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Is androgenic alopecia a result of endocrine effects on the vasculature?
Medical Hypotheses (2004) 62, 438–441
http://intl.elsevierhealth.com/journals/mehy
Is androgenic alopecia a result of endocrine effects on the vasculature? B.A. Caleb Santiago Hernandez* College of Osteopathic Medicine, The University of Health Sciences, 1750 Independence Avenue, Kansas City, MO 64106, USA Received 24 June 2003; accepted 10 November 2003
Summary Androgenic alopecia is a condition of concern for many patients. Though much has been learned about this condition, the exact pathophysiological mechanism is yet to be established. Currently most study concerning androgenic alopecia has focused on the effects of androgens on the pilosebaceous unit itself. An area of study that has received considerably less attention is that of androgens inducing baldness by indirect effects, that is, effects on tissues other than the pilosebaceous unit. In this paper, the author offers a novel hypothesis in which androgenic hair loss is mediated via the effects of androgens on the vasculature supplying the scalp. In this new hypothesis androgens effect anatomical changes in the vasculature of susceptible individuals, resulting in an environment in which hair growth is hindered and eventually ceases. The author discusses past studies demonstrating the effects of androgens on vessels and how these effects may relate to anatomical changes in the vasculature leading to hair loss. Also included is a discussion on future experimentation to test this new hypothesis. c 2003 Elsevier Ltd. All rights reserved.
Introduction Androgenic alopecia, also known as male-pattern baldness, is a medical condition important to a large segment of the population experiencing it. Though the condition is mostly cosmetic, it affects the health of those who have it in alternate ways. For example, it is known that balding has an impact on the psyche of those affected by it [1], and psychological issues may have an impact on the physical health of the person [2]. There is also recent discussion of balding being one component of multi-factorial disease syndromes that may include coronary artery disease and other diseases [3]. If a * Present address: 6640 W 80th Circle, Arvada, CO 80003, USA. Tel.: +1-303-710-2055. E-mail address: [email protected] (B.A. Caleb Santiago Hernandez).
relationship between balding and these other conditions is established, research in the pathogenesis of balding may prove useful not only in the treatment of balding, but also the treatment of these more morbid conditions (i.e. coronary artery disease and prostate disease). Though much progress has been made in the understanding of androgenic alopecia (and new treatment options have been developed as a result), the pathogenesis of androgenic alopecia is still not settled [4]. It is currently known that for male pattern baldness to occur there must be both androgens present and a genetic predisposition to balding [5]. It is also known that the conversion of testosterone to dihydrotestosterone (DHT), via the enzyme 5 a-reductase, is involved in the pathogenesis of balding [5]. What has not yet been determined is how DHT effects balding in the susceptible individual [5].
0306-9877/$ - see front matter c 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0306-9877(03)00342-6
Is androgenic alopecia a result of endocrine effects on the vasculature?
The purpose of this essay is to offer a novel hypothesis for the role of DHT in the pathogenesis of balding.
Discussion It is widely accepted that dihydrotestosterone plays a significant role in the pathogenesis of Androgenic alopecia. What escapes current understanding is the mechanism by which dihydrotestosterone causes balding [5]. Much research has focused on the direct effects of DHT on the pilosebaceous unit [6]. What has not been discussed greatly is the possibility of balding being a result of the indirect effects of DHT, in particular its effects on the vasculature supplying the scalp. The focus of this essay is to propose a novel hypothesis involving a physiological mechanism by which DHT exerts its effect on the scalp via structural and anatomical changes on the vasculature. These hypothetical changes result in a reduced blood supply to the scalp, and in time, atrophy of the hair follicle. There are two fundamental premises to this hypothesis: 1. That androgenic alopecia is associated with decreased blood flow and subsequently decreased oxygen delivery to the scalp. 2. Dihydrotestosterone affects the vasculature in such a way as to cause diminished hemodynamic properties and thus diminished blood flow to the target tissues. For the first premise there is already a fair amount of supporting literature and studies. In particular Goldman et al. [7] have observed that men suffering from androgenic alopecia had significantly lower partial pressure of oxygen values (Po2 ) in the areas of their scalp affected by balding versus unaffected areas, when measured using a transcutaneous Po2 sensor. Moreover Goldman et al. observed that when the men with balding were compared to non-bald controls, the balding men had significantly lower Po2 in the areas of balding scalp than the same areas in the non-bald controls [7]. In another study by Klemp et al. [8] subcutaneous blood flow was measured in subjects using a xenon washout method. Klemp and his colleagues observed that the subcutaneous blood flow was significantly lower in balding subjects than in subjects without balding [8]. Another group has taken a different approach to establishing an association between decreased perfusion of the scalp and hair loss. Toshitani et al. [9] developed a device to increase the blood flow and perfusion to the scalp. Subjects‘ cutaneous
439
blood flow rates were measured using laser Doppler flowmetry before and after implementation of the device. Toshitani and his associates observed an increase in cutaneous blood flow, following use of the device. They also observed that subjects using the device obtained a 40% efficacy rate for hair regrowth following long-term use of the device [9]. There are also traditional physiologic observations of ischemia resulting in loss of hair. A good example is the manifestation of vascular insufficiency in the lower extremities as a loss or thinning of the leg hair [10]. It is also noteworthy that researchers have observed a positive correlation between smoking (a known contributor to peripheral vascular disease) and an increased risk for baldness in observational studies [11]. The second premise (that androgens cause changes in the vasculature, which result in narrowing of the vessel lumen and thus a subsequent decrease in tissue perfusion) is now addressed. Although little research has been done in this area there are some studies that demonstrate a relationship between circulating dihydrotestosterone and the vasculature. Studies on baboons by McGill and Sheridan [12] have demonstrated the presence of DHT receptors in the endothelial cells of these animals. Another study by Fujimoto et al. [13] has demonstrated that DHT stimulated the proliferation of vascular smooth muscle cells. Using this information it is logical to propose that if the cells of the internal vascular wall proliferate, the lumen’s cross-sectional area will decrease in size. That is, there is an inverse relation between internal vessel-wall hypertrophy and vessel lumen diameter. A decreased cross-sectional area of the lumen will result in increased resistance to flow and subsequently reduced blood flow. Androgens may also decrease blood flow through the vasculature by a different mechanism as well. Namely, that of increasing platelet aggregation and thus, increasing the likelihood of atherosclerotic plaque formation. Ajayi et al. [14] has observed that young men given replacement doses of testosterone post-orchiectomy demonstrated an increase in platelet aggregation. Increased platelet aggregation increases the likelihood of vessel-lumen narrowing via plaque formation, resulting in diminished blood flow. By combining the information from both premises, a novel hypothesis on the pathogenesis of androgenic alopecia is created. This new hypothesis states that androgenic alopecia is a result of the conversion of testosterone to dihydrotestoterone, via 5 a-reductase. Dihydrotestosterone is then transported to the target organs (in this case the
440
vessels supplying the scalp). Dihydrotestosterone then effects structural and anatomical changes in the vasculature. These changes consist of hypertrophy of the internal vascular walls (i.e. smooth muscle and endothelium) resulting in a reduced lumen size. There is also an increased adhesion capability of the platelets, increasing the likelihood of plaque formation on the vessel walls. Both these changes, over a longitudinal period of time, result in diminished blood flow to the pilosebaceous unit and subsequently diminished hair growth. Just as in many other organ systems, the subsequent decrease in nutrition and oxygen delivery result in atrophy [15]. In this case, atrophy and miniaturization of the hair follicle [16]. There are various possibilities for testing this hypothesis. There is the potential for human studies, where biopsies taken from bald men could be compared to men without baldness (of similar age and level of health) by histological analysis, to determine if there is a significant difference in lumen size and vessel wall thickness between both groups. This can be combined with biochemical studies measuring the amounts of key androgens, androgen receptors, and enzymes (i.e. Dihydrotestosterone, DHT receptor, and 5 a-reductase, etc.) present within both groups. Androgen, androgen receptor, and enzyme levels could then be compared to vessel lumen diameter in both the bald and the non-bald groups to determine if there is a relationship between the concentrations of these bio-chemicals and vessel constitution in bald and non-bald groups of men. Another possibility for study is the use of animal models comparing the vasculature of androgen-sensitive (i.e. androgenically bald) animals to androgen insensitive or possibly castrated (i.e. reduced androgen level) animals. Using this study model, vessel cross-sections could be analyzed between both groups to determine if any significant difference is present between the bald (i.e. androgen affected) and non-bald animal groups. With both study models it would be of great importance to take samples of various vessel types from within the typical area of pattern baldness. This would be advantageous in that it would allow the researcher to determine which vessel type (i.e. medium size arteries or arterioles, etc.) is most affected by androgens.
Conclusion Some researchers have experimented with the hypothesis of vascular insufficiency as a cause of
Caleb Santiago Hernandez
balding [7–9,11]. To the author’s knowledge, none have presented this hypothesis as a mechanism by which androgens effect a state of vascular insufficiency leading to baldness. The author also recognizes that this proposed hypothesis is not mutually exclusive of any direct effects androgens may produce on the pilosebaceous unit itself. In fairness to those who have done research in this area, it is entirely possible that there are endocrine effects at both the pilosebaceous unit and the vasculature, that result in androgenic balding. To conclude, as science advances via collaboration within the scientific community, solutions are being found to common medical problems. As solutions to major problems are found, way is made for another lesser problem to come to the forefront of medical research. Androgenic alopecia is one such problem. It is the hope of the author that the ideas presented in this essay will contribute to the medical debate on this subject, and perhaps give other researchers new ideas for study. “As iron sharpens iron, so one man sharpens another” [17].
References [1] Cash TF, Price VH, Savin RC. The psychological effects of androgenic alopecia in men. J Am Assoc Dermatol 1992;26:926–31. [2] Kumar P, Clark M. Clinical medicine. 5th ed. W.B. Saunders; 2002. p. 1233–4. [3] Lotufo AP, Chae UC, Ajani AU, Hennekens HC, Manson EJ. Male pattern baldness and coronary heart disease – the physicians’ health study. Arch Intern Med 2000;160: 165–71. [4] Hoffmann T, Happle R. Current understanding of androgenic alopecia. Part I: Etiopathogenesis. Eur J Dermatol 2000;10(4):319–27. [5] Sinclair R. Fortnightly review: male pattern androgenic alopecia. Br Med J 1998;317(7162):865–9. [6] Jahoda CAB. Cellular and developmental aspects of androgenic alopecia. Exp Dermatol 1998:235–48. [7] Goldman BE, Fisher DM, Ringler SL. Transcutaneous Po2 of the scalp in male pattern baldness: a new piece in the puzzle. Plast Reconstr Surg 1996;97(6):1109–16. [8] Klemp P, Peters K, Hansted B. Subcutaneous blood flow in early male pattern baldness. J Invest Dermatol 1989; 92(5):725–6. [9] Toshitani S, Nakayama J, Yahata T, Yasuda M, Urabe H. A new apparatus for hair regrowth in male-pattern baldness. J Dermatol 1990;17(4):240–6. [10] Kumar P, Clark M. Clinical medicine. 5th ed. W.B. Saunders; 2002. p. 828. [11] Trueb RM. Association between smoking and hair loss: another opportunity for Health education against smoking? Dermatology 2003;206(3):189–91. [12] Mcgill Jr HC, Sheridan PJ. Nuclear uptake of sex steroid hormones in the cardiovascular system of the baboon. Circ Res 1981;48:238–44.
Is androgenic alopecia a result of endocrine effects on the vasculature?
[13] Fujimoto R, Morimoto I, Morita E, Sujimoto H, Ito Y, Eto S. Androgen receptors, 5 alpha-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells. J Steroid Biochem Mol Biol 1994;50:169–74. [14] Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 1995;91:2742–7.
441
[15] Cotran RS, Kumar V, Collins T. Robbins pathologic basis for disease. 6th ed. W.B. Saunders; 1999. p. 35. [16] Whiting DA. Scalp biopsy as a diagnostic and prognostic tool in androgenic alopecia. Dermatol Ther 1998;8: 24–33. [17] Proverbs 27:17. The Holy Bible, New King James Version. Copyright 1982, Thomas Nelson, Inc.
http://intl.elsevierhealth.com/journals/mehy
Is androgenic alopecia a result of endocrine effects on the vasculature? B.A. Caleb Santiago Hernandez* College of Osteopathic Medicine, The University of Health Sciences, 1750 Independence Avenue, Kansas City, MO 64106, USA Received 24 June 2003; accepted 10 November 2003
Summary Androgenic alopecia is a condition of concern for many patients. Though much has been learned about this condition, the exact pathophysiological mechanism is yet to be established. Currently most study concerning androgenic alopecia has focused on the effects of androgens on the pilosebaceous unit itself. An area of study that has received considerably less attention is that of androgens inducing baldness by indirect effects, that is, effects on tissues other than the pilosebaceous unit. In this paper, the author offers a novel hypothesis in which androgenic hair loss is mediated via the effects of androgens on the vasculature supplying the scalp. In this new hypothesis androgens effect anatomical changes in the vasculature of susceptible individuals, resulting in an environment in which hair growth is hindered and eventually ceases. The author discusses past studies demonstrating the effects of androgens on vessels and how these effects may relate to anatomical changes in the vasculature leading to hair loss. Also included is a discussion on future experimentation to test this new hypothesis. c 2003 Elsevier Ltd. All rights reserved.
Introduction Androgenic alopecia, also known as male-pattern baldness, is a medical condition important to a large segment of the population experiencing it. Though the condition is mostly cosmetic, it affects the health of those who have it in alternate ways. For example, it is known that balding has an impact on the psyche of those affected by it [1], and psychological issues may have an impact on the physical health of the person [2]. There is also recent discussion of balding being one component of multi-factorial disease syndromes that may include coronary artery disease and other diseases [3]. If a * Present address: 6640 W 80th Circle, Arvada, CO 80003, USA. Tel.: +1-303-710-2055. E-mail address: [email protected] (B.A. Caleb Santiago Hernandez).
relationship between balding and these other conditions is established, research in the pathogenesis of balding may prove useful not only in the treatment of balding, but also the treatment of these more morbid conditions (i.e. coronary artery disease and prostate disease). Though much progress has been made in the understanding of androgenic alopecia (and new treatment options have been developed as a result), the pathogenesis of androgenic alopecia is still not settled [4]. It is currently known that for male pattern baldness to occur there must be both androgens present and a genetic predisposition to balding [5]. It is also known that the conversion of testosterone to dihydrotestosterone (DHT), via the enzyme 5 a-reductase, is involved in the pathogenesis of balding [5]. What has not yet been determined is how DHT effects balding in the susceptible individual [5].
0306-9877/$ - see front matter c 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0306-9877(03)00342-6
Is androgenic alopecia a result of endocrine effects on the vasculature?
The purpose of this essay is to offer a novel hypothesis for the role of DHT in the pathogenesis of balding.
Discussion It is widely accepted that dihydrotestosterone plays a significant role in the pathogenesis of Androgenic alopecia. What escapes current understanding is the mechanism by which dihydrotestosterone causes balding [5]. Much research has focused on the direct effects of DHT on the pilosebaceous unit [6]. What has not been discussed greatly is the possibility of balding being a result of the indirect effects of DHT, in particular its effects on the vasculature supplying the scalp. The focus of this essay is to propose a novel hypothesis involving a physiological mechanism by which DHT exerts its effect on the scalp via structural and anatomical changes on the vasculature. These hypothetical changes result in a reduced blood supply to the scalp, and in time, atrophy of the hair follicle. There are two fundamental premises to this hypothesis: 1. That androgenic alopecia is associated with decreased blood flow and subsequently decreased oxygen delivery to the scalp. 2. Dihydrotestosterone affects the vasculature in such a way as to cause diminished hemodynamic properties and thus diminished blood flow to the target tissues. For the first premise there is already a fair amount of supporting literature and studies. In particular Goldman et al. [7] have observed that men suffering from androgenic alopecia had significantly lower partial pressure of oxygen values (Po2 ) in the areas of their scalp affected by balding versus unaffected areas, when measured using a transcutaneous Po2 sensor. Moreover Goldman et al. observed that when the men with balding were compared to non-bald controls, the balding men had significantly lower Po2 in the areas of balding scalp than the same areas in the non-bald controls [7]. In another study by Klemp et al. [8] subcutaneous blood flow was measured in subjects using a xenon washout method. Klemp and his colleagues observed that the subcutaneous blood flow was significantly lower in balding subjects than in subjects without balding [8]. Another group has taken a different approach to establishing an association between decreased perfusion of the scalp and hair loss. Toshitani et al. [9] developed a device to increase the blood flow and perfusion to the scalp. Subjects‘ cutaneous
439
blood flow rates were measured using laser Doppler flowmetry before and after implementation of the device. Toshitani and his associates observed an increase in cutaneous blood flow, following use of the device. They also observed that subjects using the device obtained a 40% efficacy rate for hair regrowth following long-term use of the device [9]. There are also traditional physiologic observations of ischemia resulting in loss of hair. A good example is the manifestation of vascular insufficiency in the lower extremities as a loss or thinning of the leg hair [10]. It is also noteworthy that researchers have observed a positive correlation between smoking (a known contributor to peripheral vascular disease) and an increased risk for baldness in observational studies [11]. The second premise (that androgens cause changes in the vasculature, which result in narrowing of the vessel lumen and thus a subsequent decrease in tissue perfusion) is now addressed. Although little research has been done in this area there are some studies that demonstrate a relationship between circulating dihydrotestosterone and the vasculature. Studies on baboons by McGill and Sheridan [12] have demonstrated the presence of DHT receptors in the endothelial cells of these animals. Another study by Fujimoto et al. [13] has demonstrated that DHT stimulated the proliferation of vascular smooth muscle cells. Using this information it is logical to propose that if the cells of the internal vascular wall proliferate, the lumen’s cross-sectional area will decrease in size. That is, there is an inverse relation between internal vessel-wall hypertrophy and vessel lumen diameter. A decreased cross-sectional area of the lumen will result in increased resistance to flow and subsequently reduced blood flow. Androgens may also decrease blood flow through the vasculature by a different mechanism as well. Namely, that of increasing platelet aggregation and thus, increasing the likelihood of atherosclerotic plaque formation. Ajayi et al. [14] has observed that young men given replacement doses of testosterone post-orchiectomy demonstrated an increase in platelet aggregation. Increased platelet aggregation increases the likelihood of vessel-lumen narrowing via plaque formation, resulting in diminished blood flow. By combining the information from both premises, a novel hypothesis on the pathogenesis of androgenic alopecia is created. This new hypothesis states that androgenic alopecia is a result of the conversion of testosterone to dihydrotestoterone, via 5 a-reductase. Dihydrotestosterone is then transported to the target organs (in this case the
440
vessels supplying the scalp). Dihydrotestosterone then effects structural and anatomical changes in the vasculature. These changes consist of hypertrophy of the internal vascular walls (i.e. smooth muscle and endothelium) resulting in a reduced lumen size. There is also an increased adhesion capability of the platelets, increasing the likelihood of plaque formation on the vessel walls. Both these changes, over a longitudinal period of time, result in diminished blood flow to the pilosebaceous unit and subsequently diminished hair growth. Just as in many other organ systems, the subsequent decrease in nutrition and oxygen delivery result in atrophy [15]. In this case, atrophy and miniaturization of the hair follicle [16]. There are various possibilities for testing this hypothesis. There is the potential for human studies, where biopsies taken from bald men could be compared to men without baldness (of similar age and level of health) by histological analysis, to determine if there is a significant difference in lumen size and vessel wall thickness between both groups. This can be combined with biochemical studies measuring the amounts of key androgens, androgen receptors, and enzymes (i.e. Dihydrotestosterone, DHT receptor, and 5 a-reductase, etc.) present within both groups. Androgen, androgen receptor, and enzyme levels could then be compared to vessel lumen diameter in both the bald and the non-bald groups to determine if there is a relationship between the concentrations of these bio-chemicals and vessel constitution in bald and non-bald groups of men. Another possibility for study is the use of animal models comparing the vasculature of androgen-sensitive (i.e. androgenically bald) animals to androgen insensitive or possibly castrated (i.e. reduced androgen level) animals. Using this study model, vessel cross-sections could be analyzed between both groups to determine if any significant difference is present between the bald (i.e. androgen affected) and non-bald animal groups. With both study models it would be of great importance to take samples of various vessel types from within the typical area of pattern baldness. This would be advantageous in that it would allow the researcher to determine which vessel type (i.e. medium size arteries or arterioles, etc.) is most affected by androgens.
Conclusion Some researchers have experimented with the hypothesis of vascular insufficiency as a cause of
Caleb Santiago Hernandez
balding [7–9,11]. To the author’s knowledge, none have presented this hypothesis as a mechanism by which androgens effect a state of vascular insufficiency leading to baldness. The author also recognizes that this proposed hypothesis is not mutually exclusive of any direct effects androgens may produce on the pilosebaceous unit itself. In fairness to those who have done research in this area, it is entirely possible that there are endocrine effects at both the pilosebaceous unit and the vasculature, that result in androgenic balding. To conclude, as science advances via collaboration within the scientific community, solutions are being found to common medical problems. As solutions to major problems are found, way is made for another lesser problem to come to the forefront of medical research. Androgenic alopecia is one such problem. It is the hope of the author that the ideas presented in this essay will contribute to the medical debate on this subject, and perhaps give other researchers new ideas for study. “As iron sharpens iron, so one man sharpens another” [17].
References [1] Cash TF, Price VH, Savin RC. The psychological effects of androgenic alopecia in men. J Am Assoc Dermatol 1992;26:926–31. [2] Kumar P, Clark M. Clinical medicine. 5th ed. W.B. Saunders; 2002. p. 1233–4. [3] Lotufo AP, Chae UC, Ajani AU, Hennekens HC, Manson EJ. Male pattern baldness and coronary heart disease – the physicians’ health study. Arch Intern Med 2000;160: 165–71. [4] Hoffmann T, Happle R. Current understanding of androgenic alopecia. Part I: Etiopathogenesis. Eur J Dermatol 2000;10(4):319–27. [5] Sinclair R. Fortnightly review: male pattern androgenic alopecia. Br Med J 1998;317(7162):865–9. [6] Jahoda CAB. Cellular and developmental aspects of androgenic alopecia. Exp Dermatol 1998:235–48. [7] Goldman BE, Fisher DM, Ringler SL. Transcutaneous Po2 of the scalp in male pattern baldness: a new piece in the puzzle. Plast Reconstr Surg 1996;97(6):1109–16. [8] Klemp P, Peters K, Hansted B. Subcutaneous blood flow in early male pattern baldness. J Invest Dermatol 1989; 92(5):725–6. [9] Toshitani S, Nakayama J, Yahata T, Yasuda M, Urabe H. A new apparatus for hair regrowth in male-pattern baldness. J Dermatol 1990;17(4):240–6. [10] Kumar P, Clark M. Clinical medicine. 5th ed. W.B. Saunders; 2002. p. 828. [11] Trueb RM. Association between smoking and hair loss: another opportunity for Health education against smoking? Dermatology 2003;206(3):189–91. [12] Mcgill Jr HC, Sheridan PJ. Nuclear uptake of sex steroid hormones in the cardiovascular system of the baboon. Circ Res 1981;48:238–44.
Is androgenic alopecia a result of endocrine effects on the vasculature?
[13] Fujimoto R, Morimoto I, Morita E, Sujimoto H, Ito Y, Eto S. Androgen receptors, 5 alpha-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells. J Steroid Biochem Mol Biol 1994;50:169–74. [14] Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 1995;91:2742–7.
441
[15] Cotran RS, Kumar V, Collins T. Robbins pathologic basis for disease. 6th ed. W.B. Saunders; 1999. p. 35. [16] Whiting DA. Scalp biopsy as a diagnostic and prognostic tool in androgenic alopecia. Dermatol Ther 1998;8: 24–33. [17] Proverbs 27:17. The Holy Bible, New King James Version. Copyright 1982, Thomas Nelson, Inc.