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Bromocriptine for Weight Loss
by Nandi
Introduction
Bromocriptine, a drug that mimics the action of the naturally occurring neurotransmitter dopamine, has a long history of use by body builders and life extension enthusiasts. The drug originally gained popularity due to its reputation for acting as a mild growth hormone secretagogue. This is paradoxical, since in people suffering from acromegaly, or growth hormone excess, bromocriptine has the opposite effect: it actually lowers GH levels. Bromocriptine has a number of other legitimate medical uses, including treatment of Parkinson's Disease and the lowering of prolactin levels in people suffering from prolactin secreting tumors. It has also been used successfully to treat hyperprolactinemia (elevated prolactin) that often occurs as a side effect of the administration of antipsychotic medications.
Bromocriptine and Weight Loss
Lately however, bromocriptine has gained prominence particularly on the World Wide Web as a weight loss agent. Perhaps no single person is more responsible for this resurgence of interest in the drug than Lyle McDonald, who popularized its anti-obesity properties in his recently published e-book (1). There are studies both in animals (2) and humans (3),(4) that support the ability of bromocriptine to reduce weight and body fat. The exact mechanism whereby dopaminergic agonists induce weight loss has not been elucidated.
Studies in animals have shown mixed effects of dopaminergic agonists on lipid metabolism. When dopamine and SKF 38393, a D2 receptor agonist were administered to genetically obese mice, antilipogenic effects were observed in the liver, but a combination of both lipolytic and antilipolytic effects were demonstrated in adipose tissue. In adipose tissue lipoprotein lipase activity was decreased (an antilipogenic effect) where as beta-agonist stimulated lipolysis was decreased (5). Additionally, obese mice treated with dopaminergic agonists also exhibited reduced de novo lipogenesis (2). This is the process whereby dietary carbohydrates are converted to fat. Interestingly, while de novo lipogenesis is important in animals, its contribution to fat deposition in humans is relatively unimportant (6). When humans ingest excess carbohydrates, rather than being stored as fat, the carbohydrates are preferentially used as fuel, preserving fat stores that would have otherwise been oxidized. Here is a case where the results of animal studies do not necessarily carry the same implications for humans.
Dopamine has also been implicated in appetite control. It has been postulated that dopamine modulates appetite by providing a reward stimulus, and that obese individuals have lower levels of dopamine receptors in certain portions of the brain (7). Hence to achieve the same "reward" from eating as normal individuals, obese individuals must eat more. This would provide some rationale for the treatment of obese individuals with dopaminergic agonists, but it is unclear whether normal body weight individuals possessing a normal density of dopamine receptors and/or normal dopaminergic activity in the brain would benefit from such treatment. The authors of the previously cited paper also acknowledged that it was unclear whether the relative paucity of dopamine receptors in the obese subjects was a cause or a result of their overeating. Since eating elevates dopamine levels, the brain could be compensating for elevated dopamine in chronic overeaters by downregulating the dopamine receptors. This latter possibility could call into question the use of dopaminergic agonists for appetite control. The result of increasing dopamine levels with agonists could lead to a further downregulation of the D2 receptors, leading to an increased desire to eat in order to further elevate dopamine levels. In a review of the above-cited study, Dr. Joseph Frascella of NIDA’s [National Institute of Drug Abuse] Division of Treatment Research commented on this positve feedback effect on D2 receptor downregulation:
“This deficiency could be a double-edged sword that cuts both ways. First, the reduced reward experienced by people with this deficiency may make them more likely to engage in addictive behaviors. Then, the addictive behavior itself could make the deficit worse as the brain further lowers D2 levels in response to constant overstimulation of the reward pathway. “In the end, they could be much worse off biologically than when they started,”
http://www.drugabuse.gov/NIDA_Notes...thological.html
Another mechanism by which dopamine could suppress appetite is by antagonizing neuropeptide Y (NPY). As fat stores decrease during dieting, leptin levels fall. This signals an increase in NPY, which is a potent hunger inducing neuropeptide. Treatment of genetically obese mice with bromocriptine led to a decrease in the elevated levels of hypothalamic NPY in these animals (2). Again, the implications of these observations to normal humans are unclear.
Both obesity and cocaine addiction have been linked to the dopaminergic reward pathway. As we have been discussing, food consumption elevates dopamine level, leading to a reward stimulus. In the case of cocaine, the traditional view has been that cocaine blocks the cellular dopamine transporter, blocking dopamine reuptake and increasing extracellular dopamine levels, again leading to reinforcing reward. However, this view has been called into question by the 1998 publication of a study showing that mice lacking the dopamine transporter develop cocaine addiction (8). According to the dopamine reward model of cocaine addiction, the lack of the dopamine transporter should have maintained chronically elevated dopamine levels, obviating any reward derived from cocaine use. Nevertheless the mice became addicted. The authors suggested that other neurotransmitter pathways, such as those mediated by serotonin may play a more important role in addiction. These ideas are supported by the fact that dopaminergic agonists, including bromocriptine, have not been useful in treating cocaine addiction (9).
Is it possible that the food driven reward mechanism is also dopamine independent, or at least only partially dependent on dopamine? The successful use of fenfluramine as an anorectic agent suggests this could be the case. Fenfluramine stimulates the release of serotonin and is a potent reuptake inhibitor of serotonin into nerve endings. This increases levels of serotonin in the nerve synapse, increasing levels of serotonergic nerve transmission. In both animals and humans, fenfluramine induces lack of appetite leading to weight loss. Fenfluramine was withdrawn from the market in 1997 due to findings that its use was associated with valvular heart disease.
Side Effects of Bromocriptine Treatment
As with the majority of drugs bromocriptine has a number of well characterized side effects that seem more unpleasant than dangerous, and often abate during treatment. These include nausea, orthostatic hypotension, headaches, abdominal discomfort, nasal congestion, fatigue and constipation. Besides these there are two other potential side effects that are not as well characterized, that are controversial, and that are of particular interest to bodybuilders and other athletes. The first I would like to address is the possibility that bromocriptine may lower testosterone levels in normal men, as well as increase the ovarian aromatization of testosterone to estrogen in women. The second is the potential bromocriptine may have to suppress the immune system in normal humans.
Bromocriptine and Steroidgenesis
It has been appreciated for decades that elevated levels of prolactin in males (hyperprolactinemia) can suppress testosterone production. Hyperprolactinemia disrupts the hypothalamic-pituitary-gonadal axis in women as well, leading to amenorrhea and infertility. Since bromocriptine lowers prolactin levels, when bromocriptine is administered to these patients, normal sexual function is usually restored. What is less well known is that studies done both in vitro and in humans suggest that hypoprolactinemia (low prolactin levels) also leads to suppressed testosterone production. So prolactin appears to exert a biphasic effect: too much or too little can disrupt testicular function. Normal physiological levels of prolactin appear to be necessary for normal gonadal function. (10) (11). To quote from Marin-Lopez et al, (10), where sulpiride and bromocriptine were used respectively to induce hyper and hypoprolactinemia in normal males
"the hyperprolactinemia induced a low basal level of testosterone with a higher response of this steroid to hCG...while the loss of the trophic effect of prolactin on gonadal steroidogenesis, as seen in hypoprolactinemia produces a decrease of basal testosterone levels without any alteration of the response of this steroid to hCG. We conclude that prolactin plays an important role in the steroidogenesis of Leydig cells in normal men.'' (11)
Confusing the issue is the fact that several other studies both in vitro and in vivo have shown either no effect or an increase in testosterone production due to both prolactin and bromocriptine administration (12) (13).
A number of experimental observations have led to several theories that could possibly explain how bromocriptine induced hypoprolactinemia suppresses testosterone production. Kovacevic and Sarac (14) proposed that bromocriptine competitively inhibits androgen production at the level of the testicular enzymes 17 alpha-hydroxylase and/or 17,20-lyase. These enzymes act at intermediate steps in the testicular production of testosterone. Aisaka et al. observed a decrease in luteinizing hormone (LH) levels that was mirrored by a decrease in testosterone after bromocriptine administration, suggesting that bromocriptine directly inhibits LH secretion from the pituitary (15). As we know, luteinizing hormone, or LH, secreted from the pituitary gland acts directly on testicular Leydig cells to stimulate testosterone secretion.
On the other hand Suescun et al. observed a decrease in circulating testosterone after bromocriptine administration in men with no decrease in LH levels (16), consistent with a direct testicular action of bromocriptine, as proposed by Kovacevic.
Other studies have shown that lowering prolactin decreases the binding of LH to the Leydig cell LH receptor, with a concomittent reduction in androgen production (17). These researchers concluded that
These results suggest that under normal conditions, endogenous prolactin plays a key role in maintaining the functional integrity of rat Leydig cells." (16)
So perhaps by either lowering the affinity of the LH receptor to LH, or by directly decreasing LH receptor number, bromocriptine could lower testosterone production.
As is obvious from the conflicting studies, and the variety of proposed mechanisms for bromocriptine induced testosterone suppression, there is much to be learned about the role of prolactin in maintaining normal testicular steroidogenesis.
All of the studies thus far cited have been carried out in men. What about the effects of bromocriptine in normal women? As mentioned earlier in the article, hyperprolactinemia inhibits ovulation in both animals and humans. One interesting study showed that prolactin administered to rats decreased levels of ovarian aromatase. Conversely, when bromocriptine was administered, ovarian aromatase was increased (18). Is this of any relevance to human females? Perhaps, since the same phenomenon is observed during the follicular phase of the menstrual cycle: bromocriptine increases the estradiol/testosterone ratio as a result of increased aromatization of testosterone to estrogen (19).
by Nandi
Introduction
Bromocriptine, a drug that mimics the action of the naturally occurring neurotransmitter dopamine, has a long history of use by body builders and life extension enthusiasts. The drug originally gained popularity due to its reputation for acting as a mild growth hormone secretagogue. This is paradoxical, since in people suffering from acromegaly, or growth hormone excess, bromocriptine has the opposite effect: it actually lowers GH levels. Bromocriptine has a number of other legitimate medical uses, including treatment of Parkinson's Disease and the lowering of prolactin levels in people suffering from prolactin secreting tumors. It has also been used successfully to treat hyperprolactinemia (elevated prolactin) that often occurs as a side effect of the administration of antipsychotic medications.
Bromocriptine and Weight Loss
Lately however, bromocriptine has gained prominence particularly on the World Wide Web as a weight loss agent. Perhaps no single person is more responsible for this resurgence of interest in the drug than Lyle McDonald, who popularized its anti-obesity properties in his recently published e-book (1). There are studies both in animals (2) and humans (3),(4) that support the ability of bromocriptine to reduce weight and body fat. The exact mechanism whereby dopaminergic agonists induce weight loss has not been elucidated.
Studies in animals have shown mixed effects of dopaminergic agonists on lipid metabolism. When dopamine and SKF 38393, a D2 receptor agonist were administered to genetically obese mice, antilipogenic effects were observed in the liver, but a combination of both lipolytic and antilipolytic effects were demonstrated in adipose tissue. In adipose tissue lipoprotein lipase activity was decreased (an antilipogenic effect) where as beta-agonist stimulated lipolysis was decreased (5). Additionally, obese mice treated with dopaminergic agonists also exhibited reduced de novo lipogenesis (2). This is the process whereby dietary carbohydrates are converted to fat. Interestingly, while de novo lipogenesis is important in animals, its contribution to fat deposition in humans is relatively unimportant (6). When humans ingest excess carbohydrates, rather than being stored as fat, the carbohydrates are preferentially used as fuel, preserving fat stores that would have otherwise been oxidized. Here is a case where the results of animal studies do not necessarily carry the same implications for humans.
Dopamine has also been implicated in appetite control. It has been postulated that dopamine modulates appetite by providing a reward stimulus, and that obese individuals have lower levels of dopamine receptors in certain portions of the brain (7). Hence to achieve the same "reward" from eating as normal individuals, obese individuals must eat more. This would provide some rationale for the treatment of obese individuals with dopaminergic agonists, but it is unclear whether normal body weight individuals possessing a normal density of dopamine receptors and/or normal dopaminergic activity in the brain would benefit from such treatment. The authors of the previously cited paper also acknowledged that it was unclear whether the relative paucity of dopamine receptors in the obese subjects was a cause or a result of their overeating. Since eating elevates dopamine levels, the brain could be compensating for elevated dopamine in chronic overeaters by downregulating the dopamine receptors. This latter possibility could call into question the use of dopaminergic agonists for appetite control. The result of increasing dopamine levels with agonists could lead to a further downregulation of the D2 receptors, leading to an increased desire to eat in order to further elevate dopamine levels. In a review of the above-cited study, Dr. Joseph Frascella of NIDA’s [National Institute of Drug Abuse] Division of Treatment Research commented on this positve feedback effect on D2 receptor downregulation:
“This deficiency could be a double-edged sword that cuts both ways. First, the reduced reward experienced by people with this deficiency may make them more likely to engage in addictive behaviors. Then, the addictive behavior itself could make the deficit worse as the brain further lowers D2 levels in response to constant overstimulation of the reward pathway. “In the end, they could be much worse off biologically than when they started,”
http://www.drugabuse.gov/NIDA_Notes...thological.html
Another mechanism by which dopamine could suppress appetite is by antagonizing neuropeptide Y (NPY). As fat stores decrease during dieting, leptin levels fall. This signals an increase in NPY, which is a potent hunger inducing neuropeptide. Treatment of genetically obese mice with bromocriptine led to a decrease in the elevated levels of hypothalamic NPY in these animals (2). Again, the implications of these observations to normal humans are unclear.
Both obesity and cocaine addiction have been linked to the dopaminergic reward pathway. As we have been discussing, food consumption elevates dopamine level, leading to a reward stimulus. In the case of cocaine, the traditional view has been that cocaine blocks the cellular dopamine transporter, blocking dopamine reuptake and increasing extracellular dopamine levels, again leading to reinforcing reward. However, this view has been called into question by the 1998 publication of a study showing that mice lacking the dopamine transporter develop cocaine addiction (8). According to the dopamine reward model of cocaine addiction, the lack of the dopamine transporter should have maintained chronically elevated dopamine levels, obviating any reward derived from cocaine use. Nevertheless the mice became addicted. The authors suggested that other neurotransmitter pathways, such as those mediated by serotonin may play a more important role in addiction. These ideas are supported by the fact that dopaminergic agonists, including bromocriptine, have not been useful in treating cocaine addiction (9).
Is it possible that the food driven reward mechanism is also dopamine independent, or at least only partially dependent on dopamine? The successful use of fenfluramine as an anorectic agent suggests this could be the case. Fenfluramine stimulates the release of serotonin and is a potent reuptake inhibitor of serotonin into nerve endings. This increases levels of serotonin in the nerve synapse, increasing levels of serotonergic nerve transmission. In both animals and humans, fenfluramine induces lack of appetite leading to weight loss. Fenfluramine was withdrawn from the market in 1997 due to findings that its use was associated with valvular heart disease.
Side Effects of Bromocriptine Treatment
As with the majority of drugs bromocriptine has a number of well characterized side effects that seem more unpleasant than dangerous, and often abate during treatment. These include nausea, orthostatic hypotension, headaches, abdominal discomfort, nasal congestion, fatigue and constipation. Besides these there are two other potential side effects that are not as well characterized, that are controversial, and that are of particular interest to bodybuilders and other athletes. The first I would like to address is the possibility that bromocriptine may lower testosterone levels in normal men, as well as increase the ovarian aromatization of testosterone to estrogen in women. The second is the potential bromocriptine may have to suppress the immune system in normal humans.
Bromocriptine and Steroidgenesis
It has been appreciated for decades that elevated levels of prolactin in males (hyperprolactinemia) can suppress testosterone production. Hyperprolactinemia disrupts the hypothalamic-pituitary-gonadal axis in women as well, leading to amenorrhea and infertility. Since bromocriptine lowers prolactin levels, when bromocriptine is administered to these patients, normal sexual function is usually restored. What is less well known is that studies done both in vitro and in humans suggest that hypoprolactinemia (low prolactin levels) also leads to suppressed testosterone production. So prolactin appears to exert a biphasic effect: too much or too little can disrupt testicular function. Normal physiological levels of prolactin appear to be necessary for normal gonadal function. (10) (11). To quote from Marin-Lopez et al, (10), where sulpiride and bromocriptine were used respectively to induce hyper and hypoprolactinemia in normal males
"the hyperprolactinemia induced a low basal level of testosterone with a higher response of this steroid to hCG...while the loss of the trophic effect of prolactin on gonadal steroidogenesis, as seen in hypoprolactinemia produces a decrease of basal testosterone levels without any alteration of the response of this steroid to hCG. We conclude that prolactin plays an important role in the steroidogenesis of Leydig cells in normal men.'' (11)
Confusing the issue is the fact that several other studies both in vitro and in vivo have shown either no effect or an increase in testosterone production due to both prolactin and bromocriptine administration (12) (13).
A number of experimental observations have led to several theories that could possibly explain how bromocriptine induced hypoprolactinemia suppresses testosterone production. Kovacevic and Sarac (14) proposed that bromocriptine competitively inhibits androgen production at the level of the testicular enzymes 17 alpha-hydroxylase and/or 17,20-lyase. These enzymes act at intermediate steps in the testicular production of testosterone. Aisaka et al. observed a decrease in luteinizing hormone (LH) levels that was mirrored by a decrease in testosterone after bromocriptine administration, suggesting that bromocriptine directly inhibits LH secretion from the pituitary (15). As we know, luteinizing hormone, or LH, secreted from the pituitary gland acts directly on testicular Leydig cells to stimulate testosterone secretion.
On the other hand Suescun et al. observed a decrease in circulating testosterone after bromocriptine administration in men with no decrease in LH levels (16), consistent with a direct testicular action of bromocriptine, as proposed by Kovacevic.
Other studies have shown that lowering prolactin decreases the binding of LH to the Leydig cell LH receptor, with a concomittent reduction in androgen production (17). These researchers concluded that
These results suggest that under normal conditions, endogenous prolactin plays a key role in maintaining the functional integrity of rat Leydig cells." (16)
So perhaps by either lowering the affinity of the LH receptor to LH, or by directly decreasing LH receptor number, bromocriptine could lower testosterone production.
As is obvious from the conflicting studies, and the variety of proposed mechanisms for bromocriptine induced testosterone suppression, there is much to be learned about the role of prolactin in maintaining normal testicular steroidogenesis.
All of the studies thus far cited have been carried out in men. What about the effects of bromocriptine in normal women? As mentioned earlier in the article, hyperprolactinemia inhibits ovulation in both animals and humans. One interesting study showed that prolactin administered to rats decreased levels of ovarian aromatase. Conversely, when bromocriptine was administered, ovarian aromatase was increased (18). Is this of any relevance to human females? Perhaps, since the same phenomenon is observed during the follicular phase of the menstrual cycle: bromocriptine increases the estradiol/testosterone ratio as a result of increased aromatization of testosterone to estrogen (19).
