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Castration increases and androgens decrease nitric oxide synthase activity in the brain: Physiologic implications
Abstract
Sex differences in nitric oxide synthase (NOS) activity in different regions of the rat brain and effects of testosterone and dihydrotestosterone (DHT) treatment in orchidectomized animals were investigated. Regional but no sex differences in NOS activity were detected in gonadectomized animals. Orchidectomy significantly increased NOS activity in the hypothalamus, “amygdala,†and cerebellum but not in the cortex. In the hypothalamus, the increase in NOS activity after castration and its reversal by androgen treatment was mimicked by changes in neuronal NOS mRNA level. In contrast, androgen receptor (AR) mRNA level in the hypothalamus was slightly reduced by castration and increased by treatment with DHT. Again in the hypothalamus, the increase in NOS activity in castrated rats was accompanied by an increase in the number of neuronal NOS+ cells determined immunohistochemically, whereas androgen treatment prevented this increase. The changes in NOS+ neurons correlated with the changes in the number of AR+ cells to a degree. Overlap of AR in NOS+ cells was not present in the regions of the hypothalamus analyzed. These results indicate that testosterone or, most likely, its metabolite DHT down-regulates NOS activity, mRNA expression or stabilization, and the number of neuronal NOS+ neurons
Baldness and Nitric Oxide
Well, there is at least one factor that androgenic baldness and Alzheimer’s disease have in common: atherosclerosis. The lining of blood vessels produces nitric oxide ('NO', as in MiNOxidol, the active ingredient in Rogaine) and possibly other hair growth factors; when this lining is damaged through the accumulation of atherosclerotic plaque, less nitric oxide (NO) is produced.
Please don’t draw the wrong conclusion that a balding man is doomed to go on to Alzheimer’s disease or Parkinson’s. Like most men, he’ll probably die of heart disease, which is a much better way to die. Also, 40% of men die before their 75th birthday, which also helps account for the lower rate of brain disease in the male population. Still, what happens in the scalp of a balding person (including inflammation and free-radical damage) does seem to bear resemblance to what probably goes on in the brain tissue of brain-disease victims.
The incidence of male pattern (androgenic) baldness has been found to be the highest among college professors, and lowest among skid-row winos. Winos are also known to have the cleanest arteries in the world (which of course doesn’t save them from dying of cirrhosis of the liver). Could there be a connection? Let me remind you that alcohol is an excellent vasodilator -- there is perhaps nothing quite like alcohol for dilating those peripheral blood vessels. And vasodilatation implies nitric oxide release. (I’m not recommending that anyone take up drinking. For years now I’ve been haunted by the question of whether it’s possible to duplicate the benefits of alcohol in a non-alcoholic way, which would be vastly preferable. For women, estrogens seem to do something very similar, but what about men?)
For unknown reasons, androgenic baldness is more common among blond men than dark-haired men and among Caucasians than among other races. First of all, however, we need to address the most obvious question: why is baldness so prevalent among men, and relatively rare among women, especially premenopausal women?
We need to look here at how hormones affect hair. Estrogens promote the growth of scalp hair, while they inhibit the growth of hair elsewhere on the body; DHT, the strong form of testosterone, promotes the growth of body hair, facial hair, but—it appears to inhibit the growth of scalp hair. The amount of DHT produced in the skin in turn depends on the amount of the enzyme 5-alpha-reductase available for the conversion of testosterone to DHT. Men with congenital deficiency of 5-alpha-reductase have small prostates, do not develop prostate cancer (no case has ever been reported), have little body hair, and do not grow bald.
Women often notice increased hair loss when there is a sudden drop in estrogens: post-partum, after stopping the Pill, and at the onset of menopause. It is estimated that a woman may lose as much as 20% of her hair at menopause. Both post-partum and menopausal hair loss, however, are not classified as androgenic alopecia, but as "endocrine alopecia," which should really be called "estrogen-withdrawal alopecia."
Severely hyperandrogenic women, on the other hand, can suffer from male pattern baldness even at a young age. Still, a woman can be hyperandrogenic without necessarily showing signs of androgenic alopecia, but she may have acne and increased facial and body hair. Or a woman can have androgenic alopecia without acne and/or hirsutism. This seems to be a highly individual matter.
Typically, however, it is men who start losing hair fairly early in life, sometimes already in their twenties. Men produce a lot more DHT than women do, since obviously men produce a lot more testosterone than women do (DHEA can also serve as a raw material for DHT). But it’s not the serum level of DHT that seems to matter, but the local conversion of androgens to DHT in the scalp.
Let me stress this point: it is the LOCAL excess DHT production that seems to be the root of the problem. THE SCALP FOLLICLES OF GENETICALLY SUSCEPTIBLE INDIVIDUALS HAVE MORE OF THE ENZYME 5-ALPHA-REDUCTASE, RESPONSIBLE FOR THE CONVERSION OF TESTOSTERONE TO DHT. Most women are protected by having (1) less testosterone, (2) less 5-alpha-reductase needed to convert T to DHT, and also (3) by having more aromatase, the enzyme that converts testosterone to estradiol.
It is interesting to note that male teenagers and young men, with their tremendously high testosterone output (T production begins to decline very gradually after the age of 25) tend to have a full head of hair but generally not that much chest hair and facial hair. On the other hand, it’s not unusual to see lots of chest hair and a full flowing beard on a severely balding middle-aged man. Apparently the local production of DHT, perhaps as compensation for low serum androgens, is a significant factor here. We do not yet understand how serum DHT and peripheral DHT are related, but one hypothesis is that there is an inverse relationship. It’s just a hypothesis. Estrogens are vasodilators: they promote the release of NO from the blood vessel lining. It’s also possible that estrogens increase superoxide dismutase (SOD) activity (at least that’s one of the effects of the birth-control pill). SOD quenches the superoxide radical, a very nasty little beastie that apparently inhibits NO release.
DHT acts in a more perfidious way. Here is one emerging view of it: DHT seems to induce class-II antigens within the follicle. The immune system then perceives the follicle as a "foreign body," and targets it for destruction. Progesterone inhibits 5-alpha-reductase, and it can compete with other androgens for androgen receptors (progesterone could be classified as a "non-masculinizing androgen"). Topical progesterone can thus arrest the progression of baldness, but it doesn’t promote regrowth. I repeat: there is no evidence that progesterone promotes regrowth. Just decreasing DHT in the scalp can at best arrest the progression of baldness. Proscar (finasteride) also decreases DHT by inhibiting 5-alpha-reductase. Proscar produces close to 70% reduction in serum DHT, but only about 34% reduction in skin DHT. Still, virtually all men taking Proscar (5 mg finasteride) report that the progression of baldness is arrested. But is a big reduction of serum DHT beneficial, or can it in fact be harmful? (Hint: DHT can’t be aromatized to estradiol, and estradiol has been implicated in prostate cancer. We discuss it later in this issue—see the comment by Dr. Zava.)
CORTISOL and cortisone, the so-called "stress hormones," are also androgens and are possibly implicated in baldness. We know for sure that they are involved in acne. Anecdotally, stress is known to cause hair loss. One study (Schmidt 1994) did find SIGNIFICANTLY ELEVATED CORTISOL IN ANDROGENIC ALOPECIANS, BOTH MALE AND FEMALE, as compared with controls. It also found alopecians to have significantly elevated androstenedione. In women there was also very frequent hypothyroidism and/or elevated prolactin (it’s possible that prolactin stimulates the production of androgens). Balding men, on the other hand, had higher serum estradiol than controls.
Schmidt makes a very big point of the finding that women suffering from androgenic alopecia do not necessarily have higher serum androgens (other than cortisol, generally not classified as an androgen, though it should be). She thinks that THE MAIN HORMONAL DISTURBANCE LINKED TO FEMALE ALOPECIA IS HYPOTHYROIDISM. It’s likely that hypothyroidism leads to abnormalities in both estrogen and androgen metabolism. I’m amazed that this study didn’t look at insulin, since elevated insulin has been linked to alopecia in hyperandrogenic women. Anecdotally, lowering insulin with drugs and/or diet does seem to improve hair growth in both men and women.
As you can see, the situation gets more and more complicated the more hormones you look at. Finally you just want to throw up your hands and say, "OK, it looks like all the hormones are out of whack." To put it more formally, androgenic alopecia is a multi-hormonal disorder. You can’t just say "too much DHT."
Malnutrition and stress can obviously cause hair loss, but it appears that the primary causes are genetic-hormonal-immunological and vascular (it’s not really possible to separate the endocrine system from the immune system from the nervous system and so forth). In other words, to preserve our hair, we must keep DHT and cortisol at bay and strive to preserve clean arteries. But see the mite article below for yet another complication. On a personal note, I noticed both hair loss and a distinct deterioration in hair quality during perimenopause. (Interestingly, my cholesterol suddenly began to soar.) I was beginning to have nightmares about developing a bald spot (I should have been having nightmares about getting a heart attack, but you know how it’s only human to worry more about appearance than about dying). You can imagine how thrilled I was to see complete recovery with the use of nhrt (my cholesterol dropped to 170 also). In fact I am now more bushy-maned than I had ever been after turning 40 (at least until several days ago, when my dieting, aspartame-crazed hair-dresser took out her aggression on my hair).
Of course what is easy for a woman with no special genetic susceptibility and with access to sufficient doses of female hormones is not easy for a man, or even for a woman with a genetic susceptibility. Later in this issue we’ll discuss what can be done.
For the easy cases, that is, women with some typical menopausal hair loss, here is what you need to remember: estrogens, fish oil, the flavonoids in red wine, and arginine are NO-releasers, and hence at least theoretically can stimulate hair growth. The best proven case here is estrogens. Progesterone inhibits the conversion of testosterone to DHT, so it is helpful also. Finally, topical NO-releasers are available in special shampoos. With this hormonal, nutritional, and topical arsenal, you should be able to regrow and maintain a magnificent head of hair. Night-night, and don’t let the androgens bite.
(Sources: Schmidt JB. Hormonal basis of male and female androgenic alopecia.
Skin Pharmacol 1994; 7: 61-66; Van Deusen E. What you can do about baldness. Stein and Day 1978; Jaworsky C, Klingman AM. Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis. Br J Dermatol 1992;127: 239-46; Mercutio M. Androgenic alopecia in women. Medscape/women’s health 12/7/97; Rittmaster R. 5-Alpha-reductase inhibitors. J Androl 1997; 18: 582-87; Proctor P, alopecia post on the Internet, 1997. An important part of the research was supplied by Starla Taliaferro.)
Abstract
Sex differences in nitric oxide synthase (NOS) activity in different regions of the rat brain and effects of testosterone and dihydrotestosterone (DHT) treatment in orchidectomized animals were investigated. Regional but no sex differences in NOS activity were detected in gonadectomized animals. Orchidectomy significantly increased NOS activity in the hypothalamus, “amygdala,†and cerebellum but not in the cortex. In the hypothalamus, the increase in NOS activity after castration and its reversal by androgen treatment was mimicked by changes in neuronal NOS mRNA level. In contrast, androgen receptor (AR) mRNA level in the hypothalamus was slightly reduced by castration and increased by treatment with DHT. Again in the hypothalamus, the increase in NOS activity in castrated rats was accompanied by an increase in the number of neuronal NOS+ cells determined immunohistochemically, whereas androgen treatment prevented this increase. The changes in NOS+ neurons correlated with the changes in the number of AR+ cells to a degree. Overlap of AR in NOS+ cells was not present in the regions of the hypothalamus analyzed. These results indicate that testosterone or, most likely, its metabolite DHT down-regulates NOS activity, mRNA expression or stabilization, and the number of neuronal NOS+ neurons
Baldness and Nitric Oxide
Well, there is at least one factor that androgenic baldness and Alzheimer’s disease have in common: atherosclerosis. The lining of blood vessels produces nitric oxide ('NO', as in MiNOxidol, the active ingredient in Rogaine) and possibly other hair growth factors; when this lining is damaged through the accumulation of atherosclerotic plaque, less nitric oxide (NO) is produced.
Please don’t draw the wrong conclusion that a balding man is doomed to go on to Alzheimer’s disease or Parkinson’s. Like most men, he’ll probably die of heart disease, which is a much better way to die. Also, 40% of men die before their 75th birthday, which also helps account for the lower rate of brain disease in the male population. Still, what happens in the scalp of a balding person (including inflammation and free-radical damage) does seem to bear resemblance to what probably goes on in the brain tissue of brain-disease victims.
The incidence of male pattern (androgenic) baldness has been found to be the highest among college professors, and lowest among skid-row winos. Winos are also known to have the cleanest arteries in the world (which of course doesn’t save them from dying of cirrhosis of the liver). Could there be a connection? Let me remind you that alcohol is an excellent vasodilator -- there is perhaps nothing quite like alcohol for dilating those peripheral blood vessels. And vasodilatation implies nitric oxide release. (I’m not recommending that anyone take up drinking. For years now I’ve been haunted by the question of whether it’s possible to duplicate the benefits of alcohol in a non-alcoholic way, which would be vastly preferable. For women, estrogens seem to do something very similar, but what about men?)
For unknown reasons, androgenic baldness is more common among blond men than dark-haired men and among Caucasians than among other races. First of all, however, we need to address the most obvious question: why is baldness so prevalent among men, and relatively rare among women, especially premenopausal women?
We need to look here at how hormones affect hair. Estrogens promote the growth of scalp hair, while they inhibit the growth of hair elsewhere on the body; DHT, the strong form of testosterone, promotes the growth of body hair, facial hair, but—it appears to inhibit the growth of scalp hair. The amount of DHT produced in the skin in turn depends on the amount of the enzyme 5-alpha-reductase available for the conversion of testosterone to DHT. Men with congenital deficiency of 5-alpha-reductase have small prostates, do not develop prostate cancer (no case has ever been reported), have little body hair, and do not grow bald.
Women often notice increased hair loss when there is a sudden drop in estrogens: post-partum, after stopping the Pill, and at the onset of menopause. It is estimated that a woman may lose as much as 20% of her hair at menopause. Both post-partum and menopausal hair loss, however, are not classified as androgenic alopecia, but as "endocrine alopecia," which should really be called "estrogen-withdrawal alopecia."
Severely hyperandrogenic women, on the other hand, can suffer from male pattern baldness even at a young age. Still, a woman can be hyperandrogenic without necessarily showing signs of androgenic alopecia, but she may have acne and increased facial and body hair. Or a woman can have androgenic alopecia without acne and/or hirsutism. This seems to be a highly individual matter.
Typically, however, it is men who start losing hair fairly early in life, sometimes already in their twenties. Men produce a lot more DHT than women do, since obviously men produce a lot more testosterone than women do (DHEA can also serve as a raw material for DHT). But it’s not the serum level of DHT that seems to matter, but the local conversion of androgens to DHT in the scalp.
Let me stress this point: it is the LOCAL excess DHT production that seems to be the root of the problem. THE SCALP FOLLICLES OF GENETICALLY SUSCEPTIBLE INDIVIDUALS HAVE MORE OF THE ENZYME 5-ALPHA-REDUCTASE, RESPONSIBLE FOR THE CONVERSION OF TESTOSTERONE TO DHT. Most women are protected by having (1) less testosterone, (2) less 5-alpha-reductase needed to convert T to DHT, and also (3) by having more aromatase, the enzyme that converts testosterone to estradiol.
It is interesting to note that male teenagers and young men, with their tremendously high testosterone output (T production begins to decline very gradually after the age of 25) tend to have a full head of hair but generally not that much chest hair and facial hair. On the other hand, it’s not unusual to see lots of chest hair and a full flowing beard on a severely balding middle-aged man. Apparently the local production of DHT, perhaps as compensation for low serum androgens, is a significant factor here. We do not yet understand how serum DHT and peripheral DHT are related, but one hypothesis is that there is an inverse relationship. It’s just a hypothesis. Estrogens are vasodilators: they promote the release of NO from the blood vessel lining. It’s also possible that estrogens increase superoxide dismutase (SOD) activity (at least that’s one of the effects of the birth-control pill). SOD quenches the superoxide radical, a very nasty little beastie that apparently inhibits NO release.
DHT acts in a more perfidious way. Here is one emerging view of it: DHT seems to induce class-II antigens within the follicle. The immune system then perceives the follicle as a "foreign body," and targets it for destruction. Progesterone inhibits 5-alpha-reductase, and it can compete with other androgens for androgen receptors (progesterone could be classified as a "non-masculinizing androgen"). Topical progesterone can thus arrest the progression of baldness, but it doesn’t promote regrowth. I repeat: there is no evidence that progesterone promotes regrowth. Just decreasing DHT in the scalp can at best arrest the progression of baldness. Proscar (finasteride) also decreases DHT by inhibiting 5-alpha-reductase. Proscar produces close to 70% reduction in serum DHT, but only about 34% reduction in skin DHT. Still, virtually all men taking Proscar (5 mg finasteride) report that the progression of baldness is arrested. But is a big reduction of serum DHT beneficial, or can it in fact be harmful? (Hint: DHT can’t be aromatized to estradiol, and estradiol has been implicated in prostate cancer. We discuss it later in this issue—see the comment by Dr. Zava.)
CORTISOL and cortisone, the so-called "stress hormones," are also androgens and are possibly implicated in baldness. We know for sure that they are involved in acne. Anecdotally, stress is known to cause hair loss. One study (Schmidt 1994) did find SIGNIFICANTLY ELEVATED CORTISOL IN ANDROGENIC ALOPECIANS, BOTH MALE AND FEMALE, as compared with controls. It also found alopecians to have significantly elevated androstenedione. In women there was also very frequent hypothyroidism and/or elevated prolactin (it’s possible that prolactin stimulates the production of androgens). Balding men, on the other hand, had higher serum estradiol than controls.
Schmidt makes a very big point of the finding that women suffering from androgenic alopecia do not necessarily have higher serum androgens (other than cortisol, generally not classified as an androgen, though it should be). She thinks that THE MAIN HORMONAL DISTURBANCE LINKED TO FEMALE ALOPECIA IS HYPOTHYROIDISM. It’s likely that hypothyroidism leads to abnormalities in both estrogen and androgen metabolism. I’m amazed that this study didn’t look at insulin, since elevated insulin has been linked to alopecia in hyperandrogenic women. Anecdotally, lowering insulin with drugs and/or diet does seem to improve hair growth in both men and women.
As you can see, the situation gets more and more complicated the more hormones you look at. Finally you just want to throw up your hands and say, "OK, it looks like all the hormones are out of whack." To put it more formally, androgenic alopecia is a multi-hormonal disorder. You can’t just say "too much DHT."
Malnutrition and stress can obviously cause hair loss, but it appears that the primary causes are genetic-hormonal-immunological and vascular (it’s not really possible to separate the endocrine system from the immune system from the nervous system and so forth). In other words, to preserve our hair, we must keep DHT and cortisol at bay and strive to preserve clean arteries. But see the mite article below for yet another complication. On a personal note, I noticed both hair loss and a distinct deterioration in hair quality during perimenopause. (Interestingly, my cholesterol suddenly began to soar.) I was beginning to have nightmares about developing a bald spot (I should have been having nightmares about getting a heart attack, but you know how it’s only human to worry more about appearance than about dying). You can imagine how thrilled I was to see complete recovery with the use of nhrt (my cholesterol dropped to 170 also). In fact I am now more bushy-maned than I had ever been after turning 40 (at least until several days ago, when my dieting, aspartame-crazed hair-dresser took out her aggression on my hair).
Of course what is easy for a woman with no special genetic susceptibility and with access to sufficient doses of female hormones is not easy for a man, or even for a woman with a genetic susceptibility. Later in this issue we’ll discuss what can be done.
For the easy cases, that is, women with some typical menopausal hair loss, here is what you need to remember: estrogens, fish oil, the flavonoids in red wine, and arginine are NO-releasers, and hence at least theoretically can stimulate hair growth. The best proven case here is estrogens. Progesterone inhibits the conversion of testosterone to DHT, so it is helpful also. Finally, topical NO-releasers are available in special shampoos. With this hormonal, nutritional, and topical arsenal, you should be able to regrow and maintain a magnificent head of hair. Night-night, and don’t let the androgens bite.
(Sources: Schmidt JB. Hormonal basis of male and female androgenic alopecia.
Skin Pharmacol 1994; 7: 61-66; Van Deusen E. What you can do about baldness. Stein and Day 1978; Jaworsky C, Klingman AM. Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis. Br J Dermatol 1992;127: 239-46; Mercutio M. Androgenic alopecia in women. Medscape/women’s health 12/7/97; Rittmaster R. 5-Alpha-reductase inhibitors. J Androl 1997; 18: 582-87; Proctor P, alopecia post on the Internet, 1997. An important part of the research was supplied by Starla Taliaferro.)
