Medical Hypotheses 82 (2014) 428–432
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Increased DHT levels in androgenic alopecia have been selected for to protect men from prostate cancer Shiva Bhargava ⇑ Cornell University, Ithaca, NY, USA
a r t i c l e
i n f o
Article history: Received 9 September 2013 Accepted 18 January 2014
a b s t r a c t Androgenic alopecia, a condition characterized by increased levels of DHT could have been selected for due to the benefits that prostaglandin D2 (PGD2) has on the prostate. A DHT metabolite can increase the transcription of prostaglandin D2 synthase through estrogen receptor beta. The increase of PGD2 can decrease the risk of prostate cancer and proliferation of prostate cancer cells. Therefore, the mechanisms behind male pattern baldness may also curtail the advancement of prostate cancer. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Androgenic alopecia (AGA) is a condition that affects almost 50% of the male population [1,2]. Androgens are known to play a strong role in the etiology of male pattern baldness [3–5]. Androgens bind to the androgen receptor, which serves as a transcription factor that alters gene expression. Recent positive selection of certain androgen receptor gene variants has increased the frequency of male pattern baldness [6]. Androgenic hormones are also involved in prostate growth. This is the reason behind the belief that testosterone levels and prostate growth/prostate cancer genesis are directly correlated. However, increased levels of testosterone has not shown to initiate more prostate growth or prostate cancer growth [6]. Furthermore, high concentrations of androgens may have no effect on increasing androgen receptor activity [7,8]. The active form of testosterone, DHT, when increased, has also been shown to have no initiating effects on prostate cancer [9]. Interestingly, low amounts of testosterone have been associated with prostate cancer [10,11]. It has been proposed that this is because the amount of DHT and testosterone needed to occupy every androgen receptor is well below the physiological amount. Therefore, high androgen levels would not cause a big physiological change, but low levels of androgen hormones can. The enzyme type 2 5-alpha reductase has been the target of medications treating male pattern baldness. This enzyme is the primary enzyme in the formation of DHT from testosterone. One medication, Finasteride, prevents the creation and accumulation of DHT in the scalp by blocking this enzyme. The complete mechanism behind DHT and hair loss is not yet
⇑ Tel.: +1 516 574 3119. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.01.016 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
entirely known, but a recent paper showed that increased levels of prostaglandin D2 (PGD2) in the scalp could be one contributor to hair loss [12]. This increase in PGD2 could result from increased androgen concentrations, since androgens have been shown to stimulate prostaglandin D2 synthase transcription [13,14]. Therefore, part of the missing link between hair loss and DHT is possibly this particular prostaglandin. Finasteride may also inhibit PGD2 indirectly by inhibiting DHT from being formed. Unfortunately, there are conflicting correlations between male pattern baldness and prostate cancer and no direct link has been consistently shown [2,15–21]. Nevertheless, recently, frontal balding at early ages has been consistently linked with lower incidence of prostate cancer and perhaps aggressive prostate cancer [22–24]. This paper will attempt to explain why the mechanisms behind baldness could have evolved to protect men against prostate cancer. Lastly, I suggest that frontal baldness could serve as a signal for women about the protection some men have against prostate cancer and thus their greater suitability as long term mates.
Hypothesis Arachidonic acid is a compound that can be metabolized in several different ways. I will discuss two pathways. One of these pathways has a protective effect on the prostate (prostaglandin D2 pathway), while the other a malignant effect (prostaglandin E2 (PGE2) pathway). The intermediates in this pathway are prostaglandin G2 (PGG2), and prostaglandin H2 (PGH2). High levels of prostaglandin D2 synthase has been shown to inhibit prostate cancer and in the healthy production of ‘‘normal functioning prostate cells’’ [25]. Not only can prostaglandin D2 have beneficial effects in inhibiting prostate cancer but glioma and ovarian cancers as well [25,26]. It could have a protective effect through PGD2’s
S. Bhargava / Medical Hypotheses 82 (2014) 428–432
ability to prevent angiogenesis [27]. Creation of new vasculature helps stabilize and nourish growing tumors. The prostate is one of the few tissues in the body that has the same prostaglandin D2 synthase present in the scalp. Those with male pattern baldness have three times higher amounts of prostaglandin D synthase in the scalp and therefore a higher concentration of prostaglandin D2 [12]. Increased concentrations of this enzyme can encourage the metabolism of arachidonic acid away from harmful pathways and ultimately away from the harmful effects arachidonic acid can have on the prostate. Prostaglandin E2 (the harmful pathway product) can cause the genesis of prostate cancer and growth of prostate cancer cells [28]. Having the opposite effect as PGD2 on the prostate, it makes sense that this prostaglandin has been linked to promote cell proliferation, angiogenesis and inhibit apoptosis [29–31]. If prostaglandin D2 synthase acts upon the arachidonic acid metabolite, more prostaglandin D2 could be created instead of PGE2, thereby indirectly inhibiting the deleterious PGE2 pathway. It has been shown that men who are balding have less PGE2 in their scalp than those who have no baldness due to the increased amount of the PGD2 synthase [12]. Therefore, an increase in androgen receptor or estrogen receptor activity in the scalp and elsewhere, like the prostate, could initiate more PGD2 synthase transcription. The increase in prostaglandin D2 synthase will prevent a large accumulation of PGE2 [12] and the resulting increased likelihood of prostate cancer. On a side note, PGE2 accumulation has shown to have a role in the progression of breast cancer [32]. For an overall picture, please see Fig. 1. DHT could initiate PGD2 production through estrogen receptor beta. The prostate has two estrogen receptors (alpha and beta). The beta receptor has been shown to have antiproliferative effects and is beneficial to prostate health. Interestingly, a metabolite of DHT (3b-Diol (5a-androstan-3b, 17b-diol)) has shown to activate estrogen receptor beta in the prostate and play a large role in halting prostate cancer proliferation and metastasis [33,34]. Therefore, DHT has shown to inhibit prostate cancer with an androgen independent mechanism by binding to estrogen receptor beta [33]. Interestingly, estrogen receptor beta has shown to increase transcription of PGD2 synthase in the mouse heart (see Fig. 2). This enzyme is specifically increased by estrogen receptor beta and not estrogen receptor alpha in vivo [35]. Additionally, the level of Type I 3b-Hydroxysteroid
429
Dehydrogenase is higher in men with androgenic alopecia. It has increased expression specifically at the parieto-frontal and occipital regions of the scalp [36]. This enzyme could result in more DHT being converted to 3b-Diol and more activation of estrogen receptor beta. Of course, this activation of estrogen receptor beta can increase PGD2 in the scalp ultimately resulting in hair loss. Estrogen receptor beta also seems to play a protective role in breast cancer due to its repressive role on estrogen receptor alpha [37]. Discussion Male pattern baldness is considered to result from an abundance of DHT and androgen receptor activity. It is conceivable that increased estrogen receptor activity plays a large role. Nevertheless, although higher amounts of DHT could activate more androgen receptors and estrogen receptors (beta), there are costs. Greater amounts of DHT and androgen receptors in the prostate results in increased prostate growth. Therefore, it is not surprising to learn that baldness is strongly associated with benign prostate hyperplasia, a condition characterized by a large prostate [38–39]. Nevertheless, the larger size of the prostate may be beneficial in the end, even though it can cause BPH. Smaller prostates have been linked with aggressive prostate cancer [40]. Furthermore, higher amounts of circulating androgens has been linked to less aggressive prostate cancer [41]. This information seems to suggest that larger prostates and a high amount of androgen circulation could therefore serve as a protective effect against aggressive prostate cancer. Studies have shown that men diagnosed with male pattern baldness at younger ages (30–40) have a reduced risk of developing prostate cancer [22–24]. This makes sense, since the protective effects I have outlined would be in effect. Patients with late onset male pattern baldness do not have as much of this protective effect. If hair loss at earlier ages is taken as an indication that the biochemical pathways I have delineated are occurring at higher frequencies, then it is clear how less prostate cancer would be observed. Late onset baldness could simply be reflective of earlier senescence or poorer health, and higher rates of prostate cancer and other health related issues would be more likely. The studies that studied the link between age of hair loss and prostate cancer are shown in Table 1.
Fig. 1. The link between DHT and PGD2 and its effects on the prostate.
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S. Bhargava / Medical Hypotheses 82 (2014) 428–432
Fig. 2. Illustrated is the effect of a DHT metabolite (3b-Diol (5a-androstan-3b, 17b-diol)) on estrogen receptor beta expression and the resulting effect on prostaglandin D2 synthase.
Table 1 Correlations between age of onset of different types of baldness, and likelihood of prostate cancer. Study a
1 1 1 1 1 1 2b 2 2 2 2 2 3c 3 a b c
Age
Type of baldness
Likelihood of prostate cancer
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Increased DHT levels in androgenic alopecia have been selected for to protect men from prostate cancer Shiva Bhargava ⇑ Cornell University, Ithaca, NY, USA
a r t i c l e
i n f o
Article history: Received 9 September 2013 Accepted 18 January 2014
a b s t r a c t Androgenic alopecia, a condition characterized by increased levels of DHT could have been selected for due to the benefits that prostaglandin D2 (PGD2) has on the prostate. A DHT metabolite can increase the transcription of prostaglandin D2 synthase through estrogen receptor beta. The increase of PGD2 can decrease the risk of prostate cancer and proliferation of prostate cancer cells. Therefore, the mechanisms behind male pattern baldness may also curtail the advancement of prostate cancer. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Androgenic alopecia (AGA) is a condition that affects almost 50% of the male population [1,2]. Androgens are known to play a strong role in the etiology of male pattern baldness [3–5]. Androgens bind to the androgen receptor, which serves as a transcription factor that alters gene expression. Recent positive selection of certain androgen receptor gene variants has increased the frequency of male pattern baldness [6]. Androgenic hormones are also involved in prostate growth. This is the reason behind the belief that testosterone levels and prostate growth/prostate cancer genesis are directly correlated. However, increased levels of testosterone has not shown to initiate more prostate growth or prostate cancer growth [6]. Furthermore, high concentrations of androgens may have no effect on increasing androgen receptor activity [7,8]. The active form of testosterone, DHT, when increased, has also been shown to have no initiating effects on prostate cancer [9]. Interestingly, low amounts of testosterone have been associated with prostate cancer [10,11]. It has been proposed that this is because the amount of DHT and testosterone needed to occupy every androgen receptor is well below the physiological amount. Therefore, high androgen levels would not cause a big physiological change, but low levels of androgen hormones can. The enzyme type 2 5-alpha reductase has been the target of medications treating male pattern baldness. This enzyme is the primary enzyme in the formation of DHT from testosterone. One medication, Finasteride, prevents the creation and accumulation of DHT in the scalp by blocking this enzyme. The complete mechanism behind DHT and hair loss is not yet
⇑ Tel.: +1 516 574 3119. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.01.016 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
entirely known, but a recent paper showed that increased levels of prostaglandin D2 (PGD2) in the scalp could be one contributor to hair loss [12]. This increase in PGD2 could result from increased androgen concentrations, since androgens have been shown to stimulate prostaglandin D2 synthase transcription [13,14]. Therefore, part of the missing link between hair loss and DHT is possibly this particular prostaglandin. Finasteride may also inhibit PGD2 indirectly by inhibiting DHT from being formed. Unfortunately, there are conflicting correlations between male pattern baldness and prostate cancer and no direct link has been consistently shown [2,15–21]. Nevertheless, recently, frontal balding at early ages has been consistently linked with lower incidence of prostate cancer and perhaps aggressive prostate cancer [22–24]. This paper will attempt to explain why the mechanisms behind baldness could have evolved to protect men against prostate cancer. Lastly, I suggest that frontal baldness could serve as a signal for women about the protection some men have against prostate cancer and thus their greater suitability as long term mates.
Hypothesis Arachidonic acid is a compound that can be metabolized in several different ways. I will discuss two pathways. One of these pathways has a protective effect on the prostate (prostaglandin D2 pathway), while the other a malignant effect (prostaglandin E2 (PGE2) pathway). The intermediates in this pathway are prostaglandin G2 (PGG2), and prostaglandin H2 (PGH2). High levels of prostaglandin D2 synthase has been shown to inhibit prostate cancer and in the healthy production of ‘‘normal functioning prostate cells’’ [25]. Not only can prostaglandin D2 have beneficial effects in inhibiting prostate cancer but glioma and ovarian cancers as well [25,26]. It could have a protective effect through PGD2’s
S. Bhargava / Medical Hypotheses 82 (2014) 428–432
ability to prevent angiogenesis [27]. Creation of new vasculature helps stabilize and nourish growing tumors. The prostate is one of the few tissues in the body that has the same prostaglandin D2 synthase present in the scalp. Those with male pattern baldness have three times higher amounts of prostaglandin D synthase in the scalp and therefore a higher concentration of prostaglandin D2 [12]. Increased concentrations of this enzyme can encourage the metabolism of arachidonic acid away from harmful pathways and ultimately away from the harmful effects arachidonic acid can have on the prostate. Prostaglandin E2 (the harmful pathway product) can cause the genesis of prostate cancer and growth of prostate cancer cells [28]. Having the opposite effect as PGD2 on the prostate, it makes sense that this prostaglandin has been linked to promote cell proliferation, angiogenesis and inhibit apoptosis [29–31]. If prostaglandin D2 synthase acts upon the arachidonic acid metabolite, more prostaglandin D2 could be created instead of PGE2, thereby indirectly inhibiting the deleterious PGE2 pathway. It has been shown that men who are balding have less PGE2 in their scalp than those who have no baldness due to the increased amount of the PGD2 synthase [12]. Therefore, an increase in androgen receptor or estrogen receptor activity in the scalp and elsewhere, like the prostate, could initiate more PGD2 synthase transcription. The increase in prostaglandin D2 synthase will prevent a large accumulation of PGE2 [12] and the resulting increased likelihood of prostate cancer. On a side note, PGE2 accumulation has shown to have a role in the progression of breast cancer [32]. For an overall picture, please see Fig. 1. DHT could initiate PGD2 production through estrogen receptor beta. The prostate has two estrogen receptors (alpha and beta). The beta receptor has been shown to have antiproliferative effects and is beneficial to prostate health. Interestingly, a metabolite of DHT (3b-Diol (5a-androstan-3b, 17b-diol)) has shown to activate estrogen receptor beta in the prostate and play a large role in halting prostate cancer proliferation and metastasis [33,34]. Therefore, DHT has shown to inhibit prostate cancer with an androgen independent mechanism by binding to estrogen receptor beta [33]. Interestingly, estrogen receptor beta has shown to increase transcription of PGD2 synthase in the mouse heart (see Fig. 2). This enzyme is specifically increased by estrogen receptor beta and not estrogen receptor alpha in vivo [35]. Additionally, the level of Type I 3b-Hydroxysteroid
429
Dehydrogenase is higher in men with androgenic alopecia. It has increased expression specifically at the parieto-frontal and occipital regions of the scalp [36]. This enzyme could result in more DHT being converted to 3b-Diol and more activation of estrogen receptor beta. Of course, this activation of estrogen receptor beta can increase PGD2 in the scalp ultimately resulting in hair loss. Estrogen receptor beta also seems to play a protective role in breast cancer due to its repressive role on estrogen receptor alpha [37]. Discussion Male pattern baldness is considered to result from an abundance of DHT and androgen receptor activity. It is conceivable that increased estrogen receptor activity plays a large role. Nevertheless, although higher amounts of DHT could activate more androgen receptors and estrogen receptors (beta), there are costs. Greater amounts of DHT and androgen receptors in the prostate results in increased prostate growth. Therefore, it is not surprising to learn that baldness is strongly associated with benign prostate hyperplasia, a condition characterized by a large prostate [38–39]. Nevertheless, the larger size of the prostate may be beneficial in the end, even though it can cause BPH. Smaller prostates have been linked with aggressive prostate cancer [40]. Furthermore, higher amounts of circulating androgens has been linked to less aggressive prostate cancer [41]. This information seems to suggest that larger prostates and a high amount of androgen circulation could therefore serve as a protective effect against aggressive prostate cancer. Studies have shown that men diagnosed with male pattern baldness at younger ages (30–40) have a reduced risk of developing prostate cancer [22–24]. This makes sense, since the protective effects I have outlined would be in effect. Patients with late onset male pattern baldness do not have as much of this protective effect. If hair loss at earlier ages is taken as an indication that the biochemical pathways I have delineated are occurring at higher frequencies, then it is clear how less prostate cancer would be observed. Late onset baldness could simply be reflective of earlier senescence or poorer health, and higher rates of prostate cancer and other health related issues would be more likely. The studies that studied the link between age of hair loss and prostate cancer are shown in Table 1.
Fig. 1. The link between DHT and PGD2 and its effects on the prostate.
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S. Bhargava / Medical Hypotheses 82 (2014) 428–432
Fig. 2. Illustrated is the effect of a DHT metabolite (3b-Diol (5a-androstan-3b, 17b-diol)) on estrogen receptor beta expression and the resulting effect on prostaglandin D2 synthase.
Table 1 Correlations between age of onset of different types of baldness, and likelihood of prostate cancer. Study a
1 1 1 1 1 1 2b 2 2 2 2 2 3c 3 a b c
Age
Type of baldness
Likelihood of prostate cancer
