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QUEST FOR ADVANCED CONDITION Bromocriptine - Lyle McDonald |
Bromocriptine Addendum by Lyle McDonaldSince completing my little book, a number of issues have arisen that I somehow failed to address the first time around. Most of these got covered in the addendum/FAQ that I added to the booklet but there is apparently one issue making the rounds of some of the message boards that I somehow overlooked. That issue involves a possible effect of bromocriptine in lowering testosterone levels, as reported in one study (1). There has also been some banter regarding some of the possible mechanisms involved. In this short article, which I'll be adding to the book of course, I want to address the issue, mainly to put everybody's freaking mind's to rest. Some Basics of the System To understand the data I want to look at, I need to sketch out the basics of how the human body handles gonadal hormone production. All of the information I'm going to present comes from reference 2. It can be found in any basic endocrinology textbook. For ease, I'll give you a graphic with the basics of the system. Hormonal production starts, as usual, in the brain. In this case, the main hormone of interest is called gonadotrophin releasing hormone (GnRH), which is released from the hypothalamus. I should note that both dopamine and prolactin have effects on GnRH, inhibiting it's release. GnRH goes to the pituitary where it causes the release of both leutinizing hormone and follicle-stimulating hormone (LH and FSH respectively). LH binds to a specific LH receptor in the testes (the Leydig cells to be exact) and is the main player in testosterone and estradiol (one of the estrogens) production in men, and estradiol production in women. Both testosterone and estradiol levels feedback on LH, inhibiting its release. FSH is mainly involved in sperm production in men and has far more complex roles in women. There's also much more to the overall regulation but these are the main parts that are important here. The basic scheme appears below. The Direct Research on Bromocriptine, Testosterone and Other Hormones In reporting the results of the Oseko et. al. (1) study which showed a decrease in testosterone with chronic bromocriptine use, a number of internet pundits have managed to avoid several other papers showing different results. In this section, I want to address each in some detail. I should note that all of these studies were done in normal, otherwise healthy males (with one exception) since that's the group we're really concerned with. I'll summarize in a table below for easier reading. For reasons you'll see in a second, I'm going to look at them from shortest to longest duration and I'll give as much information as the studies themselves gave. You'll see that, in many cases, it's somewhat incomplete which makes drawing conclusions a bit tough. In one study (3), Jacobs et. al. gave methysergide throughout the day to inhibit prolactin release for one day. No effect on testosterone levels were noted. In another (4), 6 males were given 2.5 mg of bromocriptine at night for 3 days. Testosterone levels increased in direct relationship to the decrease in prolactin. The same study increased prolactin levels with the drug sulpiride and noted a decrease in testosterone levels. Lacritz et. al. (5) gave 5 males 2.5 mg of bromocriptine at night for 6 days. There was no change in testosterone. Coiro et. al. (6) gave 11 males 5 mg of bromocriptine in divided doses for 7 days; there was no change in testosterone levels. Martikainen et. al. (7) tested both decreased and increased prolactin in their study in response to a hCG test. Sulpiride was used to increase prolactin for 6 days and testosterone levels were increased although it was non-significant. Bromocriptine was then given to 7 males, at 2.5 mg for 3 days followed by 5 mg for 10 days in divided doses. No change in testosterone levels occurred in response to lowered prolactin. In the first Oseko et. al. study, 5 normal men, aged 20 to 35 years of age were given 5 mg of bromocriptine per day to reduce prolactin levels for a period of 8 weeks. I want to note that the paper did not indicate when the bromocriptine was given. It can be safely assumed that it was either given all at night or in divided doses as that would tend to have the greatest overall effect on prolactin. A testosterone stimulation test (via the injection of human chorionic gonadotropin stimulation or hCG) was performed at 2 week intervals during the study. Measurements of basal testosterone, prolactin, leutinizing hormone (LH) and follicle-stimulating hormone (FSH) were also made. As expected, prolactin was reduced to the low end of the normal range. Levels of LH and FSH did not change during the study. However, both basal levels of testosterone and hCH stimulated testosterone levels were reduced in all subjects at all time points (2, 4, 6, and 8 weeks). In a related study (8), Oseko et. al. looked at the LH release from the pituitary gland in response to GnRH injection after 8 weeks of bromocriptine treatment. They showed that LH release was not affected by bromocriptine. So any effect of bromocriptine on testosterone levels in reference 7 was most likely an effect at the testes themselves. Finally, Glatthaar et. al. (9) gave 7.5 mg of bromocriptine (timing was not indicated) in 10 males who had normal prolactin levels but were infertile. The bromocriptine was given for 4 months and no change in testosterone levels was noted. These studies are summarized in table 1 below. Table 1: Summary of studies on bromocriptine and testosterone 
Frankly, I can't make any more sense out of this data than I imagine the people reading it can. Out of 8 studies, 7 of which measured testosterone levels, one showed a decrease, two showed an increase and most showed no effect (I should mention that there were one or two additional studies that I couldn't obtain at the library but I wanted to get this article out instead of waiting on them). Hardly a clear-cut case. I put them in order from shortest to longest to see if there was any clear effect of duration. That is, while bromocriptine might have one effect in the short-term, longer-term effects might be different. Unfortunately, the last study by Glatthaar throws that for a loop; it was the longest of them all with the highest dose of bromocriptine and showed no change in testosterone. Of course, since these were infertile men, it's possible that there was already some other defect present, so the bromocriptine wasn't having any additional effect. And one study in the 70's suggested a linkage between below normal prolactin and low-testosterone in infertile men (10). As well, because of a lack of information in the full studies, there's no apparent pattern in the timing of the bromocriptine. I'm going to talk about a few other things but I'll come back to this. The Mechanism Since the direct research on bromocriptine and testosterone doesn't seem to be giving any real clear pattern, let's look at possible mechanisms. Considering that the main effect of bromocriptine is on prolactin (ignoring the effects I talked about in the book), it's fairly safe to assume that any changes in testosterone levels are related to changes in prolactin through one mechanism or another. Another possibility would be a direct effect on GnRH (see figure 1 above) since dopamine inhibits GnRH release. Now, there's no doubt that hyperprolactinemia (higher than normal prolactin levels) causes problems with hormones. This includes infertility, low testosterone and a whole host of other problems. In that group, where prolactin is chronically above normal, normalizing prolactin invariably corrects hormones. Frankly, it never really occurred to me that lowering prolactin below normal would cause problems. Which is strange since I presented a roughly identical idea (that both high and low levels of a hormone can cause the same problem) in that book. What can I say, I'm a space case sometimes. So what might the mechanism be for lower than normal prolactin levels lowering testosterone. As mentioned above, earlier studies suggest a correlation of below normal prolactin and low testosterone (10). Other studies suggest that the increase in prolactin is involved in stimulating testosterone release (11). This raises the question of what the mechanism of action might be. I'll discuss some possibilities here although you'll see that it really doesn't matter in the next section. One possibility, and the one that folks on the message boards seem to be fixated on has to do with a possible role of prolactin in regulating the LH receptor in the testes. That is, normal prolactin seems to be necessary to keep LH receptor levels at the proper levels; reducing prolactin far below normal could reduce the sensitivity of the testes to LH, which would reduce testosterone output. Now, if you're talking about rats or hamsters, there's absolutely no doubt that normal prolactin levels are crucial to keeping LH receptor levels normal. Unfortunately, in humans it's not quite so clear. It turns out that prolactin has quite drastically different effects in different species so this really isn't a place where it's automatically safe to assume that what happens in rats happens in humans (12). Frankly, despite thorough searching, I was unable to find a direct link between prolactin levels and LH receptor regulation in humans. The most recent review (13) makes no mention of prolactin in regulation LH receptor number or function. White this doesn't mean that it's not a possibility that prolactin is required for normal LH receptor function in humans, but there's no data that I can find. So what about other possible mechanisms? It turns out that there are a couple of possibilities that the folks on the webboards appear to have missed (but I didn't because I'm OCD). One of the studies cited above (7), mentioned one of them. In response to sulpiride (which increased testosterone), the researchers also noted a smaller decrease in estrogen in response to hCG stimulation. They suggest that prolactin may exert an inhibitory effect on the enzyme aromatase (which converts testosterone to estrogen). If that were the case, lowering prolactin below normal might allow greater conversion of testosterone to estrogen which would be bad for most males for a whole bunch of different reasons. A third possibility is that prolactin may exert inhibitor effects on the enzyme 5-alpha reductase, which converts testosterone to it's 'evil' twin DHT (di-hydro testosterone). One of the studies above (5) showed a greater increase in DHT with hCH stimulation after bromocriptine, suggesting this as an effect. Hyperprolactinemia (above normal prolactin) is known to inhibit 5-alpha reductase (14) so it's possible that below normal prolactin would allow increased enzyme activity. However, another of the studies (7) found no effect of low prolactin on the production of DHT. As with the conversion of testosterone to estrogen, an excess of conversion of testosterone to DHT would be distinctly bad. Again, it's all about timing. Ok, so there's no clear consensus on what, if any, effect below normal prolactin might be having in terms of testosterone levels. But, for the sake of argument, and so I can dismiss the whole issue anyhow, let's assume something is going on. That is, through whatever mechanism, it does appear that too low of prolactin can be just as bad as too high. Basically ,whether normal prolactin is necessary to maintain LH receptor number, inhibit aromatase, or inhibit 5-alpha reductase, let's just assume that normal prolactin is important and move on from there. So we have to look at another issue, pattern of prolactin release. That is, is it possible to take bromocriptine (to get the beneficial effects described in my book) without affecting prolactin enough to cause problems with testosterone. The answer turns out to be yes, and it's quite easy. Many hormones in the body follow fairly typical daily rhythms. That is, outside of the other regulating factors, they tend to synchronize with time of day (usually set by sleep patterns and light levels). Prolactin is one of these hormones. Under normal circumstances, prolactin levels peak during sleep, increasing from rather low levels from about 2 am until maybe 10 am or so. At that point they return to low levels and stay there pretty much all day long (15). So why is this important? Because timing of bromocriptine is crucial in determining whether or not prolactin levels are going to be affected. Recall from my book that bromocriptine has a half-life of around 12 hours or so. This is why dosing for the treatment of high prolactin levels. They are trying to maintain dopamine receptor stimulation throughout the day to keep prolactin levels down. But what about in normals? In a normal individual, prolactin will peak in the morning, I as I mentioned above. The only way that bromocriptine is going to affect that normal increase in prolactin is if it's taken at night, to prevent the normal sleep-induced increase. Meaning that my recommendation to take bromocriptine in the morning turns out to be that much more important (even as a space-case, sometimes I get lucky). By dosing first thing in the morning, not only are most of the side effects avoided, not only do you get the metabolic/body recomposition effects, but the normal morning rise in prolactin levels aren't affected. Bingo, no problem with testosterone because the normal prolactin peak still occurs. I suppose if you were particularly concerned, you might want to move your bromocriptine dose to 10 am, to make sure that the normal prolactin peak still occurs. Beyond that, as long as bromocriptine isn't dosed in the evening, normal prolactin release will occur, and there should be no problems with testosterone production. So all of the mental energy that folks put into worrying about bromocriptine and testosterone can be safely swept away again: as long as you take bromocriptine in the morning, allowing the normal prolactin peak to occur, there should be no effect on testosterone. I guess folks will have to find some other reason not to like me now. References cited 1. Oseko, F. et. al. Effects of chronic bromocriptine-induced hypoprolactinemia on plasma testosterone responses to human chorionic gonadotropin stimulation in normal men. Fertil Steril (1991) 55: 355-357. 2. Balint Kacsoh. Endocrine Physiology. McGraw Hill Publishing, 2000. 3. Jacobs, LS. et. al. Failure of nocturnal prolactin supression by methysergide to entrain changes in testosterone in normal men. J Clin Endocrinol Metab (1978) 46: 561-566. 4. Nakagawa K et. al. Relationship of changes in serum concentrations of prolactin and testosterone during dopaminergic modulation in males. Clin Endocrinol (Oxf) 1982 17:345-52. 5. Lackritz, RM and A. Bartke. The effect of prolactin on androgen response to human chorionic gonadotropin in normal men. Fertil Steril (1980) 34: 140-143. 6. Coiro V. et. al. Restoration of normal gonadotropin responses to naloxone by chronic bromocriptine treatment in elderly men. Horm Res (1991) 36: 36-40. 7. Martikainen H. and R. Vihko. hCG-stimulaton of testicular steroidogenesis during induced hyper- and hypoprolactinemia in man. Clinical Endocrinology (1982) 16: 227-234. 8. Oseko F. et. al. Bromocriptine effects on plasma leutinizing hormone and its responses to gonadotropin-releasing hormone in normal men. Life Sciences (1993) 52: 1805-1807. 9. Glatthaar, C. et. al. pituitary function in normoprolactinaemic infertile men receiving bromocriptine. Clinical Endocrinology (Oxf.) (1980) 13: 455-459. 10. Pierrepoint, CG. et. al. Prolactin and testosterone levels in the plasma of fertile and infertile men. J Endocrinology (1978) 76: 171-172. 11. Rubin, RT. et. al. Prolactin-related testosterone secretion in normal adult men. J Clin Endocrinol Metab (1976) 42: 112-116. 12. Bartke A. et. al. Effects of physiological and abnormally elevated prolactin levels on the pituitary-testicular axis. Med Biol 1986;63(5-6):264-72 13. Saez JM. Leydig cells: endocrine, paracrine, and autocrine regulation. Endocr Rev. 1994 Oct;15(5):574-626. 14. Magrini B. et. al. Study on the relationship between plasma prolactin levels and androgen metabolism in man. J Clin Endocrinol Metab 1976 Oct;43(4):944-7 15. Linkowski, P. et. al. Genetic and environmental influences on prolactin secretion during wake and during sleep. Am J Physiol (1998) 274: E909-E919. 
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