- Email: [email protected]
The aging gonad
Molecular and Cellular Endocrinology 202 (2003) 1 /3 www.elsevier.com/locate/mce
The aging gonad Sheldon J. Segal * The Population Council, One Dag Hammarskjold Plaza, New York, NY 10017, USA
Stories about aged fathers are legion. According to the Guinness Book of World Records, Asia’s oldest natural father in 2000 was Hu Chin-yao of Taiwan, a 109-year-old member of the Ami aboriginal tribe. Credibility of such claims aside, the asserted lifetime retention of reproductive potential by the male does not represent a more advanced reproductive system than the female. To the contrary, the male system is an atavistic carry over from our evolutionary past with striking similarities to lower vertebrates, while adaptations in the female reproductive system provide the evolutionary advances needed for our highly successful process of assuring nurture and support for single newborns. The multiplication phase of spermatogonia in the testis is not restricted to fetal life, as is the multiplication phase of oo¨gonia in the ovary of the female. And, unlike the ovary, which has a limited functional span because of the follicle-depleted mechanism of atresia, the testis has no such mechanism to end its gamete production. The testis’ hormone-producing capacity, however, is not as well conserved. With aging, there is a natural depletion of the testosterone-producing Leydig cells and hormone production can be further impaired as a secondary result of other events such as vascular or neural changes that affect the testis, the pituitary, or the hypothalamus. Consequently, there is a gradual decline in testosterone production with age. For total testosterone levels in circulation, this decline is nearly 2% per year starting in men as early as in their fifties, and the percent decline is even higher of free testosterone which is the bioactive component. There can be, therefore, a ‘male menopause,’ or ‘andropause’ but its cause is quite different from the reason for menopause in women. It is not because the gonad reaches a depletion point of no return, as the ovary does in the woman.
* Corresponding author. Tel.: /1-212-339-0500; fax: /1-212-7556052. E-mail address: [email protected] (S.J. Segal).
In place of ‘male menopause’ or ‘andropause,’ most andrologists prefer to use the descriptive phrases partial androgen deficiency in aging men (PADAM) or partial endocrine deficiency (PEDAM) because these terms define more accurately the condition. PEDAM is the more comprehensive of the two because it refers not only to the androgen deficiency that can occur with aging, but also to other endocrine factors as well. Thyroid function, for example, frequently declines with aging, and growth hormone decline is also well known. These changes have not escaped the attention of aging men. It often hits home when friends joke about the midlife crisis, or ‘senior moments’, lack of concentration, nervousness, irritability or tiredness. The characteristics of aging changes in men are not unfamiliar to gynaecologists who help women manage the changes of the menopause. There is a depletion of muscle mass and strength, while deposition of abdominal fat increases. Bone mineral density declines. Hematological changes include a fall in immuno-competent cellular elements and also a decline in the concentration of red blood cells. Androgen deficiency is associated with an increase in sleep disorders, irritability and other mood changes. Some claim that it is also linked to memory loss and other cognitive functions. As both the production and availability of biologically active androgens decrease, there is a fall in sexual interest and libido. There is no single cause for these changes. While it is a delusion to think they can be put off indefinitely by so simple a solution as testosterone supplementation, this does not mean that falling hormone levels are unimportant. I have selected a few of the themes that I believe would be of interest. First a brief comment on the demography of aging, particularly as it affects Japan. Then an update on the remarkable increase in interest in testosterone supplementation therapy (TST) for men in the United States. Some comments on the perceived benefits and risks of self-treatment with so-called nutritional supplements such as DHEA and ANDRO, and finally a status report on the first designer androgen
0303-7207/03/$ - see front matter # 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0303-7207(03)00053-4
2
S.J. Segal / Molecular and Cellular Endocrinology 202 (2003) 1 /3
in clinical trials for male HRT, or the term I prefer */ hormone supplementation therapy (HST). The world is aging. In the first half of this century the percent of population over 65 will rise in virtually all countries. By mid-century, Japan will have the highest proportion of population in this dependency age group. This shift, as the size of the labor force declines, will have significant policy implications. Japan will have to reconsider such social issues as retirement age, the role of women in the labor force, immigration, health-care costs, and the role of the family in the care of the elderly. Turning next to the rising use of HST in the United States. There was a fourfold increase between 1999 and 2001, with much of the increase accounted for by prescriptions written for complaints of aging. A new product, Androgel, has dominated the market since its introduction in the year 2000. Within the first year after being introduced the transdermal gel quickly took over the lion’s share of the market, becoming a $100 million a year product in a market that had been relatively small, previously. It is a clear, colorless, quick-drying gel containing 1% testosterone by weight. It is applied on the skin of the torso (not the scrotum) in quantities that contain 50, 75 or 100 mg of testosterone. The skin serves as a reservoir for the sustained release of testosterone into the general circulation within 30 min. Daily applications establish a steady state within 24/48 h, and maintain testosterone blood levels within the normal range for many months. More recent data show that use of the gel continues to grow. Through March of 2002, prescriptions written almost doubled in 14 months and sales of the product reached the level of about $150 million per year. Turning now to perceived benefits and risks. The strongest evidence in support of claimed benefits comes from the finding that testosterone treatment can reverse many of the age-related changes. As illustrations, I have selected examples that have been quantified by measurable endpoints, using random-assignment, double-blind studies that meet the criteria of evidence-based medicine. Testosterone supplementation in older men can arrest the loss of muscle and prevent increase in body fat. Statistically significant increase in lean body mass of elderly men has been shown for supplementation therapy delivered by patch, or gel. The decline in body fat is also significant. The treatment was also effective in raising bone density. The average of about 3% over 36 months may not seem impressive, but the response differs depending on the basal testosterone level. The lower the level to begin with, the greater the response. Thus, men with a starting point of 100 ng/dl, well below normal, experience an almost 10% increase in bone density. Since we know from experience in women that every 2% increase in bone density can bring a 10%
reduction in fall and fracture rate, this outcome can be of major significance for men subject to the fracture risk of old-age frailty. Men with normal T levels to begin with showed no evidence of significant enhancement in bone mineral density. This is not surprising, since it would be unreasonable to expect therapy to make normal men, ‘more normal.’ There are, of course, cautions arising from risks that may be associated with HST for men. Most prominent among these is prostate stimulation. Treatments that create supraphysiological levels of T are certainly contra-indicated for aging men, but the risk is considerably reduced with modalities that maintain levels of T within normal limits. After all, current thinking in urology is to give men a choice of watchful waiting, without interfering with testicular function either surgically or chemically, even after finding a positive biopsy for prostate cancer. It is logically consistent to accept exogenous therapy that keeps T levels within limits that could be expected with endogenous production. Cardiovascular effects are being re-evaluated since many studies have shown that men on HST have a favorable shift in HDL to LDL cholesterol ratio, reduction in triglycerides, and reduction in the severity of coronary artery disease. Although counter-intuitive, these data are beginning to capture the interest of cardiologists. Concern about hepatotoxicity is a carry over from experience with 17-alkylated derivatives that were created for oral use. This concern need not apply to modalities that avoid the first pass to the liver, such as transdermal products and testosterone undecanoate, which, although taken orally, bypasses the liver by absorption through the lymphatic system. Polycythemia has been a very rare observation in men on T therapy and can easily be avoided by monitoring the hematocrit. An unexplained but measurable increase in episodes of sleep apnea has been recording for men on TST. It suggests that men on therapy should be evaluated for pulmonary obstructive disease. Self-treatment with testosterone precursors or metabolites, particularly among athletes and body builders, has sky-rocketed in the United States, and probably in other countries, as well. It is estimated that over-thecounter sales of products like DHEA or ANDRO are 4 /5 times higher than prescription sales of all androgen supplements combined. After the disclosure by baseball star Mark McGuire that he had been using ANDRO as a nutritional supplement, several studies were undertaken which have failed to demonstrate scientifically the benefits that athletes believe that they get from these substances, at least at the recommended doses. At the recommended dose for androstenedione (ASD), for example, 300 mg/day, it is possible to
S.J. Segal / Molecular and Cellular Endocrinology 202 (2003) 1 /3
demonstrate an increase in circulating ASD levels, but the effect on total testosterone level was negligible. There is, however, a report on the beneficial effect of DHEA on actual athletic performance. In this case the performance measured is the shot put, a sport that requires upper body strength, which is a particular function of testosterone stimulation. However, this case is drawn from the experience of the East German women’s Olympic team. It is questionable that the same could be shown for a eugonadal male athlete. Finally, some thoughts about a designer androgen. If you want to design an ideal androgen for HST the first objective would be to avoid the risk of prostate stimulation while maintaining the benefits of androgenic and anabolic supplementation therapy. We know that stimulation of the prostate is the result of the conversion of testosterone to dihydrotestosterone by 5-alpha reductase, an enzyme that is present in high concentration in prostate tissue. You would, therefore, want a molecule that is protected from 5-alpha reduction but will still retain its affinity for androgen receptors in other tissues. In other words, you would want an
3
anabolic agent with selective androgenic activity, excluding the prostate. This turns out to be possible by adding a 7-methyl group on 19-nor testosterone. The result is a considerably lower stimulation of the prostate, while the anabolic activity is not lost. Considerable pre-clinical and toxicity testing has been done with MENT, and clinical studies using an implant delivery system. Rights to the compound have been acquired by Schering AG, of Berlin which is now proceeding with its development as a transdermal gel for treatment of hypogonadism and the complaints of aging. Its status was updated by the Company at its annual press conference in March, 2002. In conclusion, maintaining muscle mass and strength, and preventing the heart-stressing deposition of abdominal fat are good reasons for aging men to consider addback therapy. In addition, evidence of other benefits including bone mineral conservation encourages use of HST for androgen deficiency in aging men. When serum testosterone levels do not exceed the physiologically normal range, for most men with androgen deficiency, the benefits of HST outweigh the risks.
The aging gonad Sheldon J. Segal * The Population Council, One Dag Hammarskjold Plaza, New York, NY 10017, USA
Stories about aged fathers are legion. According to the Guinness Book of World Records, Asia’s oldest natural father in 2000 was Hu Chin-yao of Taiwan, a 109-year-old member of the Ami aboriginal tribe. Credibility of such claims aside, the asserted lifetime retention of reproductive potential by the male does not represent a more advanced reproductive system than the female. To the contrary, the male system is an atavistic carry over from our evolutionary past with striking similarities to lower vertebrates, while adaptations in the female reproductive system provide the evolutionary advances needed for our highly successful process of assuring nurture and support for single newborns. The multiplication phase of spermatogonia in the testis is not restricted to fetal life, as is the multiplication phase of oo¨gonia in the ovary of the female. And, unlike the ovary, which has a limited functional span because of the follicle-depleted mechanism of atresia, the testis has no such mechanism to end its gamete production. The testis’ hormone-producing capacity, however, is not as well conserved. With aging, there is a natural depletion of the testosterone-producing Leydig cells and hormone production can be further impaired as a secondary result of other events such as vascular or neural changes that affect the testis, the pituitary, or the hypothalamus. Consequently, there is a gradual decline in testosterone production with age. For total testosterone levels in circulation, this decline is nearly 2% per year starting in men as early as in their fifties, and the percent decline is even higher of free testosterone which is the bioactive component. There can be, therefore, a ‘male menopause,’ or ‘andropause’ but its cause is quite different from the reason for menopause in women. It is not because the gonad reaches a depletion point of no return, as the ovary does in the woman.
* Corresponding author. Tel.: /1-212-339-0500; fax: /1-212-7556052. E-mail address: [email protected] (S.J. Segal).
In place of ‘male menopause’ or ‘andropause,’ most andrologists prefer to use the descriptive phrases partial androgen deficiency in aging men (PADAM) or partial endocrine deficiency (PEDAM) because these terms define more accurately the condition. PEDAM is the more comprehensive of the two because it refers not only to the androgen deficiency that can occur with aging, but also to other endocrine factors as well. Thyroid function, for example, frequently declines with aging, and growth hormone decline is also well known. These changes have not escaped the attention of aging men. It often hits home when friends joke about the midlife crisis, or ‘senior moments’, lack of concentration, nervousness, irritability or tiredness. The characteristics of aging changes in men are not unfamiliar to gynaecologists who help women manage the changes of the menopause. There is a depletion of muscle mass and strength, while deposition of abdominal fat increases. Bone mineral density declines. Hematological changes include a fall in immuno-competent cellular elements and also a decline in the concentration of red blood cells. Androgen deficiency is associated with an increase in sleep disorders, irritability and other mood changes. Some claim that it is also linked to memory loss and other cognitive functions. As both the production and availability of biologically active androgens decrease, there is a fall in sexual interest and libido. There is no single cause for these changes. While it is a delusion to think they can be put off indefinitely by so simple a solution as testosterone supplementation, this does not mean that falling hormone levels are unimportant. I have selected a few of the themes that I believe would be of interest. First a brief comment on the demography of aging, particularly as it affects Japan. Then an update on the remarkable increase in interest in testosterone supplementation therapy (TST) for men in the United States. Some comments on the perceived benefits and risks of self-treatment with so-called nutritional supplements such as DHEA and ANDRO, and finally a status report on the first designer androgen
0303-7207/03/$ - see front matter # 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0303-7207(03)00053-4
2
S.J. Segal / Molecular and Cellular Endocrinology 202 (2003) 1 /3
in clinical trials for male HRT, or the term I prefer */ hormone supplementation therapy (HST). The world is aging. In the first half of this century the percent of population over 65 will rise in virtually all countries. By mid-century, Japan will have the highest proportion of population in this dependency age group. This shift, as the size of the labor force declines, will have significant policy implications. Japan will have to reconsider such social issues as retirement age, the role of women in the labor force, immigration, health-care costs, and the role of the family in the care of the elderly. Turning next to the rising use of HST in the United States. There was a fourfold increase between 1999 and 2001, with much of the increase accounted for by prescriptions written for complaints of aging. A new product, Androgel, has dominated the market since its introduction in the year 2000. Within the first year after being introduced the transdermal gel quickly took over the lion’s share of the market, becoming a $100 million a year product in a market that had been relatively small, previously. It is a clear, colorless, quick-drying gel containing 1% testosterone by weight. It is applied on the skin of the torso (not the scrotum) in quantities that contain 50, 75 or 100 mg of testosterone. The skin serves as a reservoir for the sustained release of testosterone into the general circulation within 30 min. Daily applications establish a steady state within 24/48 h, and maintain testosterone blood levels within the normal range for many months. More recent data show that use of the gel continues to grow. Through March of 2002, prescriptions written almost doubled in 14 months and sales of the product reached the level of about $150 million per year. Turning now to perceived benefits and risks. The strongest evidence in support of claimed benefits comes from the finding that testosterone treatment can reverse many of the age-related changes. As illustrations, I have selected examples that have been quantified by measurable endpoints, using random-assignment, double-blind studies that meet the criteria of evidence-based medicine. Testosterone supplementation in older men can arrest the loss of muscle and prevent increase in body fat. Statistically significant increase in lean body mass of elderly men has been shown for supplementation therapy delivered by patch, or gel. The decline in body fat is also significant. The treatment was also effective in raising bone density. The average of about 3% over 36 months may not seem impressive, but the response differs depending on the basal testosterone level. The lower the level to begin with, the greater the response. Thus, men with a starting point of 100 ng/dl, well below normal, experience an almost 10% increase in bone density. Since we know from experience in women that every 2% increase in bone density can bring a 10%
reduction in fall and fracture rate, this outcome can be of major significance for men subject to the fracture risk of old-age frailty. Men with normal T levels to begin with showed no evidence of significant enhancement in bone mineral density. This is not surprising, since it would be unreasonable to expect therapy to make normal men, ‘more normal.’ There are, of course, cautions arising from risks that may be associated with HST for men. Most prominent among these is prostate stimulation. Treatments that create supraphysiological levels of T are certainly contra-indicated for aging men, but the risk is considerably reduced with modalities that maintain levels of T within normal limits. After all, current thinking in urology is to give men a choice of watchful waiting, without interfering with testicular function either surgically or chemically, even after finding a positive biopsy for prostate cancer. It is logically consistent to accept exogenous therapy that keeps T levels within limits that could be expected with endogenous production. Cardiovascular effects are being re-evaluated since many studies have shown that men on HST have a favorable shift in HDL to LDL cholesterol ratio, reduction in triglycerides, and reduction in the severity of coronary artery disease. Although counter-intuitive, these data are beginning to capture the interest of cardiologists. Concern about hepatotoxicity is a carry over from experience with 17-alkylated derivatives that were created for oral use. This concern need not apply to modalities that avoid the first pass to the liver, such as transdermal products and testosterone undecanoate, which, although taken orally, bypasses the liver by absorption through the lymphatic system. Polycythemia has been a very rare observation in men on T therapy and can easily be avoided by monitoring the hematocrit. An unexplained but measurable increase in episodes of sleep apnea has been recording for men on TST. It suggests that men on therapy should be evaluated for pulmonary obstructive disease. Self-treatment with testosterone precursors or metabolites, particularly among athletes and body builders, has sky-rocketed in the United States, and probably in other countries, as well. It is estimated that over-thecounter sales of products like DHEA or ANDRO are 4 /5 times higher than prescription sales of all androgen supplements combined. After the disclosure by baseball star Mark McGuire that he had been using ANDRO as a nutritional supplement, several studies were undertaken which have failed to demonstrate scientifically the benefits that athletes believe that they get from these substances, at least at the recommended doses. At the recommended dose for androstenedione (ASD), for example, 300 mg/day, it is possible to
S.J. Segal / Molecular and Cellular Endocrinology 202 (2003) 1 /3
demonstrate an increase in circulating ASD levels, but the effect on total testosterone level was negligible. There is, however, a report on the beneficial effect of DHEA on actual athletic performance. In this case the performance measured is the shot put, a sport that requires upper body strength, which is a particular function of testosterone stimulation. However, this case is drawn from the experience of the East German women’s Olympic team. It is questionable that the same could be shown for a eugonadal male athlete. Finally, some thoughts about a designer androgen. If you want to design an ideal androgen for HST the first objective would be to avoid the risk of prostate stimulation while maintaining the benefits of androgenic and anabolic supplementation therapy. We know that stimulation of the prostate is the result of the conversion of testosterone to dihydrotestosterone by 5-alpha reductase, an enzyme that is present in high concentration in prostate tissue. You would, therefore, want a molecule that is protected from 5-alpha reduction but will still retain its affinity for androgen receptors in other tissues. In other words, you would want an
3
anabolic agent with selective androgenic activity, excluding the prostate. This turns out to be possible by adding a 7-methyl group on 19-nor testosterone. The result is a considerably lower stimulation of the prostate, while the anabolic activity is not lost. Considerable pre-clinical and toxicity testing has been done with MENT, and clinical studies using an implant delivery system. Rights to the compound have been acquired by Schering AG, of Berlin which is now proceeding with its development as a transdermal gel for treatment of hypogonadism and the complaints of aging. Its status was updated by the Company at its annual press conference in March, 2002. In conclusion, maintaining muscle mass and strength, and preventing the heart-stressing deposition of abdominal fat are good reasons for aging men to consider addback therapy. In addition, evidence of other benefits including bone mineral conservation encourages use of HST for androgen deficiency in aging men. When serum testosterone levels do not exceed the physiologically normal range, for most men with androgen deficiency, the benefits of HST outweigh the risks.