Here's my second letter to the doctor:
In advance of our June 30 appointment, I’ve continued to have conversations with my wife, research the medical literature and develop a timeline that may shed some light on the etiology of my hypogonadism. The more we look, the less innocent the fluvastatin appears. I’ve attached some information on my gallbladder attack and a history of prescription refills that serves as a rough guide to my compliance with the therapy. In addition to what I noted in the online post about the gallbladder attack, please note the following:
1. Shortly after beginning Lescol in late 2002/early 2003, I complained to my wife of a feeling of “heaviness” … this would correlate to my description of the initial effect of HRT as a reprieve from “Jovian Gravity”.
2. Around that time, my libido receded greatly. My wife had a miscarriage in January 2003. By the time we conceived in August, she says she was wondering how we would conceive given the infrequency of our lovemaking.
3. My first real layoff from Lescol probably coincided with an upper respiratory infection around Thanksgiving 2003.
4. The domestic accident with the trash bin correlates to a resumption of Lescol therapy of approximately 50-55 days (I was consuming a stockpile of a couple of bottles of Lescol when I hit my head, and at that point I once again discontinued Lescol and never resumed [right now I have one bottle that is unopened, one that has one tablet in it--there would have been no reason to do a refill on June 5, 2004 if I thought I had more than a 30-day supply, but I remember combining two bottles, which would have given me around 55-60 days]). My thought is that low-T or anemia affected my strength and/or coordination. I can also recall tripping on the stairs more frequently. After the accident, lethargy increased somewhat.
5. I had at least one prior episode where I passed black pigment stones while on the Lescol (but without the severity of symptoms), and I believe I had one long ago while not on any medications.
6. I’m finding a great deal of anecdotal evidence on the ‘net pointing to statins as the culprits in erectile dysfunction due to hypgonadism. Their cholesterol-lowering activity appears to impair an important building block of testosterone. The European literature reports 85% spontaneous regression of ED when statins were withdrawn, if
we take ED as indicative of IHH, I would appear to be in the unfortunate 15%.
7. I have found at least one instance of pancreatitis attributed to fluvastatin, while another author questions whether it’s not a class effect due to a patient experiencing it on two different statins.
8. Although I have not found literature directly implicating statins in hemolytic anemia, liver cirrhosis from any cause (a known statin complication) would account for both black stone formation and hypogonadism.
9. The literature describes adult-onset idiopathic hypogondotropic hypogonadism as permanently responsive in one case to hCG therapy of only four months’ duration, another article describes it as responsive to long-term GnRH therapy.
One more letter (I'll probably quit after this ... possibilities are exhausted):
A few more items have come to light as I continue to research and attempt to recall items of personal and family history that may be significant.
1. In college and law school I was a binge drinker. For the past 15 or so years my alcoholic consumption has consisted of an occasional drink with dinner, perhaps several drinks on a relatively-infrequent social or holiday occasion.
2. In 1986 or so I had a lipoma removed from my left shoulder. In approximately 1997 I had liposuction under my jawline. Both procedures were uneventful.
3. In the weeks prior to the late-February 2004 gallstone attack my then-pregnant wife craved a sausage biscuit from McDonald’s each morning. Although I was not terribly fond of them, as a matter of convenience I would have one as well (I figured they couldn’t be much worse than the bacon, egg and cheese biscuits I would otherwise choose to order, and it took less time to order two of the same thing at the drive-thru). This continued up to the time of the gallstone attack, after which the sausage biscuits were no longer appealing to me. In general I eat sausage no more than 3-4 times per month. I have a bacon cheeseburger every couple of months, sometimes more frequently for a brief stretch.
4. On the day prior to the onset of the gallstone symptoms, I was not yet feeling ill, however I did not particularly want lunch, and I settled on chicken fingers as something I felt I could eat … however I remember thinking that what I was eating was pretty greasy … and I don’t usually feel that way about chicken fingers.
5. Following the liver flush I subjectively felt “ten years younger”. I omitted to mention this in my posting on the lowcarber website for fear of being seen to be engaging in hyperbole.
6. There was an incident in the first week of March of 2004 where I ate dinner at a Fridays and had a dish that was called “Sesame Jack (Daniels) Chicken Strips” or something like that—it was an asian-type dish among many Jack Daniels items on the menu. My wife had ordered it and found it not to her liking so we swapped orders. She had asked whether it contained MSG and was assured it did not. After eating it I began feeling “stoned” and my lips actually became numb. I recall slight tightness in my chest. I recall being concerned whether I would be OK to drive after my car was finished at the adjacent PepBoys. I was concerned enough to write to Fridays about it. Having never heard back, I assume there were no problems experienced by other patrons. This incident may not be significant; internet searching has disclosed that the Sichuan peppercorn, Zanthoxylum piperitum, recently returned to the U.S. after having been banned since 1968. If it was an ingredient in Fridays’ recipe that would account both for its effect on me and for my unfamiliarity with the spice.
7. The Thanksgiving 2003 upper respiratory problem was treated with Clarithromycin, a known potent inhibitor of CYP3A4, the secondary (~35%) pathway for clearance of fluvastatin (primary is CYP2C9). I believe I stopped Lescol around that time for reasons of discomfort with its effects. Possibly there was a black pigment stone incident at that time, I do not recall exactly.
8. The late July 2004 domestic accident with the trash bin correlates to a resumption of Lescol therapy of longer than the approximately 50-55 days suggested in my last letter. My wife advises that I started it back up over her objections around the time of my son’s April 30, 2004 birth (which would put duration more at 90 days).
9. It is possible that the prior episode where I passed black pigment stones while on the Lescol was sometime in the spring or early summer of 2003 (rather than at some time much earlier when I was not on any medications), I say this based on the timing of pharmacy refills … it would appear that sometime in that time frame I would have had a layoff in use of the drug, creating a stockpile. I postulate that the layoff may have been in response to a black pigment stone episode—however, the thought that runs countervailing to that notion is the idea that if I saw black pigment stones shortly after beginning Lescol and I had never seen them before, I feel I would have reported same to my primary care physician. However, a black pigment stone episode would not necessarily have provoked such a response if I had previously had one while not on Lescol. I did not respond to any black pigment stone episode by contacting my primary care physician, therefore I remain convinced that I had a black pigment stone episode prior to starting Lescol, potentially as long as 15 years ago.
10. My paternal lineage is Scotch-Irish, and the possibility that I am heterozygous for one of the hemochromatosis genes C282Y or H63D or both should not be discounted.
11. My paternal grandmother suffered from jaundice toward the end of her life, and I forgot to mention that earlier.
1. In the weeks prior to the late-February 2004 gallstone attack there was more than just orange juice consumption associated with the McDonalds sausage biscuits. My wife was in the hospital with a large DVT in her leg from February 10 through February 19 or so. I habitually breakfasted at Burger King adjacent to said hospital during that time period … with orange juice.
2. At some time during her pregnancy that I have not yet determined, she began to crave orange juice (later she stopped craving it and started craving sausage biscuits, but didn’t want OJ). I had forgotten this fact. So orange juice would have been in the house for an unspecified time period after September 2003, and once she stopped craving it I would have had to finish it on my own.
3. I habitually consume citrus-flavored sparkling waters by LaCroix as a substitute for sugared or diet sodas. These waters claim to have natural flavors. I drink 2-3 daily. I can only get lemon and lime flavored versions here in Florida. In Minneapolis, an orange flavored version can also be found. Either on the mid-2004 trip or on a trip there on one of two earlier occasions I would have picked up a 12-pack of the orange-flavored water.
4. My wife’s parents were in town the week of 6/24/04. I would expect that orange juice would have been in the house at that time and for some time afterward. My wife would not have had any of it, her orange juice craving was long gone and in fact she found it repulsive. So whatever we bought for the parents, I would have had to finish.
5. My wife and I traveled to Minneapolis 7/15/04 – 7/20/04. I recall that I did have orange juice during that time period.
6. I was feeling good and not using Lescol in the weeks prior to my wife’s DVT. In fact, the precipitating events for her DVT (besides pregnancy) were that she could no longer keep up on walks because her legs tired easily, but I wanted to run. So she started using our sit-down electric scooter while I ran. One day I ran 40 minutes. Her DVT happened right after that; the primary hypothesis on our part is that sitting for 40 minutes on a bicycle seat without having to pedal probably precipitated the DVT.
7. Based on my own psychology, I assume I would have resumed Lescol once she had a DVT. Since she developed a circulatory problem, I would have resumed a treatment that promised to prevent me from having one of my own. So the total duration of Lescol use would have been 2/10 or so to 2/29 when I had the gallstone attack (or possibly to 3/13 when I had a second gallstone attack), with plenty of OJ consumption during that period.
8. After I did the liver cleanse (I believe over the weekend of 3/13/04—-I have a notation “Gallstone Attack Meal” by an entry for an Italian restaurant where I would have ordered Fettucini Alfredo, that would have been a second gallstone attack and also the last straw that would have caused me to do the cleanse, I had forgotten it took a second attack), I resumed cycling in the months leading up to the 4/30/04 birth of my son. I recall that my rides became vigorous again, including one off-road ride in particular where I achieved a 187 heart rate. Again, around the time my son was born I resumed the Lescol and basically stopped working out. By the time we moved at the end of May, I was draggy enough that my wife didn’t feel I kept up my end of the packing and moving work.
9. In June and July of 2004 I did a lot of work around the new house we had bought. I hung 4 ceiling fans and numerous light fixtures, etc. The costs for the items I bought at home centers were easily $3,000, and I installed nearly all of it. During that time I believed I was wearing down due to the projects I was doing, the stress of having a 2-3 month old in the house, the guests in town and the out-of-town trip. However I was also using the Lescol.
I realize that all this is a lot to read. It’s been a lot for me to recall. However, I have come to believe that I have had adverse reactions to Lescol, and that my reactions my not have been idiosyncratic. If that’s the case, regardless of whether Lescol caused my hypogonadism or in fact is generally safe for people to use, the labeling lacks warnings against drinking citrus juices and perhaps even citrus flavored waters.
I would never have thought flavored sparkling water would be the
most likely candidate for causing me to have trouble with standard
dosages of almost every prescription I've used in the last 10 years.
But that's what I found. I missed my doctor's appointment Friday
because my wife wrote down the wrong time ... but over the weekend
my research and rereading of about 500 pages of journal articles
yielded the following memo to my new doctor (who wants me to stop
Androgel for 6 weeks so he can retest T, free T, FSH and LH):
The time has come for me to put together what I've learned in the
last few weeks about what happened to me on Lescol. Prior to
beginning Lescol, I was a frequent exerciser whose typical ride was
10-11 miles around the Flatwoods loop and back home on a road bike
at an average of 17.5 mph. I would also run and rollerblade.
Dr. X (my primary) found that I needed Lescol, and I began using it
in early 2003. I was not able to run or bike as I had before. During
this period though, my wife was also having difficulties keeping up
any sort of program, as she had miscarriages in early and mid-2003.
The earliest symptom of a problem with Lescol (other than low libido
and lack of desire to exercise) was fullness under the ribcage on
the right side, progressing to discomfort when any weight (such a
sleeping spouse's arm) was place on it.
Probably sometime after the midpoint of 2003, I had several
instances of gastrointestinal disturbance culminating each time in
passing black pigment stones. Having seen them before in the past at
least once (I believe associated with erythromycin, perhaps also
nefazodone or paxil, neither of which I tolerated well [jaw
clenching, etc.]), they caused concern but not consternation, and
were not even mentioned to my wife. I believe it is likely some of
these instances were associated with orange juice consumption and
one with clarithromycin use. I believe the incident in the dim past
was probably also associated with LaCroix water (more on this
below), also possibly orange juice. Each more recent incident
prompted me to temporarily cease compliance with the Lescol regimen.
It is my hypothesis that at least one flavor of citrus LaCroix water
contains furanocoumarins (perhaps only in trace amounts, however my
consumption has been prodigious in the past—I drank it like water
because it is water) by virtue of the use of natural lemon or lime
flavoring derived from peel or from one or more "botanicals"
included in the flavoring formula (perhaps even epoxybergottamin, an
extraordinarily active mechanical inhibitor of CYP3A4 present in
high concentrations in grapefruit oil [used for flavoring] and
believed to be broken down by citric acid, which I believe is not
present in the sparkling water). CYP3A4 would thus be inhibited
(perhaps to 100% in the gut, but also in the liver). A study
indicates that with ordinary CYP3A4 metabolism, the first-pass
pharmacokinetics of fluvastatin indicate saturability; with
diminished metabolism of the drug, the threshold dose for saturation
would be lower regardless of the predominance of the CYP2C9 receptor
(bergamottin has been shown to inhibit CYP2C9, however I do not know
what conditions are necessary to convert epoxybergamottin to
bergamottin, or which ones can remain in the liver).
In December 2003 and January 2004 I believe I did not take Lescol.
In mid-February '04, I again began taking Lescol while continuing to
habitually consuming orange juice at breakfast. By the end of the
month, I had an attack of gallstones/pancreatitis what-have-you.
High dosages of Lescol have been shown to cause gallbladder damage
(inflammation with mucosal hyperplasia) in beagle dogs and "mild
gallbladder changes" in rhesus monkeys. Orange juice
polymethoxylated flavones are said to be an inhibitor of P-
glycoprotein, but not CMY3A4.
I postulate that while hepatic buildup of the furanocoumarins from
the flavored sparkling water (long-term consumption has been found
to do this in rats) resulted in a hepatic buildup of fluvastatin
and/or its metabolites, the action of flavones in one case and
clarithromycin in another were necessary to inhibit P-glycoprotein
and thus potentiate the bioavailability of the stored drug (or
inhibit renal excretion of a significant metabolite) and result in
an acute gastrointestinal attack and perhaps entry of an otherwise
harmless metabolite into muscle and CNS cells.
Another product could be involved, Hansen's Energy Drink. My
consumption of it was limited to times when I exercised. Typically I
would consume one prior to a ride. I bought it by the case at Sam's
club, and I remember one case that sat in the garage a long time
without much of a dent being put in it. I believe this was during
2003. Nonetheless because it is citrus-flavored I mention it here.
Although fluvastatin would seem an unlikely candidate for the
grapefruit juice effect, I believe its relatively benign safety
profile is the reason that I am still here to write this. It has
three pathways to metabolization, and its metabolites are not
believed to enter muscle cells. In short, when things go wrong with
fluvastatin, the results are not as disastrous as with other
statins, which could account for the fact that at a sustained 80-mg
dose, fluvastatin is more likely to result in elevated ALT
transaminase levels—users are simply less likely to be able to
sustain 80-mg dosing with other statins.
Regardless of the exact mechanisms involved, I believe the potential
to learn more about the effect of occult furanocoumarins as
components of common food and beverage ingredients warrants further
investigation. So long as such interactions are misleadingly-labeled
the "grapefruit juice effect", it is probable that many people will
be unknowingly affected by habitual (over?) consumption of items
containing furanocoumarins, perhaps such everyday items as lemon
pepper, flavorings used in baked goods, pastries, frozen treats,
savory snacks and potentially even cocktail mixers.
Meanwhile, in my own individual case, I believe we can look to
either long-term overdosage or episodes of acute toxicity from
Lescol or one of its metabolites (or to the single episode of
toxicity from clarithromycin) as the reason that hypogonadism has
not spontaneously reversed on withdrawal of the Lescol.
