ANAVAR Cycle (for those interested)

[BJJ]

... Also, how is your diet (carb/pro/fat)?

BMR (Basal Metabolic Rate): 2.000 Kcal (presently 2.300).
Average daily calories about 3.600 Kcal (presently 4.000).

I always try to keep the ratio between proteins and carbs around 0,75.
Daily diet consists in:

340 gr of Protides (11,99 oz)
95 gr of Lipides (3,35 oz)
450 gr of Glucides (15,87 oz)

The above reported macro nutrients weights (PLG) are effective, meaning what the organism is able to digest.

[BJJ]

Today afternoon I'll receive the responses to my blood analyses.
If the hormonal situation gives me the possibility, I'll sudden up the oxandrolone dose to 80 mg ed, instead of 60.
Also, I am considering to split the doses in three times daily instead of two as done so far.
But again, I need to see what really happened to my inner glands and mostly the liver.
In this case, I'll also keep the schedule to add mesterolone starting from the next week, the 5th.

These are the pre-cycle results and the ones I am awaiting for:

CHOLESTEROL TTL: 168 mg/dl (?)
CHOLESTEROL HDL: 41 mg/dl (?)
INDEX RISK HDL: 4,1 (?)
CHOLESTEROL LDL: 105 mg/dl (?)
BILIRUBIN TTL: 1,98 mg/dl (?)
BILIRUBIN DIRECT: 0,22 mg/dl (?)
BILIRUBIN INDIRECT: 1,76 mg/dl (?)
CREATININE: 1,2 mg/dl (?)
AZOTEMIA: 49 mg/dl (?)
AMYLASE: 62 u/ltr (?)
TRANSAMINASE GPT/ALT: 41 u/ltr (?)
GAMMA (YGT): 28 u/ltr (?)

INSULIN: 3,34 micru/ml (?)
IGF1: (?)
TESTOSTERONE TTL: 3,86 ng/ml (?)
TESTOSTERONE FREE: 11,7 pg/ml (?)
SHBG: 38 pg/ml (?)
FSH: 2,92 micru/ml (?)
LH: 3,80 miu/ml (?)
DHEAS: 191 mcg/dl (?)
HGH: 0,2 ng/ml (?)

[Wally24]

Whats the PCT regimen for the Var only cycle BJJ??

[elpropiotorvic]

Whats the PCT regimen for the Var only cycle BJJ??

Begining of the thread

[BJJ]

Whats the PCT regimen for the Var only cycle BJJ??

In case hormonal parameters, checked during and before pct, are within a certain range:

PCT (11/18/2009 - 12/01/2009)
Week 9-10 Clomiphene 50 mg ed (ttl 700 mg), before bed


Otherwise (1):

PCT (11/18/2009 - 12/15/2009)
Week 9-12 Clomiphene 50/50/50/50 mg ed (ttl 700 mg), before bed
Week 9-12 Tamoxifen 40/20/20/20 mg ed (ttl 700 mg), breakfast

Otherwise (2):

PCT (11/18/2009 - 12/15/2009)
Week 9-12 Clomiphene 100/50/50/50 mg ed (ttl 1.750 mg), before bed
Week 9-12 Tamoxifen 40/20/20/20 mg ed (ttl 700 mg), breakfast

It all depends by my blood results.

[BJJ]

Begining of the thread

thank you!!!

[BJJ]

Whats the PCT regimen for the Var only cycle BJJ??

It is not a var only cycle.
I'll add mesterolone by the 5th week.

[BJJ]

CHOLESTEROL TTL: 168 mg/dl (after: 179)
CHOLESTEROL HDL: 41 mg/dl (after: 13) (range >=40)
INDEX RISK HDL: 4,1 (after: 13,76) (range till 5)
CHOLESTEROL LDL: 105 mg/dl (after: 157) (range 130-159, elevated borderline)
BILIRUBIN TTL: 1,98 mg/dl (after: 0,83) (range 0,2-1)
BILIRUBIN DIRECT: 0,22 mg/dl (after: 0,1) (range 0,05-0,3)
BILIRUBIN INDIRECT: 1,76 mg/dl (after: 0,73) (range till 0,7)
CREATININE: 1,2 mg/dl (after: 1,2) (range 0,8-1,3)
AZOTEMIA: 49 mg/dl (after: 62) (range 15-40)
AMYLASE: 62 u/ltr (after: 55) (range 25-115)
TRANSAMINASE GPT/ALT: 41 u/ltr (after: 86) (range 30-65)
TRANSAMINASE GOT/AST: 21 u/ltr (after: 55) (range 15-37)
GAMMA (YGT): 28 u/ltr (after: 29) (range 15-85)

INSULIN: 3,34 micru/ml (after: 3,6) (range 1,9-23)
IGF1: (184) (range 96-424)
TESTOSTERONE TTL: 3,86 ng/ml (after: 0,72) (range 1,75-7,81)
TESTOSTERONE FREE: 11,7 pg/ml (after: 5,2) (range 8-47)
SHBG: 38 pg/ml (after: 10) (range 13-71)
FSH: 2,92 micru/ml (after: 2,09) (range 1,27-19,26)
LH: 3,80 miu/ml (after: 2,19) (range 1,24-8,62)
DHEAS: 191 mcg/dl (after: 209) (range 106-464)
HGH: 0,2 ng/ml (after: <0,1) (range 0,0-10)

[ghettoboyd]

is the red your leves pre cycle?.....

[BJJ]

I'll make it clear...

[BJJ]

I'm wondering... Why no Test? You mentioned risks and reasons in the other thread, what are they?

Because I have The Gilbert's syndrome.
http://en.wikipedia.org/wiki/Gilbert%27s_syndrome

[BJJ]

So basically, my bilirubin values decreased within the normal range, as expected.
Oxandrolone seems to cure Gilberts's syndrome, my eyeballs are now white as never before.

Of course, either LDL and Transaminase went up.
Azotemia was already up and surely it could not start declining.
Strangely, creatinine stayed at the same level but this is good related to azotemia.

What I do not understand are the values related to LH, FSH and HGH compared with DHEAS.

Anyone able to explain this?

[XNathan]

Bilirubin is strongest antioxidant in human body. Decrease is becouse your liver consumend a large portion of bilirubine to reduce oxidation stress from oxandrolone.

Gilbert sy isnt bad its good! Atherosclerosis in a. carotis occure in critical degree 25 yr later than in normal people! And Gilberts has 80% less chance to have coronary heart disease.

Its more than good to have high bilirubine and yellow eyes? Small price for longer and better life.

[BJJ]

Bilirubin is strongest antioxidant in human body. Decrease is becouse your liver consumend a large portion of bilirubine to reduce oxidation stress from oxandrolone.

Gilbert sy isnt bad its good! Atherosclerosis in a. carotis occure in critical degree 25 yr later than in normal people! And Gilberts has 80% less chance to have coronary heart disease.

Its more than good to have high bilirubine and yellow eyes? Small price for longer and better life.

Thank you for your response and related info, I'll check those out.
BJJ

[BJJ]

Bilirubin is strongest antioxidant in human body. Decrease is becouse your liver consumend a large portion of bilirubine to reduce oxidation stress from oxandrolone.

Gilbert sy isnt bad its good! Atherosclerosis in a. carotis occure in critical degree 25 yr later than in normal people! And Gilberts has 80% less chance to have coronary heart disease.

Its more than good to have high bilirubine and yellow eyes? Small price for longer and better life.

Have you got any clues regarding my other question?... LH/FSH/HGH

[BJJ]

is the red your leves pre cycle?.....

So, to answer your question the red levels are the "badly" increased ones.
Some of those were higher even before starting the cycle.

[BJJ]

Today I added Tribulus to my diet (3 gr daily, breakfast/dinner) to see whether it can help with the low test.

[BJJ]

Bilirubin is strongest antioxidant in human body. Decrease is becouse your liver consumend a large portion of bilirubine to reduce oxidation stress from oxandrolone.

Gilbert sy isnt bad its good! Atherosclerosis in a. carotis occure in critical degree 25 yr later than in normal people! And Gilberts has 80% less chance to have coronary heart disease.

Its more than good to have high bilirubine and yellow eyes? Small price for longer and better life.

Confirmed that problems related to high bilirubin are solved during an oxandrolone cycle, the issue remains to see whether once the drug is out of the body completely and proper pct done, the above reported levels keep staying within the normal ranges or not, going back to the bad side.

[BJJ]

I decided to anticipate the use of Mesterolone (50 mg daily) at day 26, instead of waiting the beginning of 5th week, day 29.

[BJJ]

Click Drug Name to View Profile: Anavar

[ghettoboyd]

So, to answer your question the red levels are the "badly" increased ones.
Some of those were higher even before starting the cycle.

oh ok bro......i get it know thanx...

[BJJ]

Pharmaceutical Name: Mesterolone
Chemical Name: 1 alpha-methyl-17 beta-hydroxy-5 alpha-androstan-3-one
Empirical Formula: C20H32O2
Anabolic/Androgenic Ratio: 100-150/30-40
Half Life: 12 Hours
Average Dose: 25-200mg/day
Trade Names: Proviron, Androviron, Testiwo

Description:
Proviron (mesterolone) is basically an orally active DHT (dihydrotestosterone) preparation. For comparision, we can think of some other orally prepared DHT compounds like Winstrol, Anavar, etc. Those both act very similarly in mechanism to Proviron, but a more accurate way to think of this compound is as something like “Oral Masteron.” As I’m sure you noticed, their anabolic/androgenic ratio is very similar. Remember, DHT is 3 to 4 times as androgenic as testosterone and is, of course, incapable of forming estrogen. Also, Proviron is quite unique in that a simple look at its 4-ring structure will show us that it is not going to be too liver toxic, since it is not c17-Alpha-Alkylated, as many orals are. This modification (lacking in Proviron) makes drugs more liver toxic. Proviron has a 1-metyhl group added, instead--looks pretty great on paper, right? Well, as usual, things tend to look better on paper than they do in the body. Your body has a negative feedback loop which prevents it from having too much DHT floating around (if you’ve been paying attention up to now, you already know this). An excess of DHT will eventually be changed into another (largely not anabolic) compound.

So let’s go back to the comparison with being some sort of “Oral Masteron.” Basically Proviron is 5-alpha reduced and not capable of forming estrogen. More importantly, however, it has a very high affinity for binding to the aromatase enzyme (the enzyme responsible for converting all that good testosterone in your body into all that nasty estrogen). That means if you choose to take Proviron with testosterone (and I know you wouldn’t even be doing a cycle without including some form of testosterone) and/or any aromatizable steroid, it should actually serve to prevent estrogen build up by the aforementioned binding to the aromatase enzyme, which prevents aromatase from doing its dirty work and making a bunch of estrogen out of the other steroids you are taking. It should also be noted that Proviron also binds very well to SHBG (sex hormone binding globulin, a hormone responsible for reducing the amount of circulating free testosterone in your body) (1). As a matter of fact, in the last study I read, it bound to SHBG better than any other drug studied.

Also, I’d like to note that Proviron bound to the anabolic receptor better than any oral anabolic (except for the insanely toxic methyltrienolone), better than testosterone, but not as well as Nandrolone (1). Unfortunately, as we know, DHT also has a high affinity for binding to receptors in the scalp and prostate, causing some possible nasty side effects, like male pattern baldness and prostate enlargement. It’s important to remember that DHT and DHT derived compounds are used quite successfully to treat gynecomastia, and in this area, Proviron is no different.

Let’s delve into some of the positive points of this drug before we go any farther. androgen receptors are found in fat cells as well as muscle cells (5), and while they act on the AR in muscle cells to promote growth, they also act directly on the AR in fat cells to affect fat burning (9)(3). The stronger the androgen binds to the AR, the higher the lipolytic (fat burning) effect on adipose (fat) tissue (6)(2). As if that’s not enough good news, some steroids (notably, testosterone) even increase the numbers of ARs in muscle and fat (9)(7). Thus, if you are taking a simple stack of proviron and testosterone, you’ll have more of the Test you shoot as free testosterone floating around building muscle (compliments of the Proviron) and more androgen receptors to be bound to (compliments of your testosterone) by your Proviron, thus causing more fat loss. Testosterone and Proviron is a very nice synergistic stack, pretty nearly an “ideal” stack of an oral and injectable, because both drugs will actually act to enhance each other.

So what we have here is a steroid that can basically make other steroids more effective by preventing their conversion into estrogen, as well as increasing the amount of circulating free testosterone in your body. This of course all provides a more hardened and quality look to muscles. Proviron is very much a “synergistic” drug in this respect, and its inclusion in any cycle would definitely make all of the other steroids perform better, and provide better gains. This is all compounded by the fact that Proviron is a very lipolytic (fat-burning) drug.

Now, as if all of this weren’t enough, let’s talk about how Proviron affects your HPTA (hypothalamic-pituitary-testicular-axis), the thing that regulates the male hormonal system. When a reasonable dose of this stuff is given (100-150mgs/day), it had no depressing effect on low or normal serum FSH and LH levels (6). Follicle Stimulating Hormone (FSH) and Leutenizing Hormone (LH) are two hormones that send a signal to your testes to produce testosterone. Thus, by not suppressing those hormones, your normal testosterone levels will remain intact. This points to a novel use for this compound during post-cycle-therapy: a non-suppressive “bridge” between cycles. In fact, in yet another study, administration of Proviron (basically the same dose as in the last study) produced no changes in steroids, thyroid hormones, gonadotropins or PRL (prolactin levels—you want those to remain low) (8).

Unfortunately, this stuff is not too hot on it’s own. It’s a good drug for inclusion in a cycle containing testosterone and other armoatizable steroids, and it’s a good drug for a possible “bridge” between cycles. Alone, however, as an androgenic or anabolic agent its effects have been very weak in both studies (9), as well as in the experience of everyone I spoke to about it. This may be due to the addition of the 1-methyl-group to DHT, which makes this stuff orally active. Whatever the case, as a stand-alone anabolic or androgenic compound, it’s not too impressive.

This drug is a rare find on the black market, and many underground labs do not produce it, but if you can find it, I’d say that you shouldn’t be paying more than .50 cents for each 50mg tab.

Here’s how your body metabolizes Mesterolone: (pic)

Mesterolone References:
1. Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormonebinding globulin.Endocrinology. 1984 Jun;114(6):2100-6.
2. APMIS. 2000 Dec;108(12):838-46.
3. (Xu X, et al. "The effects of androgens on the regulation of lipolysis in adipose precursor cells." Endocrinology 1990 Feb;126(2):1229 ).
4. J Anim Sci. 1992 Nov;70(11):3381-90.
5. Am J Physiol. 1998 Jun;274(6 Pt 1):C1645-52.
6. The effect of mesterolone on sperm count, on serum follicle stimulating hormone, luteinizing hormone, plasma testosterone and outcome in idiopathic oligospermic men.Int J Gynaecol Obstet. 1988 Feb;26(1):121-8.
7. J Appl. Physiol.94 1153-61 2003
8. Effect of non aromatizable androgens on LHRH and TRH responses in primary testicular failure.Horm Metab Res. 1984 Sep;16(9):492-7.
9. [Androgen substitution in the andrological disease picture] Andrologia. 1983 May-Jun;15(3):283-6. German.

[elpropiotorvic]

i wanna know about the lh/fsh/hgh someone?

[BJJ]

.....

[BJJ]

.....

[BJJ]

Anavar, Oxandrin.
Unlike most oral steroids, which are Class II steroids giving most of their anabolic effect by means other than the androgen receptor (AR), it seems that oxandrolone probably does have good binding to the AR, and is therefore a Class I steroid, while having little other effect. By itself it is considered to be a weak anabolic.

Partly this is due to its apparent lack of non-AR-mediated activity. This can be corrected of course by stacking with a Class II steroid such as Dianabol, Anadrol®, 4-AD, or nor-4-AD: the latter two steroids require high blood levels which are not obtained by oral use of the powders.

The other part of the reason for this is that bodybuilders make unfortunate and unreasonable comparisons when judging anabolic steroids. If say 8 tablets per day does little, then the drug is pronounced useless or weak by the user. But that is only 20 mg/day, or 140 mg/week. Does 140 mg/week testosterone give much results? No. Few anabolic steroids give dramatic results at that dose. Per milligram the potency is reasonable, but each individual tablet is weak because the dosage is small.

Because of its high price, very few bodybuilders have taken large doses of oxandrolone. There is a single case in the medical literature (Forbes et al.) where it is reported that a competitive athlete self-administered 150 mg oxandrolone per day with remarkable gains. This is of uncertain credibility because unless urinalysis was done to verify that no other steroids were taken, there is no way to be certain that the athlete did not actually take more drugs than he reported. In any case, at current prices, only the quite wealthy could afford such a dose. I personally have tried 150 mg/day and considered it somewhat effective, but not dramatically so, and not a preferred regimen.

Oxandrolone does not aromatize or convert to DHT, and has a longer half life than Dianabol - 8 hours vs. 4 hours. Thus, a moderate dose taken in the morning is largely out of the system by night, yet supplies reasonable levels of androgen during the day and early evening.

Oxandrolone shares the liver toxicity problems common to 17-alkylated steroids. At one time it was thought that it did not, but both clinical and practical experience with Oxandrin has shown that at doses of 40 mg/day and higher, liver toxicity is indeed an issue with prolonged use.

Primobolan, I believe, should be considered a superior compound, offering the same activity at (usually) a lower price and without the alkylated-toxicity issue.

Oxandrolone is the chemical name of active ingredient in Oxandrin and Anavar. Oxandrin is a registered trademark of Bio-Technology General Corp. in the United States and/or other countries. Anavar was originally the registered trademark of Searle Laboratories.

Substance name: Oxandrolone [USAN:INN]
Chemical name: 17ß-hydroxy-17a-methyl-2-oxa-5a-androstan-3-one
Systematic name:N/A
Index name: 2-Oxaandrostan-3-one, 17-hydroxy-17-methyl-, (5alpha,17beta)-CAS number 53-39-4
Merck Index Number: Merck 11, 6875
Molecular formula: C19-H30-O3
Molecular weight: 306.443 g/mol
Legal status: Prescription only (US); DEA Schedule III (US)
Routes of administration: Oral

[BJJ]

Proviron (mesterolone) is an interesting anabolic steroid, though it is not of much value to bodybuilding.

It seems that the most common reason for many to consider including it in a steroid stack is for anti-estrogenic activity. In the days before anti-aromatases and the use of SERMs (selective estrogen receptor modulators) such as Clomid and Nolvadex, there was some merit to this. An amount of aromatizing steroid marginally over the amount that would be tolerable without Proviron became tolerable with the inclusion of it.

However, the effect is indeed only marginal, and much better anti-estrogenic agents now exist. When these are used, there is no need for Proviron as an anti-estrogen.

The mechanism by which it has some effectiveness in this regard is from binding weakly to the estrogen receptor without activating it, and to the aromatase enzyme. In the first case, this partially reduces the number of receptor sites momentarily available to bind estrogen, thus reducing estrogenic activity. In the second case, some fraction of aromatase molecules at any given moment are unavailable to bind and convert testosterone, their binding sites being occupied with mesterolone.

The second most common reason is probably to address a fear that libido might be lost without it. It is true that when added to normal androgen levels, Proviron has an androgenic effect that in many cases improves libido. However, most anabolic steroids also have this same property. In a steroid cycle, adding Proviron accomplishes nothing further. Or in the case of anabolic steroids such as nandrolone (Deca) which for other reasons may adversely affect libido, Proviron provides no greater help against that than do various other anabolic steroids.

One of the interesting things about Proviron is that while it assays (tests) as being an effective anabolic in the rat, it is virtually useless for building muscle in man. This may be due to enhanced conversion in muscle tissue to the diol, but it may instead be due to some unknown reason.

Another interesting thing is that it enjoys some practical use as a pro-sexual agent inbetween cycles. Typically 50 mg is taken shortly before improved performance is expected to be useful.

Contrary to common belief, Proviron is somewhat inhibitory of the HPTA. Using it during the recovery phase as part of post-cycle therapy is counterproductive. It is also inadvisable for this reason to use it continuously while intending to be off-cycle, but occasional recreational use presents no problem.

Proviron has been used in female bodybuilding, but it has almost undoubtedly the worst ratio of anabolic effect to virilizing effect of any anabolic steroid in common use. The perceived value is in fat loss and “hardening,” but friendlier choices exist for this. Most of that value is from anti-estrogenic effect, which Nolvadex can also accomplish. And for an androgen component, there are better choices, including Primobolan.

Unlike almost all other orals, Proviron is not hepatotoxic, as it is not 17-alkylated.

Tablets are typically 25 mg, and taken one or two at a time. Amounts greater than this have no further effect on improving libido off-cycle, but if used for a specific occasion, whether on-cycle or off-cycle, may temporarily improve vascularity, if it is already noticeable but has room for improvement.

Mesterolone is the chemical name of active ingredient in Proviron. Proviron was a registered trademark of Schering AG in the United States and/or other countries prior to cancellation.

Substance name: Mesterolone [USAN]
Chemical name: Androstan-3-one, 17-hydroxy-1-methyl-, (1alpha,5alpha,17beta)
Systematic name IUPAC: (1S,5S,8R,9S,10R,13S,14S,17S)-17-hydroxy-1,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one
CAS number: 1424-00-6
Merck Index Number: Merck 11, 5817
Chemical formula: C20-H32-O2
Molecular weight: 304.467 g/mol
Bioavailability: ?
Metabolism: Hepatic
Elimination half-life: ?
Excretion: Urinary (90%); Fecal (6%)
Pregnancy category: X
Legal status: Illegal (US); DEA Schedule III (US)
Routes of administration: Oral

[BJJ]

Oxandrolone

International Programme on Chemical Safety
Poisons Information Monograph 913
Pharmaceutical

This monograph does not contain all of the sections completed. This
mongraph is harmonised with the Group monograph on Anabolic Steroids
(PIM G007).

1. NAME

1.1 Substance

Oxandrolone

1.2 Group

ATC Classification:
A14 (Anabolic Agents for Systemic Use)
A14A (Anabolic steroids)

1.3 Synonyms

NSC-67068; SC-11585

1.4 Identification numbers

1.4.1 CAS number

53-39-4

1.4.2 Other numbers

1.5 Main brand names, main trade names

1.6 Main manufacturers, main importers

2. SUMMARY

2.1 Main risks and target organs

There is no serious risk from acute poisoning, but
chronic use can cause harm. The main risks are those of
excessive androgens: menstrual irregularities and
virilization in women and impotence, premature cardiovascular
disease and prostatic hypertrophy in men. Both men and women
can suffer liver damage with oral anabolic steroids
containing a substituted 17-alpha-carbon. Psychiatric changes
can occur during use or after cessation of these
agents.

2.2 Summary of clinical effects

Acute overdosage can produce nausea and gastrointestinal
upset. Chronic usage is thought to cause an increase in
muscle bulk, and can cause an exageration of male
characteristics and effects related to male hormones.
Anabolic steroids can influence sexual function. They can
also cause cardiovascular and hepatic damage. Acne and male-
pattern baldness occur in both sexes; irregular menses,
atrophy of the breasts, and clitor*****ly in women; and
testicular atrophy and prostatic hypertrophy in men.

2.3 Diagnosis

The diagnosis depends on a history of use of oral or
injected anabolic steroids, together with signs of increased
muscle bulk, commonly seen in "body-builders". Biochemical
tests of liver function are often abnormal in patients who
take excessive doses of oral anabolic steroids.

Laboratory analyses of urinary anabolic steroids and their
metabolites can be helpful in detecting covert use of these
drugs.

2.4 First aid measures and management principles

Supportive care is the only treatment necessary or
appropriate for acute intoxication. Chronic (ab)users can be
very reluctant to cease abuse, and may require professional
help as with other drug misuse.

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

Naturally-occuring anabolic steroids are synthesised in
the testis, ovary and adrenal gland from cholesterol via
pregnenolone. Synthetic anabolic steroids are based on the
principal male hormone testosterone, modified in one of three
ways:

alkylation of the 17-carbon
esterification of the 17-OH group
modification of the steroid nucleus

(Murad & Haynes, 1985).

3.2 Chemical structure

Chemical Name:
17beta-Hydroxy-17alpha-methyl-2-oxa-5alpha-androstan-3-one


Molecular Formula: C19H30O3

Molecular Weight: 306.4

3.3 Physical properties

3.3.1 Colour

White

3.3.2 State/form

Solid-crystal

3.3.3 Description

Soluble 1 in 5200 of water, 1 in 57 of alcohol,
1 in 69 of acetone, 1 in less than 5 of chloroform,
and 1 in 860 of ether.

3.4 Other characteristics

3.4.1 Shelf-life of the substance

3.4.2 Storage conditions

Protect from light.

Vials for parenteral administration should be stored
at room temperature (15 to 30°C). Visual inspection
for particulate and/or discoloration is
advisable.

4. USES

4.1 Indications

4.1.1 Indications

Anabolic agent; systemic
Anabolic steroid
Androstan derivative; anabolic steroid
Estren derivative; anabolic steroid
Other anabolic agent
Anabolic agent for systemic use; veterinary
Anabolic steroid; veterinary
Estren derivative; veterinary

4.1.2 Description

The only legitimate therapeutic indications for
anabolic steroids are:


(a) replacement of male sex steroids in men who have
androgen deficiency, for example as a result of loss
of both testes

(b) the treatment of certain rare forms of aplastic
anaemia which are or may be responsive to anabolic
androgens.

(ABPI Data Sheet Compendium, 1993)

(c) the drugs have been used in certain countries to
counteract catabolic states, for example after major
trauma.

4.2 Therapeutic dosage

4.2.1 Adults

4.2.2 Children

Not applicable

4.3 Contraindications

Known or suspected cancer of the prostate or (in men)
breast.
Pregnancy or breast-feeding.
Known cardiovascular disease is a relative contraindication.

5. ROUTES OF EXPOSURE

5.1 Oral

Anabolic steroids can be absorbed from the
gastrointestinal tract, but many compounds undergo such
extensive first-pass metabolism in the liver that they are
inactive. Those compounds in which substitution of the 17-
carbon protects the compound from the rapid hepatic
metabolism are active orally (Murad and Haynes, 1985).
There are preparations of testosterone that can be taken
sublingually.

5.2 Inhalation

Not relevant

5.3 Dermal

No data available

5.4 Eye

Not relevant

5.5 Parenteral

Intramuscular or deep subcutaneous injection is the
principal route of administration of all the anabolic
steroids except the 17-alpha-substituted steroids which are
active orally.

5.6 Other

Not relevant

6. KINETICS

6.1 Absorption by route of exposure

The absorption after oral dosing is rapid for
testosterone and probably for other anabolic steroids, but
there is extensive first-pass hepatic metabolism for all
anabolic steroids except those that are substituted at the
17-alpha position.

The rate of absorption from subcutaneous or intramuscular
depots depends on the product and its formulation. Absorption
is slow for the lipid-soluble esters such as the cypionate or
enanthate, and for oily suspensions.

6.2 Distribution by route of exposure

The anabolic steroids are highly protein bound, and is
carried in plasma by a specific protein called sex-hormone
binding globulin.

6.3 Biological half-life by route of exposure

The metabolism of absorbed drug is rapid, and the
elimination half-life from plasma is very short. The duration
of the biological effects is therefore determined almost
entirely by the rate of absorption from subcutaneous or
intramuscular depots, and on the de-esterification which
precedes it (Wilson, 1992).

6.4 Metabolism

Free (de-esterified) anabolic androgens are metabolized
by hepatic mixed function oxidases (Wilson, 1992).

6.5 Elimination by route of exposure

After administration of radiolabelled testosterone,
about 90% of the radioactivity appears in the urine, and 6%
in the faeces; there is some enterohepatic recirculation
(Wilson, 1992).

7. PHARMACOLOGY AND TOXICOLOGY

7.1 Mode of action

7.1.1 Toxicodynamics

The toxic effects are an exaggeration of the
normal pharmacological effects.

7.1.2 Pharmacodynamics

Anabolic steroids bind to specific receptors
present especially in reproductive tissue, muscle and
fat (Mooradian & Morley, 1987). The anabolic steroids
reduce nitrogen excretion from tissue breakdown in
androgen deficient men. They are also responsible for
normal male sexual differentiation. The ratio of
anabolic ("body-building") effects to androgenic
(virilizing) effects may differ among the members of
the class, but in practice all agents possess both
properties to some degree. There is no clear evidence
that anabolic steroids enhance overall athletic
performance (Elashoff et al, 1991).

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

No data available.

7.2.1.2 Children

No data available.

7.2.2 Relevant animal data

No data available.

7.2.3 Relevant in vitro data

No data

7.3 Carcinogenicity

Anabolic steroids may be carcinogenic. They can
stimulate growth of sex-hormone dependent tissue, primarily
the prostate gland in men. Precocious prostatic cancer has
been described after long-term anabolic steroid abuse(Roberts
& Essenhigh, 1986). Cases where hepatic cancers have been
associated with anabolic steroid abuse have been reported
(Overly et al, 1984).

7.4 Teratogenicity

Androgen ingestion by a pregnant mother can cause
virilization of a female fetus (Dewhurst & Gordon,
1984).

7.5 Mutagenicity

No data available.

7.6 Interactions

No data available.

7.7 Main adverse effects

The adverse effects of anabolic steroids include weight
gain, fluid retention, and abnormal liver function as
measured by biochemical tests. Administration to children can
cause premature closure of the epiphyses. Men can develop
impotence and azoospermia. Women are at risk of
virilization.

8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)

8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations

8.4 Other biomedical (diagnostic) investigations and their
interpretation

8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations

Biomedical analysis
The following tests can be relevant in the investigation of
chronic anabolic steroid abuse:
a) full blood count
b) electrolytes and renal function tests
c) hepatic function tests
d) testosterone
e) Lutenizing hormone
f) prostatic acid phosphatase or prostate related antigen
g) blood glucose concentration
h) cholesterol concentration

Toxicological analysis
-urinary analysis for anabolic steroids and their
metabolites

Other investigations
-electrocardiogram

8.6 References

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Nausea and vomiting can occur.

9.1.2 Inhalation

Not relevant

9.1.3 Skin exposure

Not relevant

9.1.4 Eye contact

Not relevant

9.1.5 Parenteral exposure

Patients are expected to recover rapidly after
acute overdosage, but there are few data. "Body-
builders" use doses many times the standard
therapeutic doses for these compounds but do not
suffer acute toxic effects.

9.1.6 Other

Not relevant

9.2 Chronic poisoning

9.2.1 Ingestion

Hepatic damage, manifest as derangement of
biochemical tests of liver function and sometimes
severe enough to cause jaundice; virilization in
women; prostatic hypertrophy, impotence and
azoospermia in men; acne, abnormal lipids, premature
cardiovascular disease (including stroke and
myocardial infarction), abnormal glucose tolerance,
and muscular hypertrophy in both sexes; psychiatric
disturbances can occur during or after prolonged
treatment (Ferner & Rawlins, 1988; Kennedy, 1992; Ross
& Deutch, 1990; Ryan, 1981; Wagner, 1989).

9.2.2 Inhalation

Not relevant

9.2.3 Skin exposure

Not relevant

9.2.4 Eye contact

Not relevant

9.2.5 Parenteral exposure

Virilization in women; prostatic hypertrophy,
impotence and azoospermia in men; acne, abnormal
lipids, premature cardiovascular disease (including
stroke and myocardial infarction), abnormal glucose

tolerance, and muscular hypertrophy in both sexes.
Psychiatric disturbances can occur during or after
prolonged treatment. Hepatic damage is not expected
from parenteral preparations.

9.2.6 Other

Not relevant

9.3 Course, prognosis, cause of death

Patients with symptoms of acute poisoning are expected
to recover rapidly. Patients who persistently abuse high
doses of anabolic steroids are at risk of death from
premature heart disease or cancer, especially prostatic
cancer. Non-fatal but long-lasting effects include voice
changes in women and fusion of the epiphyses in children.
Other effects are reversible over weeks or months.

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Chronic ingestion of high doses of anabolic
steroids can cause elevations in blood pressure, left
ventricular hypertrophy and premature coronary artery
disease (McKillop et al., 1986; Bowman, 1990; McNutt
et al., 1988).

9.4.2 Respiratory

Not reported

9.4.3 Neurological

9.4.3.1 Central nervous system

Stroke has been described in a young
anabolic steroid abuser (Frankle et al.,
1988).

Pope & Katz (1988) described mania and
psychotic symptoms of hallucination and
delusion in anabolic steroid abusers. They
also described depression after withdrawal
from anabolic steroids. There is also
considerable debate about the effects of
anabolic steroids on aggressive behaviour
(Schulte et al., 1993) and on criminal
behaviour (Dalby, 1992). Mood swings were
significantly more common in normal
volunteers during the active phase of a trial
comparing methyltestosterone with placebo (Su
et al., 1993).

9.4.3.2 Peripheral nervous system

No data available

9.4.3.3 Autonomic nervous system

No data available

9.4.3.4 Skeletal and smooth muscle

No data available

9.4.4 Gastrointestinal

Acute ingestion of large doses can cause nausea
and gastrointestinal upset.

9.4.5 Hepatic

Orally active (17-alpha substituted) anabolic
steroids can cause abnormalities of hepatic function,
manifest as abnormally elevated hepatic enzyme
activity in biochemical tests of liver function, and
sometimes as overt jaundice.

The histological abnormality of peliosis hepatis has
been associated with anabolic steroid use (Soe et al.,
1992).

Angiosarcoma (Falk et al, 1979) and a case of
hepatocellular carcinoma in an anabolic steroid user
has been reported (Overly et al., 1984).

9.4.6 Urinary

9.4.6.1 Renal

Not reported

9.4.6.2 Other

Men who take large doses of anabolic
steroids can develop prostatic hypertrophy.
Prostatic carcinoma has been described in
young men who have abused anabolic steroids
(Roberts & Essenhigh, 1986).

9.4.7 Endocrine and reproductive systems

Small doses of anabolic steroids are said to
increase libido, but larger doses lead to azoospermia
and impotence. Testicular atrophy is a common clinical

feature of long-term abuse of anabolic steroids, and
gynaecomastia can occur (Martikainen et al., 1986;
Schurmeyer et al., 1984; Spano & Ryan, 1984).

Women develop signs of virilism, with increased facial
hair, male pattern baldness, acne, deepening of the
voice, irregular menses and clitoral enlargement
(Malarkey et al., 1991; Strauss et al., 1984).

9.4.8 Dermatological

Acne occurs in both male and female anabolic
steroids abusers. Women can develop signs of virilism,
with increased facial hair and male pattern
baldness.

9.4.9 Eye, ear, nose, throat: local effects

Changes in the larynx in women caused by
anabolic steroids can result in a hoarse, deep voice.
The changes are irreversible.

9.4.10 Haematological

Anabolic androgens stimulate erythropoesis.

9.4.11 Immunological

No data available

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

No data available.

9.4.12.2 Fluid and electrolyte disturbances

Sodium and water retention can
occur, and result in oedema; hypercalcaemia
is also reported (Reynolds, 1992).

9.4.12.3 Others

Insulin resistance with a fall in
glucose tolerance (Cohen & Hickman, 1987),
and hypercholesterolaemia with a fall in high
density lipoprotein cholesterol, have been
reported (Cohen et al., 1988; Glazer,
1991;Webb et al., 1984).

9.4.13 Allergic reactions

No data available

9.4.14 Other clinical effects

No data available

9.4.15 Special risks

Risk of abuse

9.5 Other

No data available

9.6 Summary

10. MANAGEMENT

10.1 General principles

The management of acute overdosage consists of
supportive treatment, with fluid replacement if vomiting is
severe. Chronic abuse should be discouraged, and
psychological support may be needed as in the treatment of
other drug abuse. The possibility of clinically important
depression after cessation of usage should be borne in
mind.

10.2 Life supportive procedures and symptomatic/specific treatment

Not relevant

10.3 Decontamination

Not usually required.

10.4 Enhanced elimination

Not indicated

10.5 Antidote treatment

10.5.1 Adults

None available

10.5.2 Children

None available

10.6 Management discussion

Not relevant

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

A 38-year old man presented with acute urinary
retention, and was found to have carcinoma of the prostate.
He had taken anabolic steroids for many years, and worked as
a "strong-man" (Roberts and Essenhigh, 1986).

A 22-year old male world-class weight lifter developed severe
chest pain awaking him from sleep, and was shown to have
myocardial infarction. For six weeks before, he had been
taking high doses of oral and injected anabolic steroids.
Total serum cholesterol was 596 mg/dL (HDL 14 mg/dL, LDL 513
mg/dL) (McNutt et al., 1988). Values of total cholesterol
concentration above 200 mg/dL are considered undesirable.

A 22-year old body builder took two eight-week courses of
anabolic steroids. He became severely depressed after the
second course, and when the depression gradually receded, he
had prominent paranoid and religious delusions (Pope and
Katz, 1987).

A 19-year old American college footballer took intramuscular
testosterone and oral methandrostenolone over 4 months. He
became increasingly aggressive with his wife and child. After
he severely injured the child, he ceased using anabolic
steroids, and his violence and aggression resolved within 2
months (Schulte et al, 1993).

12. Additional information

12.1 Specific preventive measures

Anabolic steroid abuse amongst athletes, weight
lifters, body builders and others is now apparently common at
all levels of these sports. Not all abusers are competitive
sportsmen.
There is therefore scope for a public health campaign, for
example, based on gymnasia, to emphasize the dangers of
anabolic steroid abuse and to support those who wish to stop
using the drugs.

12.2 Other

No data available.

13. REFERENCES

ABPI Data Sheet Compendium (1993) Datapharm Publications,
London.

Bowman S. (1990) Anabolic steroids and infarction. Br Med J;
300:

Cohen JC & Hickman R. (1987) Insulin Resistance and diminished
glucose tolerance in powerlifters ingesting anabolic steroids. J
Clin Endocrinol Metab 64: 960.

14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)

Author: Dr R. E. Ferner,
West Midlands Centre for Adverse Drug Reaction
Reporting,
City Hospital Dudley Road,
Birmingham B18 7QH
England.
Tel: +44-121-5074587
Fax: +44-121-5236125
Email: [email protected]

Date: 1994

Peer review: INTOX Meeting, Sao Paulo, Brazil, September 1994
(Drs P.Kulling, R.McKuowen, A.Borges, R.Higa,
R.Garnier, Hartigan-Go, E.Wickstrom)

Editor: Dr M.Ruse, March 1998

[BJJ]

Mesterolone

International Programme on Chemical Safety
Poisons Information Monograph 904
Pharmaceutical

This monograph does not contain all of the sections completed. This
mongraph is harmonised with the Group monograph on Anabolic Steroids
(PIM G007).

1. NAME

1.1 Substance

Mesterolone

1.2 Group

ATC Classification:
A14 (Anabolic Agents for Systemic Use)
A14A (Anabolic steroids)

1.3 Synonyms

NSC-75054; SH-723

1.4 Identification numbers

1.4.1 CAS number

1424-00-6

1.4.2 Other numbers

1.5 Main brand names, main trade names

Mestoranum; Pro-viron; Proviron; Vistimon;
Pluriviron (multi-ingredient preparation)

1.6 Main manufacturers, main importers

2. SUMMARY

2.1 Main risks and target organs

There is no serious risk from acute poisoning, but
chronic use can cause harm. The main risks are those of
excessive androgens: menstrual irregularities and
virilization in women and impotence, premature cardiovascular
disease and prostatic hypertrophy in men. Both men and women
can suffer liver damage with oral anabolic steroids

containing a substituted 17-alpha-carbon. Psychiatric changes
can occur during use or after cessation of these
agents.

2.2 Summary of clinical effects

Acute overdosage can produce nausea and gastrointestinal
upset. Chronic usage is thought to cause an increase in
muscle bulk, and can cause an exageration of male
characteristics and effects related to male hormones.
Anabolic steroids can influence sexual function. They can
also cause cardiovascular and hepatic damage. Acne and male-
pattern baldness occur in both sexes; irregular menses,
atrophy of the breasts, and clitor*****ly in women; and
testicular atrophy and prostatic hypertrophy in men.

2.3 Diagnosis

The diagnosis depends on a history of use of oral or
injected anabolic steroids, together with signs of increased
muscle bulk, commonly seen in "body-builders". Biochemical
tests of liver function are often abnormal in patients who
take excessive doses of oral anabolic steroids.

Laboratory analyses of urinary anabolic steroids and their
metabolites can be helpful in detecting covert use of these
drugs.

2.4 First aid measures and management principles

Supportive care is the only treatment necessary or
appropriate for acute intoxication. Chronic (ab)users can be
very reluctant to cease abuse, and may require professional
help as with other drug misuse.

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

Naturally-occuring anabolic steroids are synthesised in
the testis, ovary and adrenal gland from cholesterol via
pregnenolone. Synthetic anabolic steroids are based on the
principal male hormone testosterone, modified in one of three
ways:

alkylation of the 17-carbon
esterification of the 17-OH group
modification of the steroid nucleus

(Murad & Haynes, 1985).

3.2 Chemical structure

Chemical Name:
17beta-Hydroxy-1alpha-methyl-5alpha-androstan-3-one.

Molecular Formula: C20H32O2

Molecular Weight: 304.5

3.3 Physical properties

3.3.1 Colour

3.3.2 State/form

3.3.3 Description

3.4 Other characteristics

3.4.1 Shelf-life of the substance

3.4.2 Storage conditions

Protect from light.

Vials for parenteral administration should be stored
at room temperature (15 to 30°C). Visual inspection
for particulate and/or discoloration is
advisable.

4. USES

4.1 Indications

4.1.1 Indications

Anabolic agent; systemic
Anabolic steroid
Androstan derivative; anabolic steroid
Estren derivative; anabolic steroid
Other anabolic agent
Anabolic agent for systemic use; veterinary
Anabolic steroid; veterinary
Estren derivative; veterinary

4.1.2 Description

The only legitimate therapeutic indications for
anabolic steroids are:

(a) replacement of male sex steroids in men who have
androgen deficiency, for example as a result of loss
of both testes


(b) the treatment of certain rare forms of aplastic
anaemia which are or may be responsive to anabolic
androgens.

(ABPI Data Sheet Compendium, 1993)

(c) the drugs have been used in certain countries to
counteract catabolic states, for example after major
trauma.

4.2 Therapeutic dosage

4.2.1 Adults

4.2.2 Children

Not applicable

4.3 Contraindications

Known or suspected cancer of the prostate or (in men)
breast.
Pregnancy or breast-feeding.
Known cardiovascular disease is a relative contraindication.

5. ROUTES OF EXPOSURE

5.1 Oral

Anabolic steroids can be absorbed from the
gastrointestinal tract, but many compounds undergo such
extensive first-pass metabolism in the liver that they are
inactive. Those compounds in which substitution of the 17-
carbon protects the compound from the rapid hepatic
metabolism are active orally (Murad and Haynes, 1985).
There are preparations of testosterone that can be taken
sublingually.

5.2 Inhalation

Not relevant

5.3 Dermal

No data available

5.4 Eye

Not relevant

5.5 Parenteral

Intramuscular or deep subcutaneous injection is the
principal route of administration of all the anabolic
steroids except the 17-alpha-substituted steroids which are
active orally.

5.6 Other

Not relevant

6. KINETICS

6.1 Absorption by route of exposure

The absorption after oral dosing is rapid for
testosterone and probably for other anabolic steroids, but
there is extensive first-pass hepatic metabolism for all
anabolic steroids except those that are substituted at the
17-alpha position.

The rate of absorption from subcutaneous or intramuscular
depots depends on the product and its formulation. Absorption
is slow for the lipid-soluble esters such as the cypionate or
enanthate, and for oily suspensions.

6.2 Distribution by route of exposure

The anabolic steroids are highly protein bound, and is
carried in plasma by a specific protein called sex-hormone
binding globulin.

6.3 Biological half-life by route of exposure

The metabolism of absorbed drug is rapid, and the
elimination half-life from plasma is very short. The duration
of the biological effects is therefore determined almost
entirely by the rate of absorption from subcutaneous or
intramuscular depots, and on the de-esterification which
precedes it (Wilson, 1992).

6.4 Metabolism

Free (de-esterified) anabolic androgens are metabolized
by hepatic mixed function oxidases (Wilson, 1992).

6.5 Elimination by route of exposure

After administration of radiolabelled testosterone,
about 90% of the radioactivity appears in the urine, and 6%
in the faeces; there is some enterohepatic recirculation
(Wilson, 1992).

7. PHARMACOLOGY AND TOXICOLOGY

7.1 Mode of action

7.1.1 Toxicodynamics

The toxic effects are an exaggeration of the
normal pharmacological effects.

7.1.2 Pharmacodynamics

Anabolic steroids bind to specific receptors
present especially in reproductive tissue, muscle and
fat (Mooradian & Morley, 1987). The anabolic steroids
reduce nitrogen excretion from tissue breakdown in
androgen deficient men. They are also responsible for
normal male sexual differentiation. The ratio of
anabolic ("body-building") effects to androgenic
(virilizing) effects may differ among the members of
the class, but in practice all agents possess both
properties to some degree. There is no clear evidence
that anabolic steroids enhance overall athletic
performance (Elashoff et al, 1991).

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

No data available.

7.2.1.2 Children

No data available.

7.2.2 Relevant animal data

No data available.

7.2.3 Relevant in vitro data

No data

7.3 Carcinogenicity

Anabolic steroids may be carcinogenic. They can
stimulate growth of sex-hormone dependent tissue, primarily
the prostate gland in men. Precocious prostatic cancer has
been described after long-term anabolic steroid abuse(Roberts
& Essenhigh, 1986). Cases where hepatic cancers have been
associated with anabolic steroid abuse have been reported
(Overly et al, 1984).

7.4 Teratogenicity

Androgen ingestion by a pregnant mother can cause
virilization of a female fetus (Dewhurst & Gordon,
1984).

7.5 Mutagenicity

No data available.

7.6 Interactions

No data available.

7.7 Main adverse effects

The adverse effects of anabolic steroids include weight
gain, fluid retention, and abnormal liver function as
measured by biochemical tests. Administration to children can
cause premature closure of the epiphyses. Men can develop
impotence and azoospermia. Women are at risk of
virilization.

8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)

8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations

8.4 Other biomedical (diagnostic) investigations and their
interpretation

8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations

Biomedical analysis
The following tests can be relevant in the investigation of
chronic anabolic steroid abuse:
a) full blood count
b) electrolytes and renal function tests
c) hepatic function tests
d) testosterone
e) Lutenizing hormone
f) prostatic acid phosphatase or prostate related antigen
g) blood glucose concentration
h) cholesterol concentration

Toxicological analysis
-urinary analysis for anabolic steroids and their
metabolites

Other investigations
-electrocardiogram

8.6 References

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Nausea and vomiting can occur.

9.1.2 Inhalation

Not relevant

9.1.3 Skin exposure

Not relevant

9.1.4 Eye contact

Not relevant

9.1.5 Parenteral exposure

Patients are expected to recover rapidly after
acute overdosage, but there are few data. "Body-
builders" use doses many times the standard
therapeutic doses for these compounds but do not
suffer acute toxic effects.

9.1.6 Other

Not relevant

9.2 Chronic poisoning

9.2.1 Ingestion

Hepatic damage, manifest as derangement of
biochemical tests of liver function and sometimes
severe enough to cause jaundice; virilization in
women; prostatic hypertrophy, impotence and
azoospermia in men; acne, abnormal lipids, premature
cardiovascular disease (including stroke and
myocardial infarction), abnormal glucose tolerance,
and muscular hypertrophy in both sexes; psychiatric
disturbances can occur during or after prolonged
treatment (Ferner & Rawlins, 1988; Kennedy, 1992; Ross
& Deutch, 1990; Ryan, 1981; Wagner, 1989).

9.2.2 Inhalation

Not relevant

9.2.3 Skin exposure

Not relevant

9.2.4 Eye contact

Not relevant

9.2.5 Parenteral exposure

Virilization in women; prostatic hypertrophy,
impotence and azoospermia in men; acne, abnormal
lipids, premature cardiovascular disease (including

stroke and myocardial infarction), abnormal glucose
tolerance, and muscular hypertrophy in both sexes.
Psychiatric disturbances can occur during or after
prolonged treatment. Hepatic damage is not expected
from parenteral preparations.

9.2.6 Other

Not relevant

9.3 Course, prognosis, cause of death

Patients with symptoms of acute poisoning are expected
to recover rapidly. Patients who persistently abuse high
doses of anabolic steroids are at risk of death from
premature heart disease or cancer, especially prostatic
cancer. Non-fatal but long-lasting effects include voice
changes in women and fusion of the epiphyses in children.
Other effects are reversible over weeks or months.

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Chronic ingestion of high doses of anabolic
steroids can cause elevations in blood pressure, left
ventricular hypertrophy and premature coronary artery
disease (McKillop et al., 1986; Bowman, 1990; McNutt
et al., 1988).

9.4.2 Respiratory

Not reported

9.4.3 Neurological

9.4.3.1 Central nervous system

Stroke has been described in a young
anabolic steroid abuser (Frankle et al.,
1988).

Pope & Katz (1988) described mania and
psychotic symptoms of hallucination and
delusion in anabolic steroid abusers. They
also described depression after withdrawal
from anabolic steroids. There is also
considerable debate about the effects of
anabolic steroids on aggressive behaviour
(Schulte et al., 1993) and on criminal
behaviour (Dalby, 1992). Mood swings were
significantly more common in normal

volunteers during the active phase of a trial
comparing methyltestosterone with placebo (Su
et al., 1993).

9.4.3.2 Peripheral nervous system

No data available

9.4.3.3 Autonomic nervous system

No data available

9.4.3.4 Skeletal and smooth muscle

No data available

9.4.4 Gastrointestinal

Acute ingestion of large doses can cause nausea
and gastrointestinal upset.

9.4.5 Hepatic

Orally active (17-alpha substituted) anabolic
steroids can cause abnormalities of hepatic function,
manifest as abnormally elevated hepatic enzyme
activity in biochemical tests of liver function, and
sometimes as overt jaundice.

The histological abnormality of peliosis hepatis has
been associated with anabolic steroid use (Soe et al.,
1992).

Angiosarcoma (Falk et al, 1979) and a case of
hepatocellular carcinoma in an anabolic steroid user
has been reported (Overly et al., 1984).

9.4.6 Urinary

9.4.6.1 Renal

Not reported

9.4.6.2 Other

Men who take large doses of anabolic
steroids can develop prostatic hypertrophy.
Prostatic carcinoma has been described in
young men who have abused anabolic steroids
(Roberts & Essenhigh, 1986).

9.4.7 Endocrine and reproductive systems

Small doses of anabolic steroids are said to
increase libido, but larger doses lead to azoospermia
and impotence. Testicular atrophy is a common clinical
feature of long-term abuse of anabolic steroids, and
gynaecomastia can occur (Martikainen et al., 1986;
Schurmeyer et al., 1984; Spano & Ryan, 1984).

Women develop signs of virilism, with increased facial
hair, male pattern baldness, acne, deepening of the
voice, irregular menses and clitoral enlargement
(Malarkey et al., 1991; Strauss et al., 1984).

9.4.8 Dermatological

Acne occurs in both male and female anabolic
steroids abusers. Women can develop signs of
virilism, with increased facial hair and male pattern
baldness.

9.4.9 Eye, ear, nose, throat: local effects

Changes in the larynx in women caused by
anabolic steroids can result in a hoarse, deep voice.
The changes are irreversible.

9.4.10 Haematological

Anabolic androgens stimulate erythropoesis.

9.4.11 Immunological

No data available

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

No data available.

9.4.12.2 Fluid and electrolyte disturbances

Sodium and water retention can
occur, and result in oedema; hypercalcaemia
is also reported (Reynolds, 1992).

9.4.12.3 Others

Insulin resistance with a fall in
glucose tolerance (Cohen & Hickman, 1987),
and hypercholesterolaemia with a fall in high

density lipoprotein cholesterol, have been
reported (Cohen et al., 1988; Glazer, 1991;
Webb et al., 1984).

9.4.13 Allergic reactions

No data available

9.4.14 Other clinical effects

No data available

9.4.15 Special risks

Risk of abuse

9.5 Other

No data available

9.6 Summary

10. MANAGEMENT

10.1 General principles

The management of acute overdosage consists of
supportive treatment, with fluid replacement if vomiting is
severe. Chronic abuse should be discouraged, and
psychological support may be needed as in the treatment of
other drug abuse. The possibility of clinically important
depression after cessation of usage should be borne in
mind.

10.2 Life supportive procedures and symptomatic/specific treatment

Not relevant

10.3 Decontamination

Not usually required.

10.4 Enhanced elimination

Not indicated

10.5 Antidote treatment

10.5.1 Adults

None available

10.5.2 Children

None available

10.6 Management discussion

Not relevant

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

A 38-year old man presented with acute urinary
retention, and was found to have carcinoma of the prostate.
He had taken anabolic steroids for many years, and worked as
a "strong-man" (Roberts and Essenhigh, 1986).

A 22-year old male world-class weight lifter developed severe
chest pain awaking him from sleep, and was shown to have
myocardial infarction. For six weeks before, he had been
taking high doses of oral and injected anabolic steroids.
Total serum cholesterol was 596 mg/dL (HDL 14 mg/dL, LDL 513
mg/dL) (McNutt et al., 1988). Values of total cholesterol
concentration above 200 mg/dL are considered undesirable.

A 22-year old body builder took two eight-week courses of
anabolic steroids. He became severely depressed after the
second course, and when the depression gradually receded, he
had prominent paranoid and religious delusions (Pope and
Katz, 1987).

A 19-year old American college footballer took intramuscular
testosterone and oral methandrostenolone over 4 months. He
became increasingly aggressive with his wife and child. After
he severely injured the child, he ceased using anabolic
steroids, and his violence and aggression resolved within 2
months (Schulte et al, 1993).

12. Additional information

12.1 Specific preventive measures

Anabolic steroid abuse amongst athletes, weight
lifters, body builders and others is now apparently common at
all levels of these sports. Not all abusers are competitive
sportsmen.
There is therefore scope for a public health campaign, for
example, based on gymnasia, to emphasize the dangers of
anabolic steroid abuse and to support those who wish to stop
using the drugs.

12.2 Other

No data available.

13. REFERENCES

ABPI Data Sheet Compendium (1993) Datapharm Publications,
London.

Bowman S. (1990) Anabolic steroids and infarction. Br Med J;
300:

Cohen JC & Hickman R. (1987) Insulin Resistance and diminished
glucose tolerance in powerlifters ingesting anabolic steroids. J
Clin Endocrinol Metab 64: 960.

14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)

Author: Dr R. E. Ferner,
West Midlands Centre for Adverse Drug Reaction
Reporting,
City Hospital Dudley Road,
Birmingham B18 7QH
England.
Tel: +44-121-5074587
Fax: +44-121-5236125
Email: [email protected]

Date: 1994

Peer review: INTOX Meeting, Sao Paulo, Brazil, September 1994
(Drs P.Kulling, R.McKuowen, A.Borges, R.Higa,
R.Garnier, Hartigan-Go, E.Wickstrom)

Editor: Dr M.Ruse, March 1998

[BJJ]

International Agency for Research on Cancer (IARC)
Summaries & Evaluations
CLOMIPHENE CITRATE
(Group 3)

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p. 172)

Clomiphene
CAS No.: 58-22-0
Chem. Abstr. Name: 2-[4-(2-Chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine

Clomiphene citrate
CAS No.: 50-41-9
Chem. Abstr. Name: 2-[4-(2-Chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine-
2-hydroxy-1,2,3-propanetricarboxylate (1:1)

A. Evidence for carcinogenicity to humans (inadequate)

Only case reports of benign and malignant tumours occurring at various sites are available [ref: 1-5]. These include testicular tumours in three young men who had received clomiphene as part of hormonal treatment for oligospermia [ref: 2], a hepatoblastoma in a female infant whose mother had received clomiphene citrate as treatment for infertility [ref: 3], a liver-cell adenoma in a woman who had received clomiphene citrate for oligomenorrhoea [ref: 4], and unilateral testicular neoplasms in two of 650 oligospermic men who had received monthly treatments with clomiphene citrate (daily for three weeks followed by a week of rest) for six to 12 months [ref: 5].

B. Evidence for carcinogenicity to animals (inadequate)

Clomiphene citrate was tested in an inadequate experiment in newborn rats by single subcutaneous injection; reproductive-tract abnormalities, including uterine and ovarian tumours, were reported [ref: 1].

C. Other relevant data

No data were available on the genetic and related effects of clomiphene citrate in humans. It did not induce chromosomal aberrations or micronuclei in bone-marrow cells of mice treated in vivo [ref: 6].

Overall evaluation

Clomiphene citrate is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 21 (1979)

References

1. IARC Monographs, 21, 551-561

2. Neoptolemos, J.P., Locke, T.J. & Fossard, D.P. (1981) Testicular tumour associated with hormonal treatment for oligospermia. Lancet, ii, 754

3. Melamed, I., Bujanover, Y., Hammer, J. & Spirer, Z. (1982) Hepatoblastoma in an infant born to a mother after hormonal treatment for steriligy. New Engl. J. Med., 307, 820

4. Carrasco, D., Barrachina, M., Prieto, M. & Berenguer, J. (1983) Clomiphene citrate and liver cell adenoma. New Engl. J. Med., 310, 1120-1121

5. Nilsson, A. & Nilsson, S. (1985) Testicular germ cell tumors after clomiphene therapy for subfertility. J. Urol., 134, 560-562

6. IARC Monographs, Suppl. 6, 184-185, 1987
Synonyms for Clomiphene

* Chloramiphene
* 2-para-(2-Chloro-1,2-diphenylvinyl)-phenoxy]triethylamine
* 2-para-(b-Chloro-a-phenylstyryl)phenoxy]triethylamine
* Clomifene
* Clomiphene B

Synonyms for Clomiphene citrate

* Clomiphene dihydrogen citrate
* 2-[p-(2-Chloro-1,2-diphenylvinyl)phenoxy]triethylamine citrate (1:1)
* Clomid
* Clomifeno
* Clomivid
* Clomphid
* Chloramiphene
* Dyneric
* Genozym
* Ikaclomin
* Mer-41
* MRL 41
* MRL/41
* NSC 35770
* Omifin
* Racemic clomiphene citrate

Last updated: 9 March 1998

International Agency for Research on Cancer (IARC)
Summaries & Evaluations
CLOMIPHENE AND CLOMIPHENE CITRATE

VOL.: 21 (1979) (p. 551)

5. Summary of Data Reported and Evaluation
(N.B. - This section should be read in conjunction with the General Remarks on Sex Hormones and with the General Conclusions on Sex Hormones.)

5.1 Experimental data
Clomiphene citrate was inadequately tested in one experiment in newborn rats by subcutaneous injection; uterine and ovarian tumours were reported.

Clomiphene citrate is embryolethal for pre- and postimplantation embryos in several species and has various teratogenic effects in rats.

5.2 Human data
There are a few case reports of the occurrence of malignant and benign tumours at various sites in patients treated with clomiphene citrate, but there is no evidence of a causal relationship.

No definite association between clomiphene citrate administration and congenital defects in humans has been demonstrated.

5.3 Evaluation
The available experimental and human data are insufficient to evaluate the carcinogenicity of clomiphene citrate.

Subsequent evaluation: Suppl. 7 (1987)

Last updated 01/12/98

[BJJ]

PHARMACEUTICALS
1. NAME
1.1 Substance
Tamoxifen
1.2 Group
Anti-oestrogen, non-steroidal derivative of triphenyl ethylene
ATC: L02B A01
1.3 Synonyms
(Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-dimethylethylamine citrate
ICI 46 474
[trans-1-(4-beta-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene]
1.4 Identification numbers
1.4.1 CAS number
10540
1.4.2 Other numbers
Tamoxifen citrate: 54965-24-1
1.5 Brand names, Trade names
Emblon (Berk)
Noltam (Lederle)
Nolvadex (ICI)
Nolvadex-D (ICI)
Nolvadex forte(ICI)
Tamofen (Tillotts)
1.6 Manufacturers, Importers
Berk Pharmaceuticals Ltd., ICI Pharmaceuticals (UK).,
Lederle Laboratories., Tillotts Laboratories.
2. SUMMARY
2.1 Main risks and target organs
There is no record of serious effects from tamoxifen after
acute overdosage.

Adverse effects in therapeutic use are usually mild. They
include effects caused by antagonism of endogenous oestrogens:
hot flushes, non-specific gastrointestinal effects (nausea and
vomiting), central nervous system effects, and rare ocular
effects. Adverse haematological effects have been reported,
also isolated cases of death from peliosis hepatis and from
hyperlipidaemia.

In the treatment of breast cancer, hypercalcaemia and tumour
flare can occur.
2.2 Summary of clinical effects
Anti-oestrogenic effects in women treated with tamoxifen
include vasomotor symptoms (hot flushes), vaginal bleeding and
(in premenopausal women) irregular menses, and pruritus
vulvae. Nausea and vomiting can occur.

Dizziness, lethargy, depression, irritability and cerebellar
dysfunction have been described.

Reversible retinopathy with macular oedema has been reported
after high cumulative doses (&gt7g), and corneal changes can
occur.


Thrombocytopenia or leukopenia have been associated with
tamoxifen treatment. Thromboembolism, which may be due to the
disease rather than the treatment, has been recorded in women
given tamoxifen for breast cancer.
2.3 Diagnosis
Based on history of exposure and occurrence of adverse effects
such as hot flushes, nausea, vomiting, ocular disorders,
tumour flare, hypercalcemia, vaginal bleeding and CNS signs
and symptoms.
2.4 First aid measures and management principles
General measures such as inducing emesis or gastric lavage may
be indicated in massive overdosage.

Treatment is symptomatic.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic.
3.2 Chemical structure
(Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-
dimethylethylamine citrate

C26H29NO, C6H8O7

[trans-1-(4-beta-dimethylaminoethoxyphenyl)-1, 2-diphenylbut-1-ene]

Molecular weight = 563.6

pKa = 8.85
3.3 Physical properties
3.3.1 Properties of the substance
Solubility in water at 37 °C = 0.05 g/100 ml.
3.3.2 Properties of the locally available formulation
No data available.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
Assumed to be at least 5 years.
3.4.2 Shelf-life of the locally available formulation
Assumed to be at least 5 years.
3.4.3 Storage conditions
Store between 15 and 30 °C
Protect from light
3.4.4 Bioavailability
(to be added)
3.4.5 Specific properties and composition
(to be added by centre).
4. USES
4.1 Indications
Treatment of advanced breast cancer and adjuvant
treatment of early breast cancer.
Treatment of anovulatory infertility.
4.2 Therapeutic dosage
4.2.1 Adults
Breast cancer: initial dose 10 mg twice daily;
if no response after 1 month, 20 mg twice daily.


Infertility: regular menstruation, 10 mg twice daily on
days 2,3,4 and 5 of cycle, increasing to 20 mg twice
daily and 40 mg twice daily in successive cycles if
ovulation does not occur.

Amenorrhoea: 10 mg twice daily on 4 successive days,
increasing to 20 mg twice daily and 40 mg twice daily
after intervals of 45 and 90 days if ovulation does not
occur.
4.2.2 Children
No data available.
4.3 Contraindications
Pregnancy is an absolute contraindication because of the anti-
oestrogenic effects.
5. ROUTES OF ENTRY
5.1 Oral
Usual route of entry
5.2 Inhalation
Not relevant.
5.3 Dermal
Not relevant.
5.4 Eye
Not relevant.
5.5 Parenteral
Not relevant.
5.6 Other
Not relevant.
6. KINETICS
6.1 Absorption by route of exposure
Peak concentrations occur 4-7 h after oral dosing. Peak
concentrations after single oral doses of 20 mg are about 40
µ/l. There is no information on absolute bioavailability.
(Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989)
6.2 Distribution by route of exposure
Tamoxifen is more than 99% protein-bound in serum,
predominantly to albumin. In patients with breast cancer,
concentrations of tamoxifen and its metabolites in pleural,
pericardial and peritoneal effusion fluid are between 20 and
100% of those in serum, but only trace amounts enter the
cerebrospinal fluid. Concentrations in breast cancer tissue
exceed those in serum.

The volume of distribution is 50-60 l/kg (Martindale, 1989;
Buckley & Goa, 1989; Lien et al., 1989)
6.3 Biological half-life by route of exposure
The elimination is biphasic, with an initial half-life of
around 7 h and a terminal half-life of 7-11 days. (Martindale,
1989; Buckley & Goa, 1989; Lien et al., 1989)
6.4 Metabolism
Tamoxifen citrate undergoes extensive hepatic metabolism to:

1-(4-ethanolyloxyphenyl)-1,2-diphenylbut-1-ene (the primary
alcohol)
N-desmethyl tamoxifen
4-hydroxy tamoxifen
4-hydroxy-N-desmethyl tamoxifen

N-desdimethyl tamoxifen

(Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989)
6.5 Elimination by route of exposure
The major excretory route is via the bile as metabolites and
enterohepatic recirculation occurs. Less than 1% is excreted
in the urine. (Martindale, 1989; Buckley & Goa, 1989; Lien et
al., 1989).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
The adverse effects observed are due mainly to its anti-
oestrogen effect, as Tamoxifen and certain of its
metabolites antagonise the effects of oestrogens in
oestrogen-sensitive tissues.
7.1.2 Pharmacodynamics
Tamoxifen and several of its metabolites (particularly 4-
hydroxytamoxifen) bind to nuclear oestrogen receptors in
oestrogen-sensitive tissues, and also to a microsomal
protein termed the 'anti-oestrogen binding site'.
Tamoxifen interferes with the physiological sequence by
which oestrogen binds to its receptor, is translocated
in the nucleus and then activates messenger RNA
synthesis. Although the tamoxifen-receptor complex is
transported in the nucleus in the same way as oestrogen-
receptor complex, it fails to activate synthesis of
mRNA. (Buckley & Goa, 1990)

A meta-analysis of published trials in breast cancer
(Early Breast Cancer Trialists, 1988) demonstrates a
reduction in odds of death of about 20% over the first 5
years from diagnosis in women aged over 50 years.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
There is no information on the acute toxicity of
tamoxifen in overdosage.

The lowest cumulative dose of tamoxifen known to
have induced retinopathy, an adverse effect
which is recognised to be dose-dependent, is 7.7
g (Griffiths, 1987)
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
In some animal species, oestrogenic agonist effects
become manifest at dosages equivalent to 10-100 times
the human therapeutic dose (ABPI, 1989).
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
A case-control study (Hardell, 1988) showed a significantly
increased relative risk of carcinoma of the uterus in women
previously treated with tamoxifen AND who had previously had
radiotherapy involving the uterus. The study showed an
increase in relative risk with tamoxifen treatment alone which

was NOT statistically significant (see also Section 7.4).
7.4 Teratogenicity
Studies in neonatal male (Taguchi, 1987) and female (Taguchi &
Nishizuka, 1985) mice at relative doses 10 times higher than
those used in humans have shown genital tract abnormalities
similar to those caused by diethylstilboestrol, a known
transplacental carcinogen (diethylstilboestrol causes vaginal
adenosis, which predisposes to clear cell carcinoma).
7.5 Mutagenicity
Tamoxifen is believed not to be mutagenic (Martindale, 1989).
7.6 Interactions
Tamoxifen POTENTIATES the anticoagulant effect of warfarin,
and this interaction can be life-threatening (Tenni et al,
1989; Ritchie & Grant, 1989).
7.7 Main adverse effects
Adverse effects are usually mild. Thrombocytopenia,
leukopenia, thromboembolism, peliosis hepatis and
hyperlipidaemia have been mentioned in case reports.

Severe hypercalcaemia can occur rarely when treatment is
started in patients with metastases to bone.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis

8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
No data available.
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
No data available.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Retinal damage and keratitis have been reported in
patients after large cumulative doses of tamoxifen,
generally over 180 mg per day for more than 1 year
(Buckley & Goa, 1989), though sometimes with smaller
doses (Griffiths, 1987). There seems to be correlation
between long-term tamoxifen administration and
endometrical proliferation (Uziely et al, 1993).
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
No data available.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
No data available.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
No data available.
9.4.2 Respiratory
No data available.
9.4.3 Neurological
9.4.3.1 CNS
A case of depression, syncope, and
incoordination has been described during therapy
with 10 mg twice daily (Pluss et al., 1984). The

symptoms resolved when tamoxifen was
discontinued and reappeared when treatment was
restarted.
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Nausea and vomiting occur with therapeutic doses in some
patients, and are anticipated in overdosage (ABPI, 1989)
9.4.5 Hepatic
A fatal case of peliosis hepatis has been reported in a
woman treated with tamoxifen for 2 years after
mastectomy for carcinoma (Loomus et al., 1983).
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Other
A case of persistent nocturnal priapism has been
reported (Fernando & Tobias, 1989).
9.4.7 Endocrine and reproductive systems
The anti-oestrogenic effects of tamoxifen in
premenopausal women receiving therapeutic doses can
cause irregular menses.

Anti-oestrogenic adverse effects in women treated with
tamoxifen include vasomotor symptoms (hot flushes),
vaginal bleeding and pruritus vulvae (Buckley & Goa,
1989).
9.4.8 Dermatological
No data available.
9.4.9 Eye, ear, nose, throat: local effects
Treatment has been associated with retinal and corneal
changes: see para 9.2.
9.4.10 Haematological
Thromboembolism may be more common in patients treated
with tamoxifen, though this is not certain, as patients
with cancer are at increased risk anyway.
A small reduction in antithrombin III concentration was
noted in a study of 11 postmenopausal women treated
with tamoxifen, but it was clinically insignificant,
and no significant reduction was seen in a group of
premenopausal women (Jordan et al., 1987).

Thrombocytopenia and leukopenia can occur during
therapy, but are not usually severe (ABPI, 1989). One
case of severe myelosuppression has been reported
(International Adjuvant Therapy Organisation, 1985).
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances

Severe hypercalcaemia, associated with
increased bone resorption, has been noted when
patients with bony metastases commenced
therapy (Martindale, 1989).
9.4.12.3 Others
Severe hyperlipidaemia is occasionally seen,
and has been ascribed to an oestrogenic effect
(Noguchi et al., 1987)
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy, breast feeding, enzyme deficiencies: no data
available (see sections 7.3 and 7.4)
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
It is unlikely that serious acute toxicity would occur, and
management is supportive. The stomach should be emptied
after massive overdosage.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
No data available.
10.2.2 Biomedical analysis
Urea, creatinine and electrolytes may be helpful in
the assessment of patients who are vomiting.
10.2.3 Toxicological analysis
Not relevant.
10.2.4 Other investigations
Not relevant.
10.3 Life supportive procedures and symptomatic/specific
treatment
Nausea and vomiting may make intravenous fluid replacement
necessary.
10.4 Decontamination
Gastric lavage may be of value in massive overdosage, but
there are no data on this subject.
10.5 Elimination
Therapy to enhance elimination is not likely to be effective,
given the large volume of distribution.
10.6 Antidote treatment
10.6.1 Adults
Not relevant.
10.6.2 Children
Not relevant.
10.7 Management discussion
No data available.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
No data available.
11.2 Internally extracted data on cases
One manufacturer (ICI) is aware of the case of a woman aged
51 years who claimed to have swallowed 100 x 10 mg tablets

of tamoxifen, and who suffered no ill effects (JI Landles,
personal communication).
11.3 Internal cases
No data available.
12. Additional information
12.1 Availability of antidotes
Not relevant.
12.2 Specific preventive measures
No data available.
12.3 Other
No data available.
13. REFERENCES
ABPI (Association of the British Pharmaceutical Industry) (1989)
Data Sheet Compendium. London.

Buckley M M-T, Goa KL (1989). Tamoxifen: a reappraisal of its
pharmacodynamic and pharmacokinetic properties and therapeutic
use. Drugs, 37: 451-490.

Early Breast Cancer Trialists Collaborative Group (1988).
Effects of adjuvant tamoxifen and of cytotoxic therapy on
mortality in early breast cancer. New Eng. J. Med., 319: 1681-
1692.

14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author: Dr R.E. Ferner
Northern Drug and Therapeutics Centre
The Wolfson Unit
Royal Victoria Infirmary
Newcastle-upon-Tyne NE1 4LP
United Kingdom

Tel: 44-91-2328511
Fax: 44-91-2323613

Date: 15 April 1990

Peer Review: Strasbourg, France, April 1990

Review: IPCS, May 1994

[BJJ]

TAMOXIFEN
(Group 1)

For definition of Groups, see Preamble Evaluation.

VOL.: 66 (1996) (p. 253)

CAS No.: 10540-29-1
Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine

CAS No.: 54965-24-1
Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine,
2-hydroxy-1,2,3-propanetricarboxylate (1:1)

5. Summary of Data Reported and Evaluation
5.1 Exposure data

Tamoxifen has been available since the early 1970s for the first-line treatment of metastatic breast cancer in postmenopausal women. Since the 1980s, it has become the therapy of choice for this condition. Tamoxifen has also become the adjuvant therapy of choice for treatment of postmenopausal, node-positive women with positive oestrogen-receptor or progesterone-receptor levels and, since the early 1990s, for the treatment of postmenopausal, node-negative women with positive oestrogen-receptor or progesterone-receptor levels. It is also widely used in treating postmenopausal receptor-negative women and premenopausal women with node-negative, receptor-positive disease. When used as adjuvant therapy, tamoxifen reduces the annual rates of both death from and recurrence of breast cancer by about 25%. Tamoxifen is commonly given at doses of 20 mg daily for periods of two to five years in the adjuvant setting, although doses of up to 40 mg daily have been used in the past. Several clinical trials are in progress to study the efficacy of tamoxifen in preventing breast cancer in healthy women believed to be at high risk of developing the disease.

Tamoxifen has been widely adopted as the first-line therapy of choice for hormone-responsive male breast cancer and is frequently used as adjuvant therapy for oestrogen receptor- or progesterone receptor-positive male breast cancer.

Tamoxifen is registered for use in nearly 100 countries and cumulative use since 1973 is estimated at 7 million patient-years.

5.2 Human carcinogenicity data

The potential effect of tamoxifen in increasing the risk of endometrial cancer has been reported in one adequate cohort study, four adequate case-control studies and 14 randomized controlled trials.

In the cohort study, based on follow-up of registered cases of breast cancer in the population-based Surveillance, Epidemiology and End Results (SEER) database in the United States, the only available data on therapy were those reported at the time of initial registration. Both groups of women with reported tamoxifen use and those with no such reported use had elevated rates of endometrial cancer compared with the rates expected from the SEER database as a whole. The risk was significantly greater for women with reported tamoxifen use. The similar stage distribution in the two groups suggests a lack of serious detection bias in this study. The absence of hysterectomies could not be confirmed in this study.

The case-control studies were based on the identification of a series of women with breast cancer who had subsequently been diagnosed with endometrial cancer, with tamoxifen exposure assessed in comparison with breast cancer patients who had not developed endometrial cancer. In two of these, case and control selection was based on the records of population-based cancer registries, and two used the same source as well as hospital-based cancer registries. For the Swedish study, although an increased risk of endometrial cancer for tamoxifen use was found, the only information on treatment was that recorded in the cancer registry. Further, the absence of hysterectomy in the control series could not be confirmed. For the remaining three case-control studies, more detailed data on treatment and on hysterectomies were obtained from medical records. In the studies in France and the Netherlands, a nonsignificant elevation of risk for endometrial cancer with use of tamoxifen was found, with a significant increase in risk with increasing duration of therapy in one. In the United States study, which reported on shorter duration of use, the point estimate of risk was less than unity.

Although several potential confounders were not systematically addressed in most studies, the Working Group considered that these were unlikely to have had a major effect on the reported relative risks.

In most of the randomized trials, small numbers of endometrial cancers were reported, and for many the data were not reported in a way that corrected for the greater survival time in most trials of the tamoxifen-treated patients compared to the control series. In two of the largest trials, however, there was a strong and statistically significant association between risk for endometrial cancer and use of tamoxifen. Although there may have been a tendency for publication bias and there is some possibility of a detection bias as a result of investigations in women with side-effects from tamoxifen, the magnitude of the risk found in the two large trials is unlikely to be explained by such biases. Further, for the trials that reported deaths in women with endometrial cancer, to date there have been eight deaths in women allocated to tamoxifen treatment groups and one in those not allocated to tamoxifen.

One case series reported significantly more high-grade endometrial tumours in tamoxifen-treated cancer patients than in patients without prior tamoxifen use. However, in at least six other studies, this difference was not found.

The SEER-based cohort study found a significantly reduced risk for contralateral breast cancers in the tamoxifen-treated women, compared with women with no reported tamoxifen use. The case-control study from the United States also reported a significant reduction of risk for contralateral cancers of the breast following tamoxifen use.

Although for some small trials there seemed to be little difference in the numbers of contralateral breast cancers in tamoxifen-treated women compared with controls, for the large trials, there was a substantially and significantly reduced risk for contralateral breast cancer in tamoxifen-treated women compared with controls. Further, in an overview analysis of nearly all trials published in 1992 with data available to 1990, there was a significant reduction of 39% in contralateral breast cancers in the tamoxifen-treated groups.

For all other cancer sites, no significant excess of any cancer has been found in either the cohort study or the trials. Although an excess of gastrointestinal cancer was reported following a combined analysis of three Scandinavian trials, this has not yet been confirmed by other studies.

5.3 Animal carcinogenicity data

Tamoxifen was tested for carcinogenicity by oral administration in one study in mice and in eight studies in rats, only one of which was a formal two-year study. In mice, the incidences of benign ovarian and testicular tumours were increased. In rats, tamoxifen induced preneoplastic liver lesions and benign or malignant liver tumours. In one study, the incidence of some tumours in hormone-dependent tissues was decreased, including in the mammary gland, although reduced weight gain may have been a contributing factor. In two studies in which tamoxifen was tested by subcutaneous implantation in intact or ovariectomized female mice, it inhibited mammary tumour development in both.

In mice, tamoxifen was reported to inhibit 3-methylcholanthrene-induced cervical cancer and virus-induced leukaemia. In several studies in both male and female rats, tamoxifen enhanced the hepatocarcinogenicity of previously administered N-nitrosodiethylamine. In one study in rats, tamoxifen enhanced the development of N-nitrosodiethylamine-induced kidney tumours. In a number of studies in rats, tamoxifen inhibited 7,12-dimethylbenz[a]anthracene-induced mammary tumour development. In two studies in hamsters, tamoxifen inhibited hormonal carcinogenesis induced by 17b-oestradiol in the kidney and zeranol in the liver.

5.4 Other relevant data

Orally administered tamoxifen is well absorbed and maximum plasma levels are reached in about 5 h. Steady-state concentrations of tamoxifen in humans are reached in 3-4 weeks and those of the primary metabolite, N-desmethyltamoxifen, in about eight weeks. Tissue concentrations tend to be higher than plasma concentrations. Metabolism involves phenyl hydroxylation, alkyl hydroxylation, demethylation and N-oxide formation. Metabolism results in more products in man and rats than in mice. Much higher oral doses of tamoxifen are required for rats or mice to achieve plasma concentrations similar to human levels.

Tamoxifen is an antioestrogen with complex pharmacology encompassing variable species-, tissue-, cell-, gene-, age- and duration of administration-specific effects from oestrogen-like agonist actions to complete blockade of oestrogen action. This complexity is consistent with the various, and sometimes paradoxical, effects that have been associated with tamoxifen administration in animals and humans.

The most frequent side-effects of tamoxifen administration are hot flushes and vaginal discharge. Tamoxifen has effects on the human uterus, inducing atrophy, hyperplasia and, less frequently, polyps. Randomized placebo-controlled trials revealed a slight increase of thromboembolic events, but also a protective effect regarding myocardial diseases, according to hospital admission rates and deaths. Tamoxifen administration has been shown to decrease blood total cholesterol and low-density lipoprotein-cholesterol concentrations in a number of studies. Several preliminary trials have suggested mildly positive effects of tamoxifen in preserving bone mineral density in postmenopausal women, but much longer follow-up is required to confirm t his potentially beneficial effect.

The acute toxicity of tamoxifen in experimental animals is low. In repeated-dose studies in rats, tamoxifen induced hypertrophy, but not cell proliferation, in the endometrial epithelium; endometrial hyperplasia was, however, reported in mice. Furthermore squamous metaplasia and atrophy of the uterine epithelium was observed in chronic studies in rats. Induction of cytochromes P450 and preneoplastic lesions have been detected in the livers of rats.

Ocular toxicity, including lipidosis of the retina and cornea and increased incidence of cataract, was reported in studies in rats of chronic exposure to tamoxifen.

In the presence of human, mouse, rat and hamster microsomes, tamoxifen binds covalently to protein. Tamoxifen has oestrogenic effects on human fetal genital tracts grown in athymic mice. In rats, doses above 2 mg/kg body weight produce irregular ossification of ribs in the fetus, which is thought to be secondary to reduction of the size of the uterus of the dam. No effects on the fetus have been reported in rabbits, marmosets or cynomolgus monkeys.

There is no direct evidence that tamoxifen is active in tests for gene mutation. Evidence for the genotoxic potential of tamoxifen is supported by data obtained on DNA adduct formation in rodent liver cells in vitro and in vivo, and in rodent and human liver microsomal systems; on unscheduled DNA synthesis in rat hepatocytes in vitro; and on the induction of clastogenic events both in vitro, in genetically-engineered human cells, and in vivo in rat liver.

There is evidence from 32P-postlabelling studies that three metabolites, (a-hydroxytamoxifen, 4-hydroxytamoxifen and (Z)-1,2-diphenyl-1-(4-hydroxyphenyl)but-1-ene (metabolite E) can be further metabolized to products that react with DNA. The major DNA adduct formed in rodent liver cells has been identified as (E)-(a-(N2-deoxyguanosinyl) tamoxifen. Human hepatocytes do not form detectable DNA adducts when treated in vitro with tamoxifen; they form 300-fold lower levels of adducts than rat and mouse hepatocytes when treated with a-hydroxytamoxifen.

Preliminary studies indicate that tamoxifen does not give rise to detectable levels of DNA adducts in human liver in vivo or in human endometrium in vitro and in vivo.

Mechanistic considerations

Tamoxifen increases liver tumour incidence in rats, which may involve both DNA damage leading to increased numbers of initiated cells and oestrogen receptor-mediated clonal expansion of those initiated cells.

The available evidence suggests that tamoxifen is carcinogenic in rat liver by a genotoxic mechanism. Preliminary information from studies of human tissues suggests that humans are less susceptible to the genotoxicity of tamoxifen. Tamoxifen also possesses tumour-promoting activity in the rat liver.

Several studies have shown that the liver contains significant quantities of oestrogen receptor in hepatocytes, Kupffer cells and endothelial cells.

Tamoxifen acts as an oestrogen agonist and/or antagonist by binding directly to the oestrogen receptor. In some tissues, such as breast, tamoxifen exhibits antioestrogenic properties by binding to the oestrogen receptor with high affinity. The tamoxifen-oestrogen receptor complex is incapable of binding to DNA-responsive elements. Thus, oestrogen receptor binding does not result in normal transcriptional activity. In other tissues, such as bone and liver, tamoxifen acts as a partial agonist, possibly because cells from those tissues contain a different array of DNA binding sites, thereby leading to typical oestrogen-mediated changes in gene expression and subsequent biological effects on growth and differentiation. Therefore, tissue-specific effects of tamoxifen-oestrogen receptor on gene expression may be involved in the ability of tamoxifen to increase or decrease tumour risk.

5.5 Evaluation

There is sufficient evidence in humans for the carcinogenicity of tamoxifen in increasing the risk for endometrial cancer and there is conclusive evidence that tamoxifen reduces the risk for contralateral breast cancer in women with a previous diagnosis of breast cancer.

There is inadequate evidence in humans for the carcinogenicity of tamoxifen in other organs.

There is sufficient evidence in experimental animals for the carcinogenicity of tamoxifen.

Overall evaluation

Tamoxifen is carcinogenic to humans (Group 1) and there is conclusive evidence that tamoxifen reduces the risk of contralateral breast cancer.

(Dr Cuzick dissociated himself from the evaluation process because he considered that the range of evaluation statements available within the framework of the Monographs was not suitable for this agent.)

For definition of the italicized terms, see Preamble Evaluation

Synonyms for Tamoxifen

* 1-para-b-Dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene
* (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]ethyldimethylamine

Synonyms for Tamoxifen citrate

* Apo-Tamox
* Citofen
* Dignotamoxi
* Duratamoxifen 5
* Emblon
* ICI-46474
* Jenoxifen
* Kessar
* Ledertam
* Noltam
* Nolvadex
* Nourytam
* Novofen
* Oestrifen
* Oncotam
* Retaxim
* Tafoxen
* Tam
* Tamaxin
* Tamifen
* Tamofen
* Tamone
* Tamoplex
* Tamoxasta
* Tamox-Gry
* Z-Tamoxifen citrate
* Tamoxigenat
* Tamox-Puren
* Taxfeno
* Terimon
* Valodex
* Zemide
* Zitazonium

Last updated 05/22/97

[BJJ]

After this deep researches, I need a break!

I have a question for those experienced with AAS while training.
Basically, today I did for the first time after many months, so I did not remember which weights I used to lift, the Dumbell Flies (Outer Pectorals).
I started with 22kgs and made 10 reps but I felt tired at the end. I thought that weight could be correct to keep going but then I decided to increase it to 24kgs, after all I am using anavar! WTF
So, each time I ended the 10 reps I added 2 kgs more and after 4 sets I reached 28 kgs (62 lbs, where I felt I was starting to use my shoulders to help).

Is this normal? I mean to start with a weight and just going up adding more even though it seemed the previous weight was enough?
Thank you.

[BJJ]

Today anavar made me happy indeed.
I used to lift (naturally) 28kgs 1 rep dumbbell curl (per arm), so 61 lbs.
I did the same weight but I made 4 sets of 8 reps and I am on day 27, not bad!

Furthermore, a guy who knows me a bit asked me what I am using not because I am bigger then used to be but because of the strength increase.
I told him I am using a mixture of powder creatine and liquid creatine...

I am in trouble now, he wants to do it too!

[elpropiotorvic]

Ha ... Getting called out sir... Say protein baby protein

[BJJ]

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[BJJ]

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[BJJ]

I am having some pangs on my rear part of the lower back.
It happened already sometimes during the last ten days but today it's bothering more than usual and it's persistent.
Anyone experienced in this before?
Yesterday, I added proviron at 50mg ed.

[fig]

Pics look good BJJ. Keep it up man!!!!

[BJJ]

Pics look good BJJ. Keep it up man!!!!

thx