gomuła, 2007). In patients with congenital absence of aromatase only the low-dose E-2 substitution results in significant changes in sexual behavior. Estradiol administration leads to increased erotic fantasies, masturbation, or sexual activity (Carani, et al., 1999).
My own research clearly shows that E-2 is required to maintain sexual functions in adult men (Gomuła, 2007). The manifestations thereof have been observed after prolonged hormonal therapy. Androgen deficiency patients had their testosterone levels increased for therapeutic purposes. During the therapy, a parallel increase occurred in serum E-2 concentrations, as the effect of the all-natural aromatase. Some patients had such high E-2 levels that they exceeded the normal physiological range. In order to reduce E-2 concentration, my patients received preparations blocking aromatase activity. As a result of this therapy, men characterized by high concentrations of testosterone (falling in the upper limits of normal), whose E-2 was detected at very low levels, had a total loss of libido. At the same time, those men suffered from erectile dysfunction, which could even lead to the inability to initiate or maintain an erection. Stopping the drug which blocked aromatase resolved the symptoms and resulted in a rapid return of high concentrations of E-2. Some authors report that in the activation of male sexual behavior the brain level conversion of testosterone to estradiol is of major importance and that testosterone's effects are not in themselves so important (Balthazar & Ball, 1998). Testosterone has a significant effect on the smooth muscle in the corpora cavernosa. Androgens may significantly affect the ultrastructure of the corpora cavernosa and these changes are responsible for erectile dysfunction (Traish & Kim, 2005).
In young men, the ratio between smooth muscle and stroma in the corpus cavernosum is 1:1. Long-term hypogonadism causes the ratio of contents in muscle tissue to be 1:5, which results in smooth muscle atrophy and in fibrotic changes of the corpora cavernosa (Yassin & Treish, 2004).
Fig. 23 represents normal cavernosal histological appearance and its loss as a result of testosterone deficiency, according to Yassin (Yassin & Treish, 2004). Androgen replacement can lead especially in hypogonadism patients to a recovery process within the trabecular tissue. This result means that testosterone therapy supports the “recovery process” not only in striated muscles in the human body /reversible process/ (Yassin & Treish, 2004).
The basic question arises as to what should the first step be in a successful erectile dysfunction prevention and in a successful erectile dysfunction treatment? If the decrease in testosterone leads to penile tissue fibrosis, smooth muscle atrophy in corpora cavernosa, and damage to mechanisms blocking the blood flow from the corpora cavernosa, how do PDE-5 inhibitors pour the proverbial oil on the troubled waters? And at the same time, testosterone restores the penile smooth muscle.
Fig. 23. Aging changes in the cavernosal tissue (Fig. 23-V) can also be induced by androgen deprivation (Fig. 23-E). The ratio of smooth muscle compartment to connective tissue which is normally 1:1 (Fig. 23 C & T) would suffer a shifting till 1:5 (Fig. 23 V & E) with a higher mRNA concentration as an expression of an increasing number of alpha adrenoceptors according to Yassin (Yassin & Treish, 2004).
Testosterone deficiency is closely linked to the reduction in libido. And when one's libido is lowered, the effectiveness of PDE-5 inhibitors is also limited. In such situations, the preventive and curative procedure is to maintain an adequate testosterone level in the body. What is more, in patients receiving PDE-5 inhibitors, the increase in the concentrations of testosterone can improve the penile vascular blood flow, which is yet another argument for using the aforementioned procedure.
It is also known that diabetes can increase the problem of erectile dysfunction. It was previously believed that diabetes leads to lower testosterone levels. In contrast, quite the opposite is happening. A drop in testosterone levels due to a decrease in glucose uptake facilitated by anabolism reduction causes diabetes. Increased levels of testosterone significantly improve glucose tolerance and reduce one's insulin levels and the HbA1c level. Testosterone deficit can thus affect sexuality, both at a particular moment and through changes in metabolic processes leading to vascular lesions. There may also be a significant delay in the increase/drop in testosterone, even for many years, which may lead to erectile dysfunction (Gomuła, 2006). Some argue that the very fact of the occurrence of erectile dysfunction, rather than the testosterone concentration level, is the main indication for hormone replacement (Shabsigh, 2003). But the mechanism of erection is based not only on testosterone levels. It is not based merely on the E-2 either. Because neither testosterone nor E-2 alone determines the adequacy of an erection. If the mechanisms of erection depended on changes in serum testosterone levels, one would have to wait many hours for an erection. Testosterone concentrations and E2 concentration increase as a result of natural endosyntesis. This lasts about 6 hours because that much time elapses from the original signals for spectral contrast in the visual cortex during the first stage of sleep, rapid eye movement (REM). And the highest concentration of testosterone for a man is at approx. 4-5 am, after about six hours of sleep. The mechanisms of erection depend on such factors as the concentration of hormones, but they do not depend on them in a direct way. To obtain or maintain an adequate erection, one needs adequate levels of testosterone and of E-2. Therefore, aromatase, which converts testosterone to E-2, is also essential. Arginase, which induces the synthesis of nitric oxide in vascular endothelial cells, also plays an important role. 4-hydroxyestradiol derivative of estradiol is a substance that at the level of brain activity plays perhaps the most important role therein. 4-hydroxyestradiol has this property that it may saturate dopamine receptors in the brain. At a high saturation level, dopamine stimulates these receptors, causing penile erection. The release of dopamine, which is one of many neurotransmitters, occurs rapidly. These two mechanisms are shown in Figure 24.
Fig. 24. Erection occurs as a result of the involvement of neurotransmitters, secreted at the time counted in seconds, and does not depend on hormonal changes, which can last for hours.
It clearly shows that we need to revise our views on the impact of hormones on our sexuality, potency, and libido, because not just hormones but also brain neurotransmitters have an impact on male sexuality.
3.7 Late-onset hypogonadism and depression
I have observed in my patients a change in their mental condition while they were under hormone therapy. A state of depression transformed itself into a state of joy. This gave enough reason to conduct a thorough analysis of the problem, which turned out to be the topic of the Ph.D. dissertation of one of my assistants (Czyżowska, 2009).
Depression is a serious medical condition where a person may feel “down” or “hopeless” for weeks or more. According to the National Institute of Mental Health, the signs and symptoms of depression include: persistent sad, anxious, or “empty” mood; feelings of hopelessness, pessimism; feelings of guilt, worthlessness, helplessness; loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex; decreased energy, fatigue, being “slowed down”; difficulty concentrating, remembering, making decisions; insomnia, early-morning awakening, or oversleeping; appetite and/or weight loss, or overeating and weight gain; thoughts of death or suicide, suicide attempts; restlessness, irritability; persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain. Treatment of sexual disorders caused by depression with antidepressants based on Selective Serotonin Reuptake Inhibitor (SSRI) has a secondary detrimental effect on erection (Hsu & Shen, 1995, Keller, et al., 1997). It results in a vicious circle – antidepressants increase erection disorders, while sexual life disorders intensify depression. The circle is closed. How can it be broken?
Evidence proving the therapeutical effect of estradiol in depression disorders has been found amongst women, however, the research has not proven explicit relation between the estradiol level and depression among men (Studd & Panay, 2004). Neurosteroids produced in the central nervous system from cholesterol or other steroidal precursors are responsible for direct functioning within the brain, while alterations in their production typical for menopause in women and men cause certain aging symptoms. They directly influence, for example, body temperature regulation (hence the heat waves and cold sweats symptoms), memory function, and emotions. Situational factors experienced by the given person, such as stress, secondarily disturb their secretions of hormones (Carruthers, 2004).
Research results demonstrated that hormone therapy for men, with hCG inducing testosterone endosynthesis causing over a double increase of testosterone and E-2 concentrations, result in substantial improvement of psychological condition and not only relieve depressive states, but also causes a progression from depression to a state of joy in life.
Based on the author’s own research on 88 men aged between 20 and 68 years, (mean age 45 years), during the hormone therapy with hCG testosterone endosynthesis increase was achieved from E-2 average value 168.72 pmol/L up to 332.44 pmol/L. The change of hormonal state of the subjects resulted in substantial improvement of their psychological state assessed on the basis of extended Beck Depression Inventory /BDI/ (Beck, 1967). The classic BDI evaluates exclusively depressive state. Condition above zero is not assessed, only depression is included. Accepting BDI as a good test however not designed to evaluate the joy of life state, I have developed the questionnaire adding reflection towards the opposite direction, i.e. towards the joy of life. Implementing such a tool for analysis of patients’ psychological state enabled the change of hormonal condition to be demonstrated as not only what causes relief from depression, but also progress to the state of joy of life.
Restoring a man’s normal concentration of testosterone and E-2 results in significant improvement of his mental health; depressive states subside. Furthermore, patients who prior to treatments were below state “0”, in depression, during the therapy note states significantly above state “0”; they move to the joy of life state, as presented in Fig. 25.
The facts above presented explicitly demonstrate a close correlation between hormonal and psychological states of man.
3.8 Late-onset hypogonadism and Parkinson's disease
*Parkinson’s disease and hormonal deficiency are inextricably linked. Both men and women suffer from Parkinson's disease because of the deficit of estradiol, and more specifically because of the deficit of 4-hydroxyestradiol (dihydroxyestradiol), which is a derivative of estradiol. The molecular structure drawings, which illustrate how dopamine and 4-hydroxyestradiol are attached to the same key site to dopamine receptor in the brain, as given above, are in subsection 2.1. Late-Onset Hypogonadism is not just testosterone deficiency. And it is only 4- hydroxyestradiol - a chemical compound, which due to its chemical structure, may saturate dopamine E-2 receptors in the brain. Therefore, in the treatment of Parkinson's disease special attention should be paid not only to testosterone levels but particularly to the concentration of E-2. The desirable concentration of E-2 is approximately 250-300 pmol/l. This implies, however, maintaining also excessively high levels of testosterone, which cause hyperactivity in patients. In such cases, apart from hCG injections, I resort to microdoses of transdermal E-2 treatment in order to obtain the desired physiological serum levels of testosterone.
3.9 LOH and mortality & morbidity from coronary artery disease
During the non-invasive therapy of LOH when the increased T concentration levels can be sustained for longer periods. T can not only protect man against atherogenic factors but also may cause long-term coronary dilatation. This is due to testosterone interaction with arginase activity, which results in increased synthesis of nitric oxide in endothelial cells in the entire vascular system. Nitric oxide is a well-known vasodilator, which acts systemically. The synthesis of NO is also used in the treatment of erectile dysfunction (ED) by applying fosfodiesterase 5 inhibitors (PDE-5-I). Interestingly, nowadays these PDE-5 inhibitors become popular as a treatment of choice for some cardiovascular diseases. Large scale clinical studies on long term effects of treatment of LOH with hCG on CAD were not yet reported, but case reports from my colleagues in cardiology who clinically follow some of my patients with exercise tests are positive, including diminishing or disappearance of so-called angina pectoris pain.
3.10 Late-onset hypogonadism and immune resistance
4. The treatment of late-onset hypogonadism
4.1 Late-onset hypogonadism and hCG therapy
The effect of the treatment of 908 patients taking hCG was described in 2010 (Gomula & Rabijewski, 2010). Below, I present a further study of 1200 men (age range 20-89 years; mean, 54). The mean follow-up period of the patients was over 37 months. During the therapy with hCG (2 x 5000 i.u. per week), there was an average increase in serum concentrations of total testosterone from 18.4 nmol/L to 38.59 nmol/L. It was noted that during the hCG therapy, there was no increase in SHBG. On the contrary, the SHBG concentrations even showed a slight decrease. This meant that as the result of hCG treatment, free and bioavailable testosterone concentrations increased. The rise was proportional to that in total testosterone, as was reported (Fiers & Kaufman, 1999). There was an average increase in free testosterone concentrations from 0.0829 ng/mL (1.98%) to 0.201 ng/mL (2.29%) The bio-available testosterone concentration also increased: − on average from 1.94 ng/mL (46.4%) to 4.71 ng /mL (53.6%). At the same time, there was a steady increase in the average concentration of estradiol, from 138.6 pmol/L to 280.9 pmol/L. In parallel, the average PSA level decreased by 40% (from 3.09 ng/mL to 1.83 ng/mL) after 37 months of therapy. These results are shown in Table 9, below.
4.2 LOH and the possibility to restore testosterone endosynthesis
4.3 Late-onset hypogonadism and androversion
5. Conclusions
This has turned out to be the most troublesome section… Not because I had objective problems, no, but because of my ethical issues. Among the authors of LOH therapy guidelines, which were established at international levels, there are my long-time friends. I do not want to upset them because I strongly believe that what they did was acting in good faith, but I cannot exclude the fact that they had been insidiously stimulated by the pharmaceutical industry. Yet, the ultimate aim of a physician’s actions is acting for the good of a patient, so in such context, the friendship takes a second place. Consequently, the conclusions that are listed below are very delicate ethically but unambiguously to the point.
1. There is no doubt now that testosterone deficit, which grows with age, negatively affects the man’s biology in its broad meaning.
2. The own material presented in the paper allows the author to conclude that the minimal reference values for testosterone concentration levels, at which testosterone therapy should be initiated, which are accepted universally so far, are definitely too low.
3. Introducing a therapy to increase testosterone levels only when for many years testosterone deficit has inflicted irreversible anatomical changes, seems to be clearly delayed and is harmful to the man’s health.
4. Applying testosterone replacement therapy to a man with LOH makes sense only when it is impossible to provoke the man’s own testosterone endosynthesis. If a man is still able to rebuild his own testosterone endosynthesis, the treatment with hCG is recommended, otherwise, the testosterone replacement therapy will soon make him infertile. Moreover applying testosterone replacement therapy for a long time will result in testicular atrophy.
5. Consequently, the guidelines and recommendations on LOH treatment should be verified and modified as soon as possible.
Andrzej Gomuła*
The Andropause Institute, Warsaw, Poland
1. Introduction
Long-term testosterone deficiency related to age may adversely affect the health, anatomy, and physiology of man. The implementation of testosterone boost therapy only at the time, when for many years, as the result of testosterone deficiency, irreversible anatomical changes have occurred, is clearly too late. The age-related progressive decrease in testosterone serum concentration levels causes anatomical and functional abnormalities. It is the cause of lipid disorders; it excarberates type-2 diabetes, it is also the common cause of cardiovascular diseases. It contributes to other health problems such as atherosclerosis, hypertension, osteoporosis, and obesity and it manifests itself by decreased libido and potency. There is also a strong relationship between the age-related decrease in testosterone and Parkinson's disease and Alzheimer's disease. Benign prostatic hyperplasia (BPH) and carcinoma of the prostate are closely associated with testosterone deficiency and comedo-carcinoma — the most malignant form of prostate cancer — is directly proportional to the decrease in serum testosterone. Good therapy for increasing testosterone serum levels can reverse the problems associated with aging such as type-2 diabetes, sexual dysfunction, osteoporosis, hyperlipidemia, and ischemic heart disease. It can even reverse symptoms of Parkinson's disease. Using synthetic testosterone is often recommended in the treatment of testosterone deficiency. Unfortunately, synthetic testosterone can cause side effects such as infertility and long-term use of testosterone may also lead to irreversible testicular atrophy. Therefore, patients receiving long-term testosterone therapy are all dependent on adequate doses of synthetic testosterone until the end of their lives. Meanwhile, intramuscular administration of hCG to stimulate endogenous testosterone synthesis has been known since the 1950s. The induction of endogenous testosterone production by hCG has been effective in all age groups while being safe at the same time. In this paper, the author presents problems caused by testosterone deficiency and outlines the possibility of the treatment, which increases the induction of testosterone endosynthesis by hCG. It has not yet been determined how to diagnose testosterone deficiency. The age-related serum testosterone concentration reference range has not been established yet either. The paper presents the first attempt to establish international standards for testosterone serum concentration levels in different age groups.
2. Late-onset hypogonadism
Testosterone exerts influence on multiple life processes such as blood cell production, bone formation, lipid metabolism, protein metabolism, carbohydrate metabolism, liver function, and spermiogenesis (Gooren, 2000). This can affect the structure and function of many organs in the human body. They include skin, hair, muscle, brain, and bones. It also has a significant effect on fertility and sexual behavior. Testosterone plays a very important role in a man's life. At the mitochondrial level of every single cell, it is the catalyst for protein synthesis. It has an effect on the brain's function, and thus determines the physical and sexual condition. It increases libido and improves sexual potency. It stimulates the immune system and affects multiple metabolic processes. It reduces body fat accumulation. It can affect muscle mass and strength. It increases bone mass and accelerates wound healing. Testosterone is responsible for our memory processes. Computer memory circuits are manufactured using metal arranged on silicon. In the process of human memory, proteins are involved. The testosterone that catalyzes the synthesis of various proteins is also a catalyst for storage protein synthesis. Protein synthesis becomes less efficient with age, proteins formed are unstable. Their decay means that an old man remembers what was years ago and cannot remember what just happened. In the literature, there have been isolated reports about the role of testosterone in the etiology of Alzheimer's disease (Hogervorst, 2004).
Testosterone also aids in immune system protein synthesis, which protects us against infection. Hormone intake in pregnant women during the first trimester of pregnancy significantly affects hormone balance in young men. Although hormone therapy allows the woman to keep her pregnancy from failing, it is also essential for organogenesis, and in particular for the reproductive organs of male fetuses. According to the definition in Standards of Endocrinology, “Testosterone deficit disorder manifests itself in a decrease in libido and potency, in constant fatigue, in deterioration of mood and in sleep quality, in nervousness, in hot flushes, in low testosterone, and in elevated serum gonadotropin concentrations” (Zgliczyński & Zgliczyński, 2002).
2.1 Hypogonadism – Primary, secondary, LOH
2.2 Andropause, ADAM, PADAM, LOH, TDS
2.3 Late-onset hypogonadism and age-related testosterone levels
3. Late-onset hypogonadism and other diseases
3.1 Late-onset hypogonadism is not just testosterone deficiency
So far the aging process and clinical and biochemical changes which cause aging have been linked to a reduction in testosterone concentration. This approach is, however, too simplistic. Testosterone is the direct precursor to estradiol, which is the most potent endogenous estrogen, and to many other hormone derivatives which have a significant impact on the normal structure and on the function of the human body. Therefore therapy to increase testosterone is inextricably linked with estradiol supplementation. Here special attention should be paid to the fact that not all preparations of testosterone can be converted to estradiol and to other derivatives, which makes such supplementation seem not to improve, but, sometimes, to make the situation worse. Estrogen affects the skeletal bone and cardiovascular systems in many radical ways. The decline in estrogen is associated with osteoporosis, premature atherosclerosis, a marked risk of myocardial infarction, and loss of bone mass (Gooren & Bunck, 2004).
While testosterone can act directly on cells, it can also be converted to dihydroxytestosterone (DHT) by 5α-reductase. The same chemical reaction occurs which converts estradiol to 4- hydroxyestradiol. In addition to hormonal effects, this compound has the peculiarity of saturation binding for dopamine receptors widely distributed in the brain. If one compares the chemical structure of dopamine with that of 4-hydroxyestradiol, it is possible to find the key to the dopamine receptor − a benzene ring with two hydroxyl groups attached to the ring − which can be seen in Figure 8.
Dopamine receptors saturation in the human brain has some very important implications of many physiological and pathological states. Dopamine deficiency causes Parkinson's disease. Dopamine plays a crucial role in our mental health. Also, male sexual fitness is closely related to hormonal balance and, especially to dopamine and 4-hydroxyestradiol. Outlined below are some of the entities associated with testosterone deficit or with the deficit of testosterone derivatives.
3.2 Late-onset hypogonadism and type 2 diabetes
3.3 Late-onset hypogonadism and hyperlipidemia
3.4 Late-onset hypogonadism and osteoporosis
3.5 Late-onset hypogonadism, chronic prostatitis, BPH, and prostate cancer
3.5.1 Late-onset hypogonadism, BPH, and chronic prostatitis
3.5.2 LOH and prostate cancer
3.6 Late-onset hypogonadism, sexual drive, potency, and libido
For many years, we have been reassured that only androgens have a key role in both stimulating and maintaining sexual function in men. It was believed that testosterone and the existence of a normal level of libido were inseparably connected (Shabsigh, 2003, Morales, et al., 2004). Nevertheless, sexual dysfunction in men is directly associated not only with testosterone but also with estradiol (E-2) and with other neurohormonal factors. Erectile dysfunction was linked to the development of benign prostatic hyperplasia (BPH), without even taking into account the fact that both benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) were often caused by the hormone deficit. The effects of women's hormone replacement therapy on their psychological and sexual functioning are still the subject of the research in the borderline field between medicine and psychology. Female hormone therapy in treating menopause is common around the world. Meanwhile, several years ago it was stated that the effects of this therapy on men were not known. Hormone replacement therapy for men has been lagging for at least 20 years compared with hormone replacement therapy in women (Tenover, 1999). There is a decline in testosterone production in elderly men that can lead to a decrease in sexual desire (Kaufman & T’Sjoen, 2002). Androgen therapy can stop and even reverse this degenerating process (Hajjar, et al., 1997, Morales, et al., 2004). Information on the importance of testosterone in male sexuality is often divergent. It is known that surgical and pharmacological castration leads to impotence. On the other hand, it is recognized that testosterone deficiency is considered to be of little importance in the development of erectile dysfunction or in the life force. (Anderson, 2003, Montorsi et al., 2003).
There was no sexual orientation change in men who underwent surgical castration. Sexual desire was preserved by the majority of the patients, but interest in sex decreased, which was associated with decreased frequency/intensity of orgasms (Zverina, et al., 1990). Testosterone replacement therapy suitable for men with primary testicular failure as a result of surgery conduces to a return to good sexual health and to good psycho-social outcomes (Fossa, et al., 1999). A drop in men’s testosterone levels results in reduced libido and sexual potency. The implementation of hormonal therapy in hypogonadal men at the time when testosterone levels increase significantly, approaching the upper limit for normal, causes regular nocturnal erections. It also increases the number of spontaneous erections and increases sexual activity (Burries, et al., 1992, Tariq, 2002). Other authors also propose that libido is closely tied to testosterone levels and that hormone replacement therapy increases the frequency of sexual thoughts and significantly improves one's libido (Davidson, et al., 1982, Kwan, et al., 1983). Testosterone induces nitric oxide synthesis in vascular endothelium through its influence on arginase activity. This leads to the opening of vascular pathways; facilitates blood flow into the corpora cavernosa, and enhances penile erection. The same mechanism is used in the treatment of erectile dysfunction (ED) with PDE-5 inhibitors. It is currently the primary means of treating ED.
However, such treatment might not be effective when there is a decrease in male libido (the decrease is one of the symptoms of andropause) as a result of a decrease in the level of testosterone which is a hormone produced in a man's testicles. The occurrence of erectile dysfunction causes an increase in depression. Meanwhile, the treatment of depression through the introduction of SSRIs (selective serotonin reuptake inhibitors) affects the deterioration of erectile function in a secondary way (Hsu & Shen, 1995, Keller, et al., 1997). Thus, Andropause Erectile Dysfunction Treatment and male depression treatment are often ineffective. It is worth remembering, however, that andropause can start from any age but generally around age 30, a relatively young age, when a man still has some 40 years of life. Erectile dysfunction, especially in young men, has not yet been linked with their hormonal status.
I have found that during hormone therapy my patients are affected by changes in their sexual health. A thorough analysis of the problem became the subject of the doctoral dissertation of one of my assistants (Czyżowska, 2009).
My research on 88 men aged 20-68 years, (mean age 45), clearly shows an increase in testosterone endosynthesis at the time of hCG Hormone Therapy, on average from 17.93 nmil/L to 40.86 nmol/L. At the same time, a significant increase in E-2 was found in those examined, on average from 168.72 pmol/L to the value of 332.44 pmol/L. The change in hormone levels of those examined resulted in a significant improvement in their sexual performance, libido, and erectile potency, evaluated using the International Index of Erectile Function (IIEF-5) questionnaire. The average value of IIEF-5 before therapy was 13.4 points (SD = 5.0), and during therapy − 19.88 points (SD = 4.3). The data are shown in numbers in Table 7, and graphically in Figures 21÷22.
As noted above, the serum concentration of E-2 plays a dominant role in male sexual health. Low levels of aromatase, which result in extremely low E-2 concentrations, may, nevertheless, be important in male sexual performance without affecting sexual orientation and gender identity (Gomuła, 2006, Gomuła, 2007). In patients with congenital absence of aromatase only the low-dose E-2 substitution results in significant changes in sexual behavior. Estradiol administration leads to increased erotic fantasies, masturbation, or sexual activity (Carani, et al., 1999).
My own research clearly shows that E-2 is required to maintain sexual functions in adult men (Gomuła, 2007). The manifestations thereof have been observed after prolonged hormonal therapy. Androgen deficiency patients had their testosterone levels increased for therapeutic purposes. During the therapy, a parallel increase occurred in serum E-2 concentrations, as the effect of the all-natural aromatase. Some patients had such high E-2 levels that they exceeded the normal physiological range. In order to reduce E-2 concentration, my patients received preparations blocking aromatase activity. As a result of this therapy, men characterized by high concentrations of testosterone (falling in the upper limits of normal), whose E-2 was detected at very low levels, had a total loss of libido. At the same time, those men suffered from erectile dysfunction, which could even lead to the inability to initiate or maintain an erection. Stopping the drug which blocked aromatase resolved the symptoms and resulted in a rapid return of high concentrations of E-2. Some authors report that in the activation of male sexual behavior the brain level conversion of testosterone to estradiol is of major importance and that testosterone's effects are not in themselves so important (Balthazar & Ball, 1998). Testosterone has a significant effect on the smooth muscle in the corpora cavernosa. Androgens may significantly affect the ultrastructure of the corpora cavernosa and these changes are responsible for erectile dysfunction (Traish & Kim, 2005).
In young men, the ratio between smooth muscle and stroma in the corpus cavernosum is 1:1. Long-term hypogonadism causes the ratio of contents in muscle tissue to be 1:5, which results in smooth muscle atrophy and in fibrotic changes of the corpora cavernosa (Yassin & Treish, 2004).
Fig. 23 represents normal cavernosal histological appearance and its loss as a result of testosterone deficiency, according to Yassin (Yassin & Treish, 2004). Androgen replacement can lead especially in hypogonadism patients to a recovery process within the trabecular tissue. This result means that testosterone therapy supports the “recovery process” not only in striated muscles in the human body /reversible process/ (Yassin & Treish, 2004).
The basic question arises as to what should the first step be in a successful erectile dysfunction prevention and in a successful erectile dysfunction treatment? If the decrease in testosterone leads to penile tissue fibrosis, smooth muscle atrophy in corpora cavernosa, and damage to mechanisms blocking the blood flow from the corpora cavernosa, how do PDE-5 inhibitors pour the proverbial oil on the troubled waters? And at the same time, testosterone restores the penile smooth muscle.
Fig. 23. Aging changes in the cavernosal tissue (Fig. 23-V) can also be induced by androgen deprivation (Fig. 23-E). The ratio of smooth muscle compartment to connective tissue which is normally 1:1 (Fig. 23 C & T) would suffer a shifting till 1:5 (Fig. 23 V & E) with a higher mRNA concentration as an expression of an increasing number of alpha adrenoceptors according to Yassin (Yassin & Treish, 2004).
Testosterone deficiency is closely linked to the reduction in libido. And when one's libido is lowered, the effectiveness of PDE-5 inhibitors is also limited. In such situations, the preventive and curative procedure is to maintain an adequate testosterone level in the body. What is more, in patients receiving PDE-5 inhibitors, the increase in the concentrations of testosterone can improve the penile vascular blood flow, which is yet another argument for using the aforementioned procedure.
It is also known that diabetes can increase the problem of erectile dysfunction. It was previously believed that diabetes leads to lower testosterone levels. In contrast, quite the opposite is happening. A drop in testosterone levels due to a decrease in glucose uptake facilitated by anabolism reduction causes diabetes. Increased levels of testosterone significantly improve glucose tolerance and reduce one's insulin levels and the HbA1c level. Testosterone deficit can thus affect sexuality, both at a particular moment and through changes in metabolic processes leading to vascular lesions. There may also be a significant delay in the increase/drop in testosterone, even for many years, which may lead to erectile dysfunction (Gomuła, 2006). Some argue that the very fact of the occurrence of erectile dysfunction, rather than the testosterone concentration level, is the main indication for hormone replacement (Shabsigh, 2003). But the mechanism of erection is based not only on testosterone levels. It is not based merely on the E-2 either. Because neither testosterone nor E-2 alone determines the adequacy of an erection. If the mechanisms of erection depended on changes in serum testosterone levels, one would have to wait many hours for an erection. Testosterone concentrations and E2 concentration increase as a result of natural endosyntesis. This lasts about 6 hours because that much time elapses from the original signals for spectral contrast in the visual cortex during the first stage of sleep, rapid eye movement (REM). And the highest concentration of testosterone for a man is at approx. 4-5 am, after about six hours of sleep. The mechanisms of erection depend on such factors as the concentration of hormones, but they do not depend on them in a direct way. To obtain or maintain an adequate erection, one needs adequate levels of testosterone and of E-2. Therefore, aromatase, which converts testosterone to E-2, is also essential. Arginase, which induces the synthesis of nitric oxide in vascular endothelial cells, also plays an important role. 4-hydroxyestradiol derivative of estradiol is a substance that at the level of brain activity plays perhaps the most important role therein. 4-hydroxyestradiol has this property that it may saturate dopamine receptors in the brain. At a high saturation level, dopamine stimulates these receptors, causing penile erection. The release of dopamine, which is one of many neurotransmitters, occurs rapidly. These two mechanisms are shown in Figure 24.
Fig. 24. Erection occurs as a result of the involvement of neurotransmitters, secreted at the time counted in seconds, and does not depend on hormonal changes, which can last for hours.
It clearly shows that we need to revise our views on the impact of hormones on our sexuality, potency, and libido, because not just hormones but also brain neurotransmitters have an impact on male sexuality.
3.7 Late-onset hypogonadism and depression
I have observed in my patients a change in their mental condition while they were under hormone therapy. A state of depression transformed itself into a state of joy. This gave enough reason to conduct a thorough analysis of the problem, which turned out to be the topic of the Ph.D. dissertation of one of my assistants (Czyżowska, 2009).
Depression is a serious medical condition where a person may feel “down” or “hopeless” for weeks or more. According to the National Institute of Mental Health, the signs and symptoms of depression include: persistent sad, anxious, or “empty” mood; feelings of hopelessness, pessimism; feelings of guilt, worthlessness, helplessness; loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex; decreased energy, fatigue, being “slowed down”; difficulty concentrating, remembering, making decisions; insomnia, early-morning awakening, or oversleeping; appetite and/or weight loss, or overeating and weight gain; thoughts of death or suicide, suicide attempts; restlessness, irritability; persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain. Treatment of sexual disorders caused by depression with antidepressants based on Selective Serotonin Reuptake Inhibitor (SSRI) has a secondary detrimental effect on erection (Hsu & Shen, 1995, Keller, et al., 1997). It results in a vicious circle – antidepressants increase erection disorders, while sexual life disorders intensify depression. The circle is closed. How can it be broken?
Evidence proving the therapeutical effect of estradiol in depression disorders has been found amongst women, however, the research has not proven explicit relation between the estradiol level and depression among men (Studd & Panay, 2004). Neurosteroids produced in the central nervous system from cholesterol or other steroidal precursors are responsible for direct functioning within the brain, while alterations in their production typical for menopause in women and men cause certain aging symptoms. They directly influence, for example, body temperature regulation (hence the heat waves and cold sweats symptoms), memory function, and emotions. Situational factors experienced by the given person, such as stress, secondarily disturb their secretions of hormones (Carruthers, 2004).
Research results demonstrated that hormone therapy for men, with hCG inducing testosterone endosynthesis causing over a double increase of testosterone and E-2 concentrations, result in substantial improvement of psychological condition and not only relieve depressive states, but also causes a progression from depression to a state of joy in life.
Based on the author’s own research on 88 men aged between 20 and 68 years, (mean age 45 years), during the hormone therapy with hCG testosterone endosynthesis increase was achieved from E-2 average value 168.72 pmol/L up to 332.44 pmol/L. The change of hormonal state of the subjects resulted in substantial improvement of their psychological state assessed on the basis of extended Beck Depression Inventory /BDI/ (Beck, 1967). The classic BDI evaluates exclusively depressive state. Condition above zero is not assessed, only depression is included. Accepting BDI as a good test however not designed to evaluate the joy of life state, I have developed the questionnaire adding reflection towards the opposite direction, i.e. towards the joy of life. Implementing such a tool for analysis of patients’ psychological state enabled the change of hormonal condition to be demonstrated as not only what causes relief from depression, but also progress to the state of joy of life.
Restoring a man’s normal concentration of testosterone and E-2 results in significant improvement of his mental health; depressive states subside. Furthermore, patients who prior to treatments were below state “0”, in depression, during the therapy note states significantly above state “0”; they move to the joy of life state, as presented in Fig. 25.
The facts above presented explicitly demonstrate a close correlation between hormonal and psychological states of man.
3.8 Late-onset hypogonadism and Parkinson's disease
*Parkinson’s disease and hormonal deficiency are inextricably linked. Both men and women suffer from Parkinson's disease because of the deficit of estradiol, and more specifically because of the deficit of 4-hydroxyestradiol (dihydroxyestradiol), which is a derivative of estradiol. The molecular structure drawings, which illustrate how dopamine and 4-hydroxyestradiol are attached to the same key site to dopamine receptor in the brain, as given above, are in subsection 2.1. Late-Onset Hypogonadism is not just testosterone deficiency. And it is only 4- hydroxyestradiol - a chemical compound, which due to its chemical structure, may saturate dopamine E-2 receptors in the brain. Therefore, in the treatment of Parkinson's disease special attention should be paid not only to testosterone levels but particularly to the concentration of E-2. The desirable concentration of E-2 is approximately 250-300 pmol/l. This implies, however, maintaining also excessively high levels of testosterone, which cause hyperactivity in patients. In such cases, apart from hCG injections, I resort to microdoses of transdermal E-2 treatment in order to obtain the desired physiological serum levels of testosterone.
3.9 LOH and mortality & morbidity from coronary artery disease
During the non-invasive therapy of LOH when the increased T concentration levels can be sustained for longer periods. T can not only protect man against atherogenic factors but also may cause long-term coronary dilatation. This is due to testosterone interaction with arginase activity, which results in increased synthesis of nitric oxide in endothelial cells in the entire vascular system. Nitric oxide is a well-known vasodilator, which acts systemically. The synthesis of NO is also used in the treatment of erectile dysfunction (ED) by applying fosfodiesterase 5 inhibitors (PDE-5-I). Interestingly, nowadays these PDE-5 inhibitors become popular as a treatment of choice for some cardiovascular diseases. Large scale clinical studies on long term effects of treatment of LOH with hCG on CAD were not yet reported, but case reports from my colleagues in cardiology who clinically follow some of my patients with exercise tests are positive, including diminishing or disappearance of so-called angina pectoris pain.
3.10 Late-onset hypogonadism and immune resistance
4. The treatment of late-onset hypogonadism
4.1 Late-onset hypogonadism and hCG therapy
The effect of the treatment of 908 patients taking hCG was described in 2010 (Gomula & Rabijewski, 2010). Below, I present a further study of 1200 men (age range 20-89 years; mean, 54). The mean follow-up period of the patients was over 37 months. During the therapy with hCG (2 x 5000 i.u. per week), there was an average increase in serum concentrations of total testosterone from 18.4 nmol/L to 38.59 nmol/L. It was noted that during the hCG therapy, there was no increase in SHBG. On the contrary, the SHBG concentrations even showed a slight decrease. This meant that as the result of hCG treatment, free and bioavailable testosterone concentrations increased. The rise was proportional to that in total testosterone, as was reported (Fiers & Kaufman, 1999). There was an average increase in free testosterone concentrations from 0.0829 ng/mL (1.98%) to 0.201 ng/mL (2.29%) The bio-available testosterone concentration also increased: − on average from 1.94 ng/mL (46.4%) to 4.71 ng /mL (53.6%). At the same time, there was a steady increase in the average concentration of estradiol, from 138.6 pmol/L to 280.9 pmol/L. In parallel, the average PSA level decreased by 40% (from 3.09 ng/mL to 1.83 ng/mL) after 37 months of therapy. These results are shown in Table 9, below.
4.2 LOH and the possibility to restore testosterone endosynthesis
4.3 Late-onset hypogonadism and androversion
5. Conclusions
This has turned out to be the most troublesome section… Not because I had objective problems, no, but because of my ethical issues. Among the authors of LOH therapy guidelines, which were established at international levels, there are my long-time friends. I do not want to upset them because I strongly believe that what they did was acting in good faith, but I cannot exclude the fact that they had been insidiously stimulated by the pharmaceutical industry. Yet, the ultimate aim of a physician’s actions is acting for the good of a patient, so in such context, the friendship takes a second place. Consequently, the conclusions that are listed below are very delicate ethically but unambiguously to the point.
1. There is no doubt now that testosterone deficit, which grows with age, negatively affects the man’s biology in its broad meaning.
2. The own material presented in the paper allows the author to conclude that the minimal reference values for testosterone concentration levels, at which testosterone therapy should be initiated, which are accepted universally so far, are definitely too low.
3. Introducing a therapy to increase testosterone levels only when for many years testosterone deficit has inflicted irreversible anatomical changes, seems to be clearly delayed and is harmful to the man’s health.
4. Applying testosterone replacement therapy to a man with LOH makes sense only when it is impossible to provoke the man’s own testosterone endosynthesis. If a man is still able to rebuild his own testosterone endosynthesis, the treatment with hCG is recommended, otherwise, the testosterone replacement therapy will soon make him infertile. Moreover applying testosterone replacement therapy for a long time will result in testicular atrophy.
5. Consequently, the guidelines and recommendations on LOH treatment should be verified and modified as soon as possible.
