Tag Archives: estrogen

HPTA

Inhibitian and Recovery of Natural Testosterone Production

picture of HPTA

There is no way to entirely avoid the problem, but there are ways to minimize the problem and recover natural testosterone levels reasonably quickly after a cycle

by Bill Roberts

One of the most significant side effects of anabolic/androgenic steroid (AAS) use is inhibition of natural testosterone production. There is no way to entirely avoid the problem, but there are ways to minimize the problem and recover natural testosterone levels reasonably quickly after a cycle. In this article, we will look at the problem of inhibition, its causes, and the best solutions currently known.
The Causes of Inhibition

Elevated hormone levels, in general, will cause inhibition of natural testosterone production. Many bodybuilders have come to believe that elevated estrogen levels alone are the sole cause of inhibition, and believe that by blocking estrogen, they can block inhibition.

This is not true. For example, consider the results seen in the second 2-on / 4-off cycle case study reported on Meso-Rx where Jim used 50 mg/day of trenbolone acetate, which does not aromatize, 50 mg/day of Dianabol, which does aromatize, with 250 mg/day of Cytadren as an aromatase inhibitor and 50 mg/day Clomid as an estrogen receptor blocker. His estrogen levels remained in the normal range, though elevated from baseline, since apparently the Cytadren was not sufficient to block aromatization completely. The Clomid should easily have been able to overcome normal estrogen levels, and so if the estrogen-only theory of inhibition were correct, Jim should have been suffering no inhibition. But the fact is, his testosterone levels dropped to only 1/10 his baseline value. Estrogen alone was not the cause of his inhibition. It could not have been the cause of any of it, given the normal levels and the Clomid use.

So much for the estrogen-only theory of inhibition that has been claimed by other writers. That isn’t to say, though, that estrogen is not also inhibitory: it is.

What then besides estrogen can cause inhibition? DHT, which does not aromatize, has been extensively shown to cause inhibition of testosterone production. Androgen alone, then, is sufficient to cause inhibition. In Jim’s case, androgen use was moderately heavy, and androgen alone would seem the cause of the inhibition.

Progesterone is another hormone that can cause inhibition, when used long-term. Paradoxically, in the short term it can be stimulatory. Other relevant factors include beta agonists, opiates, melatonin, prolactin, and probably other compounds. With the exception of beta agonists (e.g. ephedrine and Clenbuterol) and opiates (natural endorphins on the one hand being inhibitory, and Nubain blocking such inhibition) manipulation of these would not seem useful in bodybuilding.
————————————————————————–

The Hypothalamic/Pituitary/Testicular Axis (HPTA)

To understand inhibition of testosterone production, we need to know first how it is produced and how production is controlled. The broad general picture is that the hypothalamus receives a variety of inputs, for example, levels of various hormones, and decides whether or not more sex hormones should be produced. If the inputs are high, for example, high estrogen or high androgen or both, then it decides that little or no sex hormones should now be produced, but if all inputs are low, then it may decide that more sex hormones should be produced. It seems that the hypothalamus doesn’t respond only to current hormone levels, but also to the past history of hormone levels.

The hypothalamus itself cannot produce any sex hormones – instead it produces LHRH, or luteinizing hormone (LH) releasing hormone, also called GnRH (gonadotropin releasing hormone.) This then stimulates the pituitary gland.

The pituitary uses the amount of LHRH as one of its signals in deciding how much LH it should produce. Proper response depends on having sufficient receptors for LHRH. These receptors must be activated for LH to be produced. The pituitary also uses sex hormone levels, both current and the past history, in deciding how much LH to produce. Some aspects of the pituitary’s behavior are peculiar. For example, too much LHRH results in the pituitary downregulating LHRH receptors, with the result that very high LHRH production, which one would think should result in high testosterone production, actually lowers testosterone production. Another oddity is that while high estrogen levels inhibit the pituitary, still some estrogen is required to maintain a high number of LHRH receptors. So both very low and high levels of estrogen can inhibit LH production.

LH produced by the pituitary then stimulates the testicles to produce testosterone. Here, the amount of LH is the main factor, and high levels of sex hormones do not seem to cause inhibition at this level.
————————————————————————

Inhibition From AAS Cycles

Because high androgen levels sustained around the clock will cause inhibition, traditional cycles simply cannot avoid inhibition of LH production while on cycle. There are three ways to avoid it:

Avoid having high androgen levels around the clock. This can be done, for example, by using oral AAS only in the morning, with the last dose being approximately at noontime. Even 100 mg/day Dianabol can be used in this fashion with little inhibition. The problem with this approach is that gains are not very good compared to what is seen when high androgen levels are sustained around the clock.
Use an amount and kind of AAS that is low enough to avoid much inhibition. Primobolan at 200-400 mg/week may achieve this effect. Again, gains will be compromised compared to a more substantial cycle. Testosterone esters and Deca are substantially inhibitory even at 100 mg/week so using a low dose of these drugs will simply result in both inhibition and poor gains.
In principle, one could use an antiandrogen, but this would totally defeat the purpose of the cycle.
Where AAS doses are sufficient for good gains, an interesting pattern is seen. For the first two weeks of the cycle, only the hypothalamus is inhibited, and it produces much less LHRH as a result of the high levels of sex hormones it senses. The pituitary is not inhibited at all: in fact, it is actually sensitized, and will respond to LHRH (if any is provided) even moreso than normally. After two weeks however, the pituitary also becomes inhibited, and even if LHRH is provided, the pituitary will produce little or no LH. This then is a deeper type of inhibition. After this point, there seems to be no definite further “switching point” where inhibition again becomes deeper and harder to reverse. As a general rule, I would say that there seems to be little difference between using AAS for 3 weeks vs. 8 weeks: recovery is about the same either way. Between 8 and 12 weeks, it becomes more and more likely that recovery will be difficult and slow, though even at 12 weeks it is common for recovery to not be too problematic, taking only a few weeks. Cycles past 12 weeks seem much more likely to cause substantial problems with recovery. In the hundreds of consultations I have done for people with recovery problems, very few (I can recall two) were for very short cycles such as 6 weeks, while most were for usages of 12 weeks straight or more.

I do not know what changes take place in the hypothalamus and pituitary over a long period of time that result in this problem, but it certainly is true that long-term inhibition makes recovery more difficult on average. I suspect the problem may have to do with change in the “clock” that regulates the pulse rate of LHRH secretion, but I am not sure that that is so.
Drugs of Use With Regard to Inhibition

Cytadren: This drug can be used to reduce conversion of testosterone, Dianabol, and Equipoise (not an exclusive list of aromatizable AAS, but the main ones) to estrogen. Some feel that when estrogen levels are kept under control during the cycle, recovery is faster after the cycle is over, though that is not proven. It is a good idea though. And if testosterone esters were used prior to ending the cycle, some levels of these will remain for weeks, and continued use of Cytadren will help prevent conversion to estrogen, and thereby reduce inhibition. The best dosing pattern, in my opinion, is to take ½ tab (125 mg) on arising, and then ¼ tab at six and 12 hours later. Use of more Cytadren than this, or a different pattern, may lead to an adverse effect on cortisol production, with subsequent cortisol rebound after discontinuing the drug. Some individuals suffer some lethargy (feeling of tiredness and laziness, or sleepiness) from Cytadren, but that is uncommon at this dose.

Arimidex: This accomplishes the same purposes as Cytadren but without the possible side effects mentioned above. It is however far more expensive. A typical dose is 1 mg./day. The timing of the dosage does not matter, since the drug has a long half-life.

Clomid: After a cycle is over, Clomid at 50 mg/day is usually very effective in restoring natural testosterone production. It acts by blocking estrogen receptors at the hypothalamus and pituitary. If androgen levels are not elevated, this is enough to cause production of at least normal amounts of LH, or often more LH than normal. During the cycle Clomid cannot prevent inhibition, though some think using it during the cycle will allow a faster recovery afterwards. That is not proven though. If nothing else, though, it is useful as an antigyno/antibloating agent during the cycle.

Nolvadex: This works in the same manner as Clomid, but not nearly so well with regard to reversing inhibition. It is better to use this only as an anti-gyno/antibloating agent, if at all. If Clomid is used, there is no need for Nolvadex.

HCG: This does nothing with regard to inhibition of the hypothalamus and pituitary. Rather it acts like LH, and causes the testicles to produce testosterone just as if LH were present. It is useful then for avoiding testicular atrophy during the cycle. The best dosing method is to use small amounts frequently: 500 IU per day is sufficient, and 1000 IU may optionally be used. The amount may be given as a single daily dose or divided into two doses. Administration may be intramuscular or subcutaneous. More is not better: too much HCG can result in downregulation of the LH receptors in the testes, and is therefore counterproductive. Overdosing of HCG can also result in gynecomastia.

Ephedrine/clenbuterol: It is possible that the beta agonist activities of these drugs may assist in recovery. Personally, I do recommend the use of ephedrine post-cycle to those who can use it. Clenbuterol has the same effect but acts around the clock, having a longer half life, and allowing a higher effective dose (amount times potency) due to having less relative effect on beta receptors in the heart. I am not sure that Clenbuterol has any better effect with regard to recovery though.

Oral AAS: These do not assist recovery of natural testosterone production, but if used only in the morning, can help sustain muscle mass while in the recovery phase, with little or no adverse effect on recovery.

Tribulus: If this is of benefit, I have not been able to observe it myself. I have only tried the Tribestan brand, but this is the brand that earned tribulus its reputation.

Melatonin: While disrupted sleep patterns definitely inhibit recovery, I have seen no evidence that taking melatonin at night speeds recovery. It is useful though for those who have allowed their sleep patterns to be disrupted and who wish to reset their natural clocks.
————————————————————————-

General Recommendations

Pharmaceutical drugs should of course not be self-prescribed: the following are simply recommendations of what works well, not of what to do without physician’s advice. Enough said.

The best cycle plans are either brief two week cycles with short acting drugs, which allow a very fast recovery (less than one week) or cycle of approximately 6-10 weeks, which usually allow reasonable recovery and allow quite a bit of time to make gains. Cycles in the 3-5 week range are less efficient because they combine the disadvantage of relatively little time gaining with the disadvantage of slower recovery.

If a cycle lasts 8 weeks or longer, I think it is best to use HCG during the cycle if possible, as described above. HCG should not be used during the recovery itself since it will increase androgen and estrogen levels, which will be inhibitory to the hypothalamus and pituitary. Clomid use should begin, if it was not used during the cycle, as soon as androgen levels drop enough that recovery becomes possible. This would be about two weeks after the last injection of long acting steroid esters, assuming reasonable doses such as 500 mg/week. Clomid use should start with 300 mg on the first day (50 mg six times) to quickly get blood levels as high as needed, and then maintained with 50 mg/day. This is needed because of the half-life of the drug. It should be continued until one is sure that natural testosterone production is back and testicle size is returned to normal, with the exception that if use has been more than about 6 weeks, one might try dropping it for a few weeks to see what happens. If no further improvement occurs, then Clomid would be resumed. It has been studied medically for long-term use and found safe for periods of at least a year. However, a small percentage of users develop vision problems from Clomid, which are generally reversible upon discontinuing the drug. So if you have this problem, certainly the drug should be discontinued.

If aromatizable injectables were used, an antiaromatase would be useful for 3 weeks or so after the last injection, or 4 weeks if dosage was high (a gram per week or more.)

Lastly, ephedrine seems to be of some help. The same dose as used for dieting (e.g. 25 mg three times per day) seems quite sufficient.

Long term inhibition can potentially be a serious side-effect of AAS use, and this risk should be minimized by avoiding excessively long cycles. This really does not compromise gains greatly, since the body cannot grow rapidly week in, week out, 52 weeks per year anyway. And even moderate post-cycle inhibition is something we wish to minimize, since it is frustrating to lose much of one’s gains in the first few weeks after a cycle as a result of low natural testosterone and no AAS being used. The advice given above is generally successful in minimizing such losses, and I hope you will find it useful

greg_valentino600x337

Anabolic Steroid side effects and addiction

greg_valentino600x337

Anabolic steroids (AS) are effective in enhancing athletic performance. The trade off, however, is the occurrence of adverse side effects which can jeopardize health. Since AS have effects on several organ systems, a myriad of side effects can be found. In general, the orally administered AS have more adverse effects than parenterally administered AS. In addition, the type of AS is not only important for the advantageous effects, but also for the adverse effects. Especially the AS containing a 17-alkyl group have potentially more adverse affects, in particular to the liver. One of the problems with athletes, in particular strength athletes and bodybuilders, is the use of oral and parenteral AS at the same time (“stacking”), and in dosages which may be several (up to 40 times) the recommended therapeutical dosage. The frequency and severity of side effects is quite variable. It depends on several factors such as type of drug, dosage, duration of use and the individual sensitivity and response.

AS may affect sexual desire. Although few investigations on this issue have been published, it appears that during AS use sexual desire is increased, although the frequency of erectile dysfunction is increased. This may seem contradictory, but sexual appetite is androgen dependent, while erectile function is not. Erectile dysfunction can be caused by many factors, and men who suffer from this condition should speak with their doctor. You may also order Viagra, Cialis and Levitra online without having a prescription in hand through eDrugstore.MD. Simply provide your medical information, and a U.S.-licensed doctor will consider your request for a prescription for FDA-approved, brand-name Viagra, Cialis and Levitra. Since sexual desire and aggressiveness are increased during AS use, the risk of getting involved in sexual assault may be increased.

Liver Function

AS may exert a profound adverse effect on the liver. This is particularly true for orally administered AS. The parenterally administered AS seem to have less serious effects on the liver. Testosterone cypionate, testosterone enanthate and other injectable anabolic steroids seem to have little adverse effects on the liver. However, lesions of the liver have been reported after parenteral nortestosterone administration, and also occasionally after injection of testosterone esters. The influence of AS on liver function has been studied extensively. The majority of the studies involve hospitalized patients who are treated for prolonged periods for various diseases, such as anemia, renal insufficiency, impotence, and dysfunction of the pituitary gland. In clinical trials, treatment with anabolic steroids resulted in a decreased hepatic excretory function. In addition, intra hepatic cholestasis, reflected by itch and jaundice, and hepatic peliosis were observed. Hepatic peliosis is a hemorrhagic cystic degeneration of the liver, which may lead to fibrosis and portal hypertension. Rupture of a cyst may lead to fatal bleeding.

Benign (adenoma’s) and malign tumors (hepatocellular carcinoma) have been reported. There are rather strong indications that tumors of the liver are caused when the anabolic steroids contain a 17-alpha-alkyl group. Usually, the tumors are benign adenoma’s, that reverse after stopping with steroid administration. However, there are some indications that administration of anabolic steroids in athletes may lead to hepatic carcinoma. Often these abnormalities remain asymptomatic, since peliosis hepatis and liver tumors do not always result in abnormalities in the blood variables that are generally used to measure liver function.

AS use is often associated with an increase in plasma activity of liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), lactate dehydrogenase (LDH), and gamma glutamyl transpeptidase (GGT). These enzymes are present in hepatocytes in relatively high concentrations, and an increase in plasma levels of these enzymes reflect hepatocellular damage or at least increased permeability of the hepatocellular membrane.

In longitudinal studies of athletes treated with anabolic steroids, contradictory results were obtained on the plasma activity of liver enzymes (AST, AST, LDH, GGT, AP). In some studies, enzymes were increased, whereas in others no changes were found. When increases were found, the values were moderately increased and normalized within weeks after abstinence. There are some suggestions that the occurrence of hepatic enzyme leakage, is partly determined by the pre-treatment condition of the liver. Therefore, individuals with abnormal liver function appear to be at risk.

Anabolic Steroids and the Male Reproductive System

AS are derivatives of testosterone, which has strong genitotropic effects. For this reason, it will not be surprising that side effects include the reproductive system. Application of anabolic steroids leads to supra-physiological concentrations of testosterone or testosterone derivatives. Via the feed back loop, the production and release of luteinizing hormone (LH) and follicle stimulation hormone (FSH) is decreased.

Prolonged use of anabolic steroids in relatively high doses will lead to hypogonadotrophic hypogonadism, with decreased serum concentrations of LH, FSH, and testosterone.

There are strong indications that the duration, dosage, and chemical structure of the anabolic steroids are important for the serum concentrations of gonadotropins. A moderate decrease of gonadotropin secretion causes atrophy of the testes, as well as a decrease of sperm cell production. Oligo, azoospermia and an increased number of abnormal sperm cells have been reported in athletes using AS, resulting in a decreased fertility. After stopping AS use, the gonadal functions will restore within some months. There are indications, however, that it may take several months.

In bodybuilding, where usually high dosages are uses, after stopping steroid use, often choriogonadotropins are administered to stimulate testicular function. The effectiveness of this therapy is unknown.

The various studies suggest that using more than one type of anabolic steroid at the same time (“stacking”) causes a stronger inhibition of the gonadal functions than using one single anabolic steroid. After abstention from anabolic steroids these changes in fertility usually reverse within some months. However, several cases of have been reported in which the situation of hypogonadism lasted for more than 12 weeks.

A well known side effect of AS in males is breast formation (gynecomastia). Gynecomastia is caused by increased levels of circulating estrogens, which are typical female sex hormones. The estrogens estradiol and estrone are formed in males by peripheral aromatization and conversion of AS. The increased levels of circulation estrogens in males stimulate breast growth. In general, gynecomastia is irreversible.

AS may affect sexual desire. Although few investigations on this issue have been published, it appears that during AS use sexual desire is increased, although the frequency of erectile dysfunction is increased. This may seem contradictory, but sexual appetite is androgen dependent, while erectile function is not. Since sexual desire and aggressiveness are increased during AS use, the risk of getting involved in sexual assault may be increased.

Anabolic Steroids and the Female Reproductive System

In the normal female body small amounts of testosterone are produced, and as in males, artificially increasing levels by administration of AS will affect the hypothalamic-pituitary-gonadal axis. An increase in circulating androgens will inhibit the production and release of LH and FSH, resulting in a decline in serum levels of LH, FSH, estrogens and progesterone. This may result in inhibition of follicle formation, ovulation, and irregularities of the menstrual cycle. The irregularities of the menstrual cycle are characterized by a prolongation of the follicular phase, shortening of the luteal phase or amenorrhea. Although these changes are generally more pronounced in younger women, large inter-individual responsiveness to anabolic steroids exists. The effects of AS dosages as generally used in sport, on the hypothalamic-pituitary-gonadal axis in females are hardly studied.

Other side effects of anabolic steroid use in females are increased sexual desire and hypertrophy of the clitoris. The few systematic studies that have been conducted suggest that the effects are similar to the effects in patients, treated with anabolic steroids.

Anabolic steroid use by pregnant women may lead to pseudohermaphroditism or to growth retardation of the female fetus. Anabolic steroid use may even lead to fetal death. However, these side effects have not been studied systematically. It is likely that the severity of the side effects is related to the dosage, duration of use and the type of the drug.

Additional side effects of anabolic steroids specifically in women are acne, hair loss, withdrawal of the frontal hair line, male pattern boldness, lowering of the voice, increased facial hair growth, and breast atrophy. The lowering of the voice, decreased breast size, clitoris hypertrophy and hair loss are generally irreversible. Females using AS may develop masculine facial traits, male muscularity, and coarsening of the skin.

When anabolic steroids are administered in growing children side effects include virilization, gynecomastia, and premature closure of the epiphysis, resulting in cessation of longitudinal growth.

Serum Lipoproteins and the Cardiovascular System

AS also affect the cardiovascular system and the serum lipid profile. Relatively few studies have been done to investigate the effect of anabolic steroids on the cardiovascular system. No longitudinal studies have been conducted on the effect of anabolic steroids on cardiovascular morbidity and mortality.

Most of the investigations have been focused on risk factors for cardiovascular diseases, and in particular the effect of anabolic steroids on blood pressure and on plasma lipoproteins. In most cross-sectional studies serum cholesterol and triglycerides between drug-free users and non-users is not different. However, during anabolic steroid use total cholesterol tends to increase, while HDL-cholesterol demonstrates a marked decline, well below the normal range. Serum LDL-cholesterol shows a variable response: a slight increase or no change. The response of total cholesterol seems to be influenced by the type of training that is done by the athlete. When a great deal of the exercise consists of aerobic exercise, the increasing effect of AS is counterbalanced by an exercise-induced increasing effect, which may result in a net decline in total cholesterol. Aerobic training does not seem to be able to offset the steroid-induced decline in HDL-cholesterol and its subfractions HDL-2, and HDL-3.

The precise effect of anabolic steroids on LDL-cholesterol is unknown yet. It appears that anabolic steroids influence hepatic triglyceride lipase (HTL) and lipoprotein lipase (LPL). Males usually have higher levels of HTL, while females have higher LPL activity. HTL is primarily responsible for the clearance of HDL-cholesterol, while LPL takes care of cellular uptake of free fatty acids and glycerol. Androgens and anabolic steroids stimulate HTL, presumably resulting in decreased serum levels of HDL-cholesterol.

The effect of anabolic steroids on triglycerides is not well known. It is suggested that relatively low doses do not affect the serum triglyceride levels, while it cannot be excluded that higher doses elicit an increase.

No unanimity exists about the influence of anabolic steroids on arterial blood pressure. The response is most probably dose dependent. There is some data suggesting that high doses increase diastolic blood pressure, whereas low doses fail to have a significant effect on diastolic blood pressure. Increases in diastolic blood pressure normalize within 6-8 weeks after abstinence from anabolic steroids. It appears that repeated intermittent use of anabolic steroids does not affect diastolic blood pressure during drug free periods.

There is evidence that the use of anabolic steroids does elicit structural changes in the heart and that the ischemic tolerance is decreased after steroid use. Echocardiographic studies in bodybuilders, using anabolic steroids, reported a mild hypertrophy of the left ventricle, with a decreased diastolic relaxation, resulting in a decreased diastolic filling. Some investigators have associated cardiomyopathy, myocardial infarction, and cerebro-vascular accidents with abuse of anabolic steroids. However, a possible causal relationship could not been proved, because longitudinal studies that are necessary to prove such a relationship, have not been conducted yet. There is convincing evidence that oral administration of anabolic steroids has stronger adverse effects on the mentioned variables than parenteral administration.

Although the effects of anabolic steroids have an unfavorable influence on the risk factors for cardiovascular disease, no data are available about the long term effects. Most of the mentioned effects appear to reverse within 6-8 weeks after abstention. It is unknown, however, whether the structural changes as reported in the heart, are reversible as well.

Psychological Effects

Administration of AS may affect behavior. Increased testosterone levels in the blood are associated with masculine behavior, aggressiveness and increased sexual desire. Increased aggressiveness may be beneficial for athletic training, but may also lead to overt violence outside the gym or the track. There are reports of violent, criminal behavior in individuals taking AS. Other side effects of AS are euphoria, confusion, sleeping disorders, pathological anxiety, paranoia, and hallucinations.

Anabolic steroid users may become dependent on the drug, with symptoms of withdrawal after cessation of drug use. The withdrawal symptoms consist of aggressive and violent behavior, mental depression with suicidal behavior, mood changes, and in some cases acute psychosis. At present it is unknown which individuals are particularly at risk. It is likely that great individual differences in responsiveness may exist. Some individuals try to minimize the withdrawal affects by administration of human choriogonadotropins (hCG), in order to enhance endogenous testosterone production. However, it is unknown in how far the hCG administration is successful in ameliorating the withdrawal effects.

* ROID RAGE (extreme uncontrollable aggression due to high levels of testosterone)
* Irritability..
* Aggressiveness…
* Depression…
* Mood swings…
* Altered libido…
* Psychosis…
* Mental addiction…

Additional Physical Effects
* Cancer…
* Liver Damage…
* Feminizing effects in males (growth of breast tissue)…
* Male attributes in females (deepening of voice, excessive hair growth)…
* Enlarged clitoris…
* Shrunken testicles…
* Limb loss…
* Heart disease/heart attacks…
* Physical addiction…
* HIV/AIDS from the sharing of needles…
* Reduced sperm count…
* Impotence…
* Infertility…
* Baldness…
* Pain and difficulty urinating…
* Enlarged prostate…
* Baldness…
* Smaller Breast in women…
* Menstrual cycle stops…
* Adolescents experience premature closure of the growth plates (stunted growth)…

Possible unwanted side effects (more on http://en.wikipedia.org/wiki/Anabolic_steroid#Possible_unwanted_side_effects)

Many androgens are capable of being metabolized to compounds which can interact with other steroid hormone receptors including the estrogen, progesterone, and glucocorticoid receptors, producing additional (usually) unwanted effects:

* Possible elevated blood pressure
* Cholesterol levels –Some steroids can cause a increase in LDL, and decreased HDL levels[7]. This can cause a increase in risk of cardiovascular disease[8] or coronary artery disease[9] in men with high risk of bad cholesterol.
* Acne– Due to the stimulation of sebaceous gland[10][11]
* Conversion to DHT (Dihydrotestosterone). This can accelerate or cause premature baldness and prostate cancer.
* Altered left ventricle morphology – AAS can induce an unfavourable enlargement and thickening of the left ventricle, which loses its diastolic properties with the mass increase.[12] However the negative relation of left ventricle morphology to decreased cardiac function has been disputed.[13]
* Hepatotoxicity – Caused particularly by oral anabolic steroid compounds which are 17-alpha-alkylated in order to not be destroyed by the digestive system.
* Gingival overgrowth – AAS is closely associated with significant levels of gingival enlargement.[14]

Additional Side Effects

In addition to the mentioned side effects several others have been reported. In both males and females acne are frequently reported, as well as hypertrophy of sebaceous glands, increased tallow excretion, hair loss, and alopecia. There is some evidence that anabolic steroid abuse may affect the immune system, leading to a decreased effectiveness of the defense system. Steroid use decreases the glucose tolerance, while there is an increase in insulin resistance. These changes mimic Type II diabetes. These changes seem to be reversible after abstention from the drugs.

There are some case reports suggesting a causal relationship between anabolic steroid use and the occurrence of Wilms tumor, and prostatic carcinoma. In the literature also sleep apnea has been reported, which has been associated with AS-induced increased in hematocrit, leading to blood stasis and thrombosis.

AS use may affect thyroid function. Administration of AS has been found to decrease thyroid stimulation hormone (TSH), and the products of the thyroid gland. In addition, thyroid binding globulin (TBG). These changes reversed within weeks after discontinuation of AS use.

A serious consequence of AS use may be the multiple drug abuse. On the one hand athletes use different kinds of drugs in an attempt to counterbalance the side effects: hCG, thyroid hormones, anti-estrogens, anti-depressants. On the other hand people try to support the anabolic effects of AS by using additional anabolic hormones as for instance: different types of AS at the same time, growth hormone, insulin, erythropoietine, and clenbuterol. Because most of this takes place outside the official medical circuit, it is likely that these practices may lead to serious conditions.

AS may affect sexual desire. Although few investigations on this issue have been published, it appears that during AS use sexual desire is increased, although the frequency of erectile dysfunction is increased. This may seem contradictory, but sexual appetite is androgen dependent, while erectile function is not. Erectile dysfunction can be caused by many factors, and men who suffer from this condition should speak with their doctor. You may also order Viagra, Cialis and Levitra online without having a prescription in hand through eDrugstore.MD. Simply provide your medical information, and a U.S.-licensed doctor will consider your request for a prescription for FDA-approved, brand-name Viagra, Cialis and Levitra. Since sexual desire and aggressiveness are increased during AS use, the risk of getting involved in sexual assault may be increased.

Other Sources PDF Downloads
Steroid Abuse and Addiction – Download
NIDA InfoFacts: Steroids (Anabolic-Androgenic) – Download

References
(not referred to in the above review)

1. Alen, M., P. Rahkila. Anabolic-androgenic steroid effects on endocrinology and lipid metabolism in athletes. Sports Med. 6: 327-332, 1988

2. American College of Sports Medicine. Position stand on the use of anabolic-androgenic steroids in sport. Med. Sci. Sports Exerc. 19(5): 534-539, 1987

3. Bahrke, M.S., C.E. Yesalis, J.E. Wright. Psychological and behavioral effects of endogenous testosterone levels and anabolic-androgenic steroids among athletes; a review. Sports Med. 10(5): 303-337, 1990

4. Cohen, J.C., R. Hickman. Insulin resistance and diminished glucose tolerance in power lifters ingesting anabolic steroids. J. Clin. Endocrinol. Metab. 64: 960-963, 1987

5. De Piccoli, B., F. Giada, A. Benettin, F. Sartori, E. Piccolo. Anabolic steroid use in body builders: an echocardiographic study of left ventricular morphology and function. Int. J. Sports Med. 12(4): 408-412, 1991

6. Haupt, H.A. Anabolic steroids and growth hormone. Am. J. Sports Med. 21(3): 468-474, 1993

7. Wilson, J.D. Androgen abuse in athletes. Endocr. Rev. 9(2): 181-199, 1988

Gynecomastia: Etiology, Diagnosis, And Treatment

by H. Hajdo Everything you need to know about gyno.BREAST DEVELOPMENT

Male breast development occurs in an analogous fashion to female breast development. At puberty in the female breast, complex hormonal interplay occurs resulting in growth and maturation of the adult female breast.

In early fetal life, epithelial cells, derived from the epidermis of the area programmed to later become the areola, proliferate into ducts, which connect to the nipple at the skin’s surface. The blind ends of these ducts bud to form alveolar structures in later gestation. With the decline in fetal prolactin, placental estrogen and progesterone at birth, the infantile breast regresses until puberty (13).

During thelarche, the initial clinical appearance of the breast bud, growth and division of the ducts occur, eventually giving rise to club-shaped terminal end buds, which then form alveolar buds. Approximately a dozen alveolar buds will cluster around a terminal duct, forming the type 1 lobule. Eventually, the type 1 lobule will mature into types 2 and 3 lobules, called ductules, by increasing its number of alveolar buds to as many as 50 in type 2 and 80 in type 3 lobules. The entire differentiation process takes years after the onset of puberty and, if pregnancy is not achieved, may never be completed (38).

HORMONAL REGULATION OF BREAST DEVELOPMENT

The initiation and progression of breast development involves a coordinated effort of pituitary and ovarian hormones, as well as local mediators (see Figure).

<!–[if !vml]–><!–[endif]–>

ESTROGEN, GH AND IGF-1, PROGESTERONE, & PROLACTIN

Estrogen and progesterone act in an integrative fashion to stimulate normal adult female breast development. Estrogen, acting through its ER a receptor, promotes duct growth, while progesterone, also acting through its receptor (PR), supports alveolar development (13). This is demonstrated by experiments in ER a knockout mice which display grossly impaired ductal development, whereas the PR knockout mice possess significant ductal development, but lack alveolar differentiation (25,6).

Although estrogens and progestogens are vital to mammary growth, they are ineffective in the absence of anterior pituitary hormones (13). Thus, neither estrogen alone nor estrogen plus progesterone can sustain breast development without other mediators, such as GH and IGF-1, as confirmed by studies involving the administration of estrogen and GH to hypophysectomized and oophorectomized female rats, which resulted in breast ductal development. The GH effects on ductal growth are mediated through stimulation of IGF-1. This is demonstrated by studies of estrogen and GH administration to IGF-1 knockout rats that showed significantly decreased mammary development when compared to age-matched IGF-1- intact controls. Combined estrogen and IGF-1 treatment in these IGF-1 knockout rats restored mammary growth. (21, 36). In addition, Walden et al. demonstrated that GH-stimulated production of IGF-1 mRNA in the mammary gland itself, suggesting that IGF-1 production in the stromal compartment of the mammary gland acts locally to promote breast development (43). Furthermore, other data indicates that estrogen promotes GH secretion and increased GH levels, stimulating the production of IGF-1, which synergizes with estrogen to induce ductal development.

Like estrogen, progesterone has minimal effects in breast development without concomitant anterior pituitary hormones; again indicating that progesterone interacts closely with pituitary hormones. For example, prolonged treatment of dogs with progestogens such as depot medroxyprogesterone acetate or with proligestone caused increased GH and IGF-1 levels, suggesting that progesterone may also have an effect on GH secretion (29). In addition, clinical studies have correlated maximal cell proliferation to specific phases in the female menstrual cycle. For example, maximal proliferation occurs not during the follicular phase when estrogens reach peak levels and progesterone is low (less than 1 ng/mL[3.1nmol}), but rather, it occurs during the luteal phase when progesterone reaches levels of 10-20 ng/mL (31- 62nmol) and estrogen levels are two to three times lower than in the follicular phase (38). Furthermore, immunohistochemical studies of ER and PR showed that the highest percentage of proliferating cells, found almost exclusively in the type 1 lobules, contained the highest percentage of ER and PR positive cells (38). Similarly, there is immunocytological presence of ER, PR, and androgen receptors (AR) in gynecomastia and male breast carcinoma. ER, PR and AR expression was observed in 100% (30/30) of gynecomastia cases (37). Given these data and the fact that PR knockout mice lack alveolar development in breast tissue, it appears as if progesterone, analogous to estrogen, may increase GH secretion and act through its receptor on mammary tissue to enhance breast development, specifically alveolar differentiation (25, 16).

Prolactin is another anterior pituitary hormone integral to breast development. Prolactin is not only secreted by the pituitary gland but may be produced in normal mammary tissue epithelial cells and breast tumors. (39, 23). Prolactin stimulates epithelial cell proliferation only in the presence of estrogen and enhances lobulo-alveolar differentiation only with concomitant progesterone.

ANDROGEN AND AROMATASE

Estrogen effects on the breast may be the result of either circulating estradiol levels or locally produced estrogens. Aromatase P450 catalyzes the conversion of the C19 steroids, androstenedione, testosterone, and 16-a-hydroxyandrostenedione to estrone, estradiol-17b and estriol. As such, an overabundance of substrate or an increase in enzyme activity can increase estrogen concentrations and thus initiate the cascade to breast development in females and males. For example, in the more complete forms of androgen insensitivity syndromes in genetically male (XY) patients, excess androgen aromatizes into estrogen resulting in not only gynecomastia, but also a phenotypic female appearance. Furthermore, the biologic effects of over expression of the aromatase enzyme in female and male mice transgenic for the aromatase gene result in increased breast proliferation. In female transgenetics, over expression of aromatase promotes the induction of hyperplastic and dysplastic changes in breast tissue. Over expression of aromatase in male transgenics caused increased mammary growth and histologic changes similar to gynecomastia, an increase in estrogen and progesterone receptors and an increase in downstream growth factors such as TGF-beta and bFGF (15). Thus, although androgens do not stimulate breast development directly, they may do so if they aromatize to estrogen. This occurs in cases of androgen excess or in patients with increased aromatase activity.

PHYSIOLOGIC gynecomastia gynecomastia, breast development in males, can occur normally during three phases of life. The first occurs shortly after birth in both males and females. This is caused by the high levels of estradiol and progesterone produced by the mother during pregnancy, which stimulates newborn breast tissue. It can persist for several weeks after birth and can cause mild breast discharge called "witch's milk" (38).

Puberty marks the second situation in which gynecomastia can occur physiologically. In fact, up to 60% of boys have detectable gynecomastia by age 14. Although it is mostly bilateral, it can occur unilaterally, and usually resolves within 3 years of onset (38). Interestingly, in early puberty, the pituitary gland releases gonadotropins in order to stimulate testicular production of testosterone mostly at nighttime. Estrogens, however, rise throughout the entire day. Some studies have shown that a decreased androgen to estrogen ratio exists in boys with pubertal gynecomastia when compared with boys who do not develop gynecomastia (30). Furthermore, another study showed increased aromatase activity in the skin fibroblasts of boys with gynecomastia. Thus, the mechanism by which pubertal gynecomastia occurs may be due to either decreased production of androgens or increased aromatization of circulating androgens, thus increasing the estrogen to androgen ratio (26).

The third age range in which gynecomastia is frequently seen is during older age (>60 years). Although the exact mechanisms by which this can occur have not been fully elucidated, evidence suggests that it may result from increased peripheral aromatase activity secondary to the increase in total body fat, coupled with mild hypogonadism associated with aging. For instance, investigators have shown increased urinary estrogen levels in obese individuals, and have demonstrated aromatase expression in adipose tissue (32). Thus, like the gynecomastia of obesity, the gynecomastia of aging may partly result from increased aromatase activity, causing increased circulating estrogen levels (7). Moreover, not only does total body fat increase with age, but there may be an increase in aromatase activity in the adipose tissue already present, increasing circulating estrogens even further. Lastly, SHBG increases with age in men. Since SHBG binds estrogen with less affinity than testosterone, the bioavailable estradiol to bioavailable testosterone ratio may increase in the obese older male.

PATHOLOGIC gynecomastia INCREASED ESTROGEN

Since the development of breast tissue in males occurs in an analogous manner to that in females, the same hormones that affect female breast tissue can cause gynecomastia. The testes secrete only 6-10 mg of estradiol and 2.5 mg of estrone per day. Since this only comprises a small fraction of estrogens in circulation (i.e. 15% of estradiol and 5% of estrone), the remainder of estrogen in males is derived from the extraglandular aromatization of testosterone and androstenedione to estradiol and estrone, respectively (27). Thus, any cause of estrogen excess from overproduction to peripheral aromatization of androgens can initiate the cascade to breast development.

TUMORS

Testicular tumors can lead to increased blood estrogen levels by: estrogen overproduction; androgen overproduction with aromatization in the periphery to estrogens; and by ectopic secretion of gonadotropins which stimulate otherwise normal Leydig cells. Tumors causing an overproduction of estrogen represent an unusual but important cause of estrogen excess. Examples of estrogen-secreting tumors include: Leydig cell tumors, Sertoli cell tumors, granulosa cell tumors and adrenal tumors.

Interstitial cell tumors, or Leydig cell tumors constitute 1%-3% of all testis tumors. Usually, they occur in men between the ages of 20 and 60, although up to 25% of them occur prepubertally. In prepubertal cases, isosexual precocity, rapid somatic growth, and increased bone age with elevated serum testosterone and urinary 17-ketosteroid levels are the presenting features. In adults, elevated estrogen levels coupled with a palpable testicular mass and gynecomastia may develop. Though mostly benign, Leydig cell tumors may be malignant and metastasize to lung, liver, and retroperitoneal lymph nodes (34, 14).

Sertoli cell tumors comprise less than 1% of all testicular tumors and occur at all ages, but one third have occurred in patients less than 13 years, usually in boys under 6 months of age. Although they arise in young boys, they usually do not produce endocrinologic effects in children. Again, the majority are benign, but up to 10% are malignant. gynecomastia occurs in one third of cases, presumably due to increased estrogen production (34).

Granulosa cell tumors, which occur very rarely in the testes, can also overproduce estrogen. In fact, only eleven cases have been reported with gynecomastia as a presenting feature in half of them (28).

Germ cell tumors are the most common cancer in males between the ages of 15 and 35. They are divided into seminomatous and nonseminomatous subtypes and include embryonal carcinoma, yolk sac carcinoma, choriocarcinoma and teratomas. Elevated alpha fetoprotein (AFP) and b HCG function as reliable markers in some tumors. As a result of the increased b HCG, acting analogously to LH to stimulate the Leydig cell LH receptor, testicular estrogen production is also increased, which, in turn, can cause gynecomastia. Although germ cell tumors generally arise in the testes, they can also originate extra-gonadally, specifically in the mediastinum. These extragonadal tumors also possess the capability of producing b HCG, but they must be differentiated from a multitude of other tumors such as large cell carcinomas of the lung which can synthesize ectopic b HCG (31).

Some neoplasms that overproduce estrogens also possess aromatase overactivity. Sertoli Cell tumors in boys with Peutz-Jegher syndrome, an autosomal dominant disease characterized by pigmented macules on the lips, gastrointestinal polyposis and hormonally active tumors in males and females, for instance, have repeatedly demonstrated aromatase overactivity, resulting in gynecomastia, rapid growth and advanced bone age as presenting features (18, 44, 10). Feminizing Sertoli cell tumors with increased aromatase activity can also be seen in the Carney complex, an autosomal dominant disease characterized by cardiac myxomas, cutaneous pigmentation, adrenal nodules and hypercortisolism. Other than sex-cord tumors, fibrolamellar hepatocellular carcinoma has also been shown to possess ectopic aromatase activity, causing severe gynecomastia in a 17-year-old boy (2). Furthermore, adrenal tumors can secrete excess dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS) and androstenedione which can then be aromatized peripherally to estradiol.

<!--[if !vml]–><!–[endif]–>

NON-TUMOR CAUSES OF ESTROGEN EXCESS

INCREASED AROMATASE ACTIVITY

Besides tumors, other conditions have been associated with excessive aromatization of testosterone and androgens to estrogen, which results in gynecomastia. For instance, a familial form of gynecomastia has been discovered, in which affected family members have an elevation of extragonadal aromatase activity (5). As stated, obesity may cause estrogen excess through increased aromatase activity in adipose tissue. Furthermore, hyperthyroidism induces gynecomastia through several mechanisms, including increased aromatase activity (38).

DISPLACEMENT OF ESTROGENS FROM SHBG

Another cause of gynecomastia from estrogen excess includes steroid displacement from sex-hormone binding globulin (SHBG). SHBG binds androgens more avidly than estrogen. Thus, any condition or drug that can displace steroids from SHBG, will more easily displace estrogen, allowing for higher circulating levels of estrogen. Drugs can cause gynecomastia by numerous mechanisms besides displacement from SHBG. These drugs and their mechanisms will be addressed in a subsequent section.

DECREASED TESTOSTERONE AND ANDROGEN RESISTANCE

Breast development requires the presence of estrogen. Androgens, on the other hand oppose the estrogenic effects. Thus, an equilibrium exists between estrogen and androgens in the adult male to prevent growth of breast tissue, whereby either an increase in estrogen or a decrease in androgen can tip the balance toward gynecomastia. Increased estrogen levels will increase glandular proliferation by several mechanisms. These include direct stimulation of glandular tissue and by suppressing LH, therefore decreasing testosterone secretion by the testes and exaggerating the already high estrogen to androgen ratio.

Besides increased estrogen production, decreased testosterone levels can cause an elevation in the estrogen to androgen ratio, producing gynecomastia. Primary hypogonadism, with its reduction in serum testosterone and increased serum LH levels increases testicular estradiol production and is associated with an increased estrogen to androgen ratio. Klinefelter’s syndrome, occurring in 1 in 500 males who possess an XXY karyotype and primary testicular failure, features gynecomastia as well, again presumably secondary to decreased testosterone production, compensatory increased LH secretion, overstimulation of the Leydig cells and relative estrogen excess. In addition, any acquired testicular disease resulting in primary hypogonadism such as viral and bacterial orchitis, trauma, or radiation can also promote gynecomastia by the same mechanisms (27). Lastly, enzyme deficiencies in the testosterone synthesis pathway from cholesterol also result in depressed testosterone levels and hence a relative increase in estrogen. Deficiency of 17-oxosteroid reductase, the enzyme that catalyzes the conversion of androstenedione to testosterone and estrone and estrone to estradiol, for example, will cause elevation in estrone and androstenedione, which is then further aromatized to estradiol (7).

Secondary hypogonadism, if severe enough, results in low serum testosterone and unopposed estrogen effect from increased conversion of adrenal precursors to estrogens (27). Thus, patients with Kallmann’s syndrome, a form of congenital secondary hypogonadism with anosmia, also develop gynecomastia. In fact, hypogonadism from whatever cause constitutes most cases of gynecomastia.

The androgen resistance syndromes, including complete and partial testicular feminization (e.g. Reifenstein’s syndrome) are characterized by gynecomastia and varying degrees of pseudohermaphroditism. Kennedy Syndrome, a neurodegenerative disease, is also associated with decreased effective testosterone due to a defective androgen receptor (38). The gynecomastia is the combined result of decreased androgen responsiveness at the breast level and increased estrogen levels as a result of elevated androgen precursors of estradiol and estrone. As such, androgens in these diseases are not recognized by the peripheral tissues including the breast and pituitary. Androgen resistance at the pituitary results in elevated serum LH levels and increased circulating testosterone. The increased serum testosterone is then aromatized peripherally, promoting gynecomastia. Thus, gynecomastia is the result of increased estradiol levels which arise due to unopposed androgen unresponsiveness.

OTHER DISEASES

Other disease states have also resulted in gynecomastia.

Men with end stage renal disease may have reduced testosterone, and elevated gonadotropins. This apparent primary testicular failure may then lead to increased breast development (16).

The gynecomastia of liver disease, particularly cirrhosis, does not have a clear etiology. Some have speculated that the gynecomastia is the result of estrogen overproduction, possibly secondary to increased extraglandular aromatization of androstenedione, which may have decreased hepatic clearance in cirrhotics. However, testosterone administration to cirrhotics causes a rise in estradiol, but decreases the prevalence of gynecomastia (11, 3, 33). Therefore, although the association of gynecomastia with liver disease is apparent, current data are conflicting and the mechanism by which this occurs remains unclear.

As previously stated, thyrotoxicosis is associated with gynecomastia. Patients often have elevated estrogen which may result from a stimulatory effect of thyroid hormone on peripheral aromatase. Testosterone may also be increased possibly due to thyroid-hormone-stimulated increase in SHBG, as free testosterone is usually normal. Since SHBG binds testosterone more avidly than estradiol, there is a higher ratio of free estradiol to free testosterone. Thus, with normal testosterone and increased estrogen, there is an elevated estrogen to testosterone ratio. In addition, LH is also increased, which may also stimulate testicular estrogen synthesis (16, 9). gynecomastia can also follow spinal cord disorders. Most patients with spinal cord disorders display depressed testosterone levels and, in fact, can develop testicular atrophy with resultant hypogonadism and infertility. Some have speculated that this may result from recurrent urinary tract infections, increased scrotal temperature, and a neuropathic bladder, which ultimately cause acquired primary testicular failure. The exact mechanism, however, remains elusive (17).

Refeeding gynecomastia refers to breast development in men recovering from a malnourished state (13). Although most cases regress within seven months, the etiology of this phenomenon has not been fully elucidated.

HIV patients can also develop gynecomastia. There is a high incidence of androgen deficiency due to multifactorial causes, including primary and secondary hypogonadism (27).

DRUGS

A significant percentage of gynecomastia is caused by medications or exogenous chemicals that result in increased estrogen effect. This may occur by several mechanisms: 1) they possess intrinsic estrogen-like properties, 2) they increase endogenous estrogen production, or 3) they supply an excess of an estrogen precursor (e.g. testosterone or androstenedione) which can be aromatized to estrogen. Examples of drugs that cause gynecomastia are listed in Tables 2 and 3. Contact with estrogen vaginal creams, for instance, can elevate circulating estrogen levels. These may or may not be detected by standard estrogenic qualitative assays. An estrogen-containing embalming cream has been reported to cause gynecomastia in morticians (4, 12). Recreational use of marijuana, a phytoestrogen, has also been associated with gynecomastia. It has been suggested that digitalis causes gynecomastia due to its ability to bind to estrogen receptors (16, 35). The appearance of gynecomastia has been described in body builders and athletes after the administration of aromatizable androgens. The gynecomastia was presumably caused by an excess of circulating estrogens due to the conversion of androgens to estrogen by peripheral aromatase enzymes (8).

Drugs and chemicals that cause decreased testosterone levels either by causing direct testicular damage, by blocking testosterone synthesis, or by blocking androgen action can produce gynecomastia. For instance, chemotherapeutic drugs, such as alkylating agents, cause Leydig cell and germ cell damage, resulting in primary hypogonadism. Flutamide, an anti-androgen used as treatment for prostate cancer, blocks androgen action in peripheral tissues, while cimetidine blocks androgen receptors. Ketoconazole, on the other hand, can inhibit steroidogenic enzymes required for testosterone synthesis. Spironolactone causes gynecomastia by several mechanisms. Like ketoconazole, it can block androgen production by inhibiting enzymes in the testosterone synthetic pathway (i.e. 17a hydroxylase and 17-20-desmolase), but it can also block receptor-binding of testosterone and dihydrotestosterone (40). In addition to decreasing testosterone levels and biologic effects, spironolactone also displaces estradiol from SHBG, increasing free estrogen levels. Ethanol increases the estrogen to androgen ratio and induces gynecomastia by multiple mechanisms as well. Firstly, it is associated with increased SHBG, which decreases free testosterone levels. Secondly, it increases hepatic clearance of testosterone, and thirdly, it has a direct toxic effect on the testes themselves (27). Unfortunately, besides the drugs stated, a multitude of others cause gynecomastia by unknown mechanisms (Table 3).

<!–[if !vml]–><!–[endif]–>

Table 3. Drugs that cause gynecomastia by uncertain mechanisms:
Cardiac and antihypertensive medications:
Calcium channel blockers (verapamil, nifedipine, diltiazem)
ACE Inhibitors (captopril, enalapril
b blockers
Amiodarone
Methyldopa
Reserpine
Nitrates

Psychoactive drugs:
Neuroleptics
Diazepam
Neuroleptics
Diazepam
Phenytoin
Tricyclic antidepressants
Haloperidol
Drugs for infectious diseases:
Indinavir
Isoniazid
Ethionamide
Griseofulvin

Drugs of Abuse:
amphetamines

Other:
Theophylline
Omeprazole
Auranofin
Diethylpropion
Domperidone
Penicillamine
Sulindac
Heparin

MALE BREAST CANCER

Male breast cancer is rare and comprises only 0.2 percent of all male cancers. Although uncommon, it has been associated with gynecomastia and necessitates inclusion in the differential diagnosis. Other risks include Klinefelter’s syndrome, exogenous estrogen exposure, family history, and testicular disorders. It is unclear if these are specific risks for breast cancer are linked to the stimulatory process responsible for gynecomastia. New evidence suggests obesity and consumption of red meat may also raise the risk for the development of male breast cancer (19).

PATIENT EVALUATION

HISTORY AND PHYSICAL EXAMINATION

At presentation, all patients require a thorough history and physical exam. Particular attention should be given to medications, drug and alcohol abuse, as well as other chemical exposures. Symptoms of underlying systemic illness, such as hyperthyroidism, liver disease, or renal failure should be sought. Furthermore, the clinician must recall neoplasm as a possible etiology and should establish the duration and timing of breast development. Obviously, rapid breast growth that has occurred recently is more concerning than chronic gynecomastia. Additionally, the clinician should inquire about fertility, erectile dysfunction and libido to rule out hypogonadism, either primary or secondary, as a potential cause.

In our experience, the breast examination is best performed with the patient supine and with the examiner palpating from the periphery to the areola. The glandular mass should be measured in diameter. gynecomastia is diagnosed by finding subareolar breast tissue of 2 cm in diameter or greater. Malignancy is suspected if an immobile firm mass is found on physical examination. Skin dimpling, nipple retraction or discharge, and axillary lymphadenopathy further support malignancy as a possible diagnosis.

A thorough testicular exam is essential. Bilaterally small testes imply testicular failure, while asymmetric testes or a testicular mass suggest the possibility of neoplasm. Visual field impairment may suggest pituitary disease. Physical findings of underlying systemic conditions such as thyrotoxicosis, HIV disease, liver, or kidney failure should also be assessed.

LABORATORY EVALUATION

All patients who present with gynecomastia should have serum testosterone, estradiol, LH and b HCG measured. Further testing should be tailored according to the history, physical examination and the results of these initial tests. An elevated b HCG or a markedly elevated serum estradiol suggests neoplasm and a testicular ultrasound is warranted to identify a testicular tumor, keeping in mind, however, that other non-testicular tumors can also secrete b HCG. A low testosterone level, with an elevated LH and normal to high estrogen level indicates primary hypogonadism. If the history suggests Klinefelter’s Syndrome, then a karyotype should be performed for definitive diagnosis. Low testosterone, low LH and normal estradiol levels imply secondary hypogonadism, and hypothalamic or pituitary causes should be sought. If testosterone, LH and estradiol levels are all elevated, then the diagnosis of androgen resistance should be entertained. Liver, kidney and thyroid function should be assessed if the physical examination suggests liver failure, kidney failure, or hyperthyroidism, respectively. Furthermore, if examination of breast tissue suggests malignancy, a biopsy should be performed. This is of particular importance in patients with Klinefelter’s syndrome, who have an increased risk of breast cancer.

TREATMENT

Treatment of the underlying endocrinologic or systemic disease that has caused gynecomastia is mandatory. Testicular tumors, such as Leydig cell, Sertoli cell or granulosa cell tumors should be surgically removed. In addition to surgery, germ cell tumors are further managed with chemotherapy involving cisplatin, bleomycin and either vinblastine or etoposide (34, 14). Should underlying thyrotoxicosis, renal or hepatic failure be discovered, appropriate therapy should be initiated. Medications that cause gynecomastia should also be discontinued whenever possible based on their role in management of the underlying condition. Of course, if a breast biopsy indicates malignancy, then mastectomy should be performed.

If no pathologic abnormality is detected, then appropriate treatment is close observation. A careful breast exam should be done initially every 3 months until the gynecomastia regresses or stabilizes, after which a breast exam can be performed yearly. It is important to remember that some cases of gynecomastia, especially that which occurs in pubertal boys, can resolve spontaneously.

MEDICAL TREATMENT

If the gynecomastia is severe, does not resolve, and does not have a treatable underlying cause, some medical therapies may be attempted. These include testosterone, dihydrotestosterone, danazol, clomiphene citrate, tamoxifen and the aromatase inhibitor testolactone. Testosterone treatment of hypogonadal men with gynecomastia often fails to produce breast regression once gynecomastia is established. Unfortunately, testosterone treatment may actually produce the side effect of gynecomastia by being aromatized to estradiol. Thus, although testosterone is used to treat hypogonadism, its use to specifically counteract gynecomastia is limited (42). Dihydrotestosterone, a non-aromatizable androgen, has been used in patients with prolonged pubertal gynecomastia with good response rates (22). Since dihydrotestosterone is given either intramuscularly or percutaneously, this may restrict its usefulness. Danazol, a weak androgen that inhibits gonadotropin secretion, resulting in decreased serum testosterone levels, has been studied in a prospective placebo-controlled trial, whereby gynecomastia resolved in 23 percent of the patients, as opposed to 12 percent of the patients on placebo (20). Unfortunately, undesirable side effects including edema, acne, and cramps have limited its use (27). Investigators have reported a 64 percent response rate with 100 mg/day of clomiphene citrate, a weak estrogen and moderate antiestrogen (24). Lower doses of clomiphene have shown varied results, indicating that higher doses may need to be administered, if clomiphene is to be attempted. tamoxifen, also an antiestrogen, has been studied in 2 randomized, double-blind studies in which a statistically significant regression in breast size was achieved, although complete regression was not documented (1). One study compared tamoxifen with danazol in the treatment of gynecomastia. Although patients taking tamoxifen had a greater response with complete resolution in 78 percent of patients treated with tamoxifen, as compared to only a 40 percent response in the danazol-treated group, the relapse rate was higher for the tamoxifen group (41). Although complete breast regression may not be achieved and a chance of recurrence exists with therapy, tamoxifen, due to relatively lower side effect profile, may be a more reasonable choice when compared to the other therapies. If used, tamoxifen should be given at a dose of 10 mg twice a day for at least 3 months (27). An aromatase inhibitor, testolactone, has also been studied in an uncontrolled trial with promising effects (45). Further studies must be performed on this drug before any recommendations can be established on its usefulness in the treatment of gynecomastia.

SURGICAL TREATMENT

When medical therapy is ineffective, particularly in cases of longstanding gynecomastia, or when the gynecomastia interferes with the patient’s activities of daily living, then surgical therapy is appropriate. This includes removal of glandular tissue coupled with liposuction, if needed. In our experience, uses of delicate cosmetic surgical techniques are warranted to prevent unsightly scarring.

SUMMARY

In summary, gynecomastia is a relatively common disorder. The causes of its development range vastly from benign physiologic processes to rare neoplasms. Thus, in order to properly diagnose the etiology of the gynecomastia, the clinician must understand the hormonal factors involved in breast development. Parallel to female breast development, estrogen, along with GH and IGF-1 is required for breast growth in males. Since a balance exists between estrogen and androgens in males, any disease state or medication that can increase circulating estrogen or decrease circulating androgen, causing an elevation in the estrogen to androgen ratio, can induce gynecomastia. Due to the diversity of possibly etiologies, including neoplasm, performing a careful history and physical is imperative. Once gynecomastia has been diagnosed, treatment of the underlying cause is warranted. If no underlying cause is discovered, then close observation is appropriate. If the gynecomastia is severe, however, medical therapy can be attempted and if ineffective, glandular tissue can be removed surgically.

References:

1. Alagaratnam TT: Idiopathic gynecomastia treated with tamoxifen; a preliminary report. Clin Ther 9:483-7, 1987

2. Agarwal VR, Takayama K, Van Wyk JJ, Sasano H, Simpson ER, Bulun SE: Molecular Basis of Severe gynecomastia Associated with Aromatase Expression in a Fibrolamellar Hepatocellular Carcinoma. Journal of Clinical Endocrinology and Metab 83(5): 1797-1800, 1988

3. Bahnsen M, Gluud C, Johnsen SG: Pituitary-testicular Function in Patients with Alcoholic Cirrhosis of the Liver. European Journal of Clinical Investigation 11: 473-479, 1981.

4. Bhat N, Rosato E, Gupta P: gynecomastia in a mortician: A case report. Acta Cytol 34:31, 1990.

5. Berkovitz GD, Guerami, Brown TR, MacDonald PC Migeon CJ: Familial gynecomastia with Increased Extraglandular Aromatization of Plasma Carbon 19-Steroids. Journal of Clinical Investigation 75: 1763-1769, 1985.

6. Bocchinfuso WP, Korach KS: Mammary Gland Development and Tumorigenesis in Estrogen Receptor Knockout Mice. Journal of Mammary Gland Biology and Neoplasia 90: 323-334, 1997.

7. Braunstein: Aromatase and gynecomastia. Endocrine-Related Cancer 6: 315-324, 1999.

8. Calzada L, Torres-Calleja JM, Martinez N: Measurement of Androgen and Estrogen Receptors in Breast Tissue from Subjects with Anabolic Steroid-Dependent gynecomastia. Life Sciences 69 (2110): 1465-1479.

9. Chan WB, Yeung VT, Chow CC, So WY, Cockram CS: Gynaecomastia as a Presenting Feature of Thyrotoxicosis. Postgraduate Medical Journal 75(882): 229-231, 1999.

10. Coen P, Kulin H, Ballantine T, Zaino r, Frauenhoffer E, Boal D, Inkster S, Brodie A, Santen R: An Aromatase-Producing Sex-cord Tumor Resulting in Prepubertal gynecomastia. New England Journal of Medicine 324 (5): 317-22, 1991.

11. Edman DC, Hemsell DL, Brenner PF: Extraglandular Estrogen Formation in Subjects with Cirrhosis. Gastroenterology 69: 819, 1975.

12. Finkelstein J, McCully W, MacLaughlin D, et al.: The mortician’s mystery: gynecomastia and reversible hypogonadotropic hypogonadism in an embalmer. N Eng J Med 319:961, 1988.

13. Franz A, Wilson J: Williams Textbook of Endocrinology ninth edition, 877-885, 1998.

14. Gana BM: Leydig Cell Tumor, British Journal of Urology 75(5): 676-8, 1995.

15. Gill K, Kirma N, Tekmal RR: Overexpression of Aromatase in Transgenic Male Mice Results in the Induction of gynecomastia and other Biochemical Changes in Mammary Gland. Journal of Steroid Biochemistry and Molecular Biology 77(1):13-18, 2001.

16. Glass AR: gynecomastia. Endocrinology and Metabolism Clinics of North America. 23(4): 825-837, 1994.

17. Herito RJ, Dankner R, Berezin M, Zeilig G, Ohry A: gynecomastia Following Spinal Cord Disorder. Archives of Physical Medicine and Rehabilitation 78(5): 534-537, 1997.

18. Hertl MC, Wiebel J, Schafer H, Willig HP, Lambrecht W. Feminizing Sertoli Cell Tumors Associated with Peutz-Jeghers Syndrome: An Increasingly Recognized Cause of Prepubertal gynecomastia. Plastic Reconstructive Surgery 102(4):1151-57, 1998.

19. Hsing A, McLaughlin J, Cocco p, Chen H, Fraumeni JF: Risk factors for male breast cancer. Cancer Causes and Control 9; 269-275, 1998.

20. (Jones DJ, Holt SD, Surtees P, et al: A comparison of danazol and placebo in the treatment of adult idiopathic gynaecomastia: results of a prospective study in 55 patients. Ann R Coll Surg Engl, 72:296-8, 1990.)

21. Kleinberg DL, Feldman M, Ruan W: IGF-1: An Essential Factor in Terminal End Bud Formation and Ductal Morphogenesis. Journal of Mammary Gland Biology and Neoplasia 5(1):7-17, 2000.

22. Kuhn JM, Roca R, Laudat MH, et al: Studies on the treatment of idiopathic gynecomastia with percutaneous dihydrotestosterone. Clin Endo 19: 513-20, 1983.)

23. LeProvost F, Leroux, C, Martin P Gaye P, Djiane, J, Prolactin Gene Expression in Ovine and Caprine Mammary Gland, Neuroendocrinology 60: 305-313, 1994.

24. Leroith D, Sobel R, Glick SM: The effect of clomiphene citrate on pubertal gynaecomastia. Acta Endocrinol (copenh). 95:177-80, 1980.

25. Lubahn, DB, Moyer JS, Golding TS: Alteration of Reproductive Function but not Prenatal Sexual Development after Insertional Disruption of the Mouse Estrogen Receptor Gene. Proc Soc Natl Acad Sci USA 90:11162-11166, 1993.

26. Mahoney CP: Adolescent gynecomastia. Differential Diagnosis and Management. Pediatric Clinics of North America 37(6): 1389-1404, 1990.

27. Mathur R, Braunstein: Gynecomastia: Pathomechanisms and Treatment Strategies. Hormone Research 48:95-102, 1997.

28. Matoska J, Ondrus D, Talerman A: Malignant Granulosa Cell Tumor of the Testes Associated with gynecomastia and LongSurvival. Cancer 69(7): 1769-72, 1992.

29. Mol JA, Van Garderen E, Rutteman GR, Rijnberk A: New Insights in the Molecular Mechanism of Progestin-induced Proliferation of Mammary Epithelium: Induction of the Local Biosynthesis of Growth Hormone in the Mammary Gland of Dogs, Cats, and Humans. Journal of Steroid Biochemistry and Molecular Biology 57 (1-2): 67-71, 1996.

30. Moore DC, Schlaepfer, LP, Sizonenko PC: Hormonal Changes During Puberty: Transient Pubertal Gynecomastia; Abnormal Androgen-Estrogen Ratios. Journal of Clinical Endocrinology and Metabolism 58:492-499, 1984.

31. Moran CA, Suster S: Primary Mediastinal Choriocarcinoma: A Clinicopathologic and Immunohistochemical Study of Eight Cases. American Journal of Surgical Pathology 21(9): 1007-1012, 1997.

32. Niewoehner CB, Nuttall FQ: gynecomastia in Hospitalized Male Population. American Journal of Medicine 77: 633-638, 1984.

33. Olivo J, Gordon GG, Raifi F: Estrogen Metabolism in Hyperthyroidism and in Cirrhosis of the Liver. Steroids 26: 47-56, 1975.

34. Richie J: Campbell’s Urology 7th Edition, 2439-2443, 1998.

35. Rifka SM, Pita JC, Vigersky RA, et al. Interaction of digitalis and spironolactone with human sex steroid receptors. J Clin Endocrinol Metab 1977; 46:228-244.

36. Ruan W, Kleinberg DL: Insulin-like Growth Factor I is Essential for Terminal End Bud Formation and Ductal Morphogenesis during Mammary Development. Endocrinology 140(11): 5075-81, 1999.

37. Sasano H, Kimura m, Shizawa s, Kimura N, Nagua H, Aromatase and Steroid Receptors in gynecomastia and Male Breast Carcinoma: an Immunohistochemical Study. Journal of Clinical Endocrinology and Metabolism 81 (8): 3063-7, 1996.

38. Santen R: Endocrinology fourth edition vol. 3: 2335-2341, 2001

39. Steinmetz R, Grant A, Malven, P: Transcription of Prolactin Gene in Milk Secretory Cells of the Rat Mammary Gland. Journal of Endocrinology 36: 305-313,1993.

40. Thompson DF, Carter J: Drug-induced gynecomastia. Pharmacotherapy 13(1): 37-45, 1993.

41. Ting AC, Chow LW, Leung YF: Comparison of tamoxifen with danazol in the management of idiopathic gynecomastia. Am Surg 66(1):38-40, 2000.

42. Treves N: Gynecomastia: the origins of mammary swelling in the male: and analysis of 406 patients with breast hypertrophy, 525 with testicular tumors, and 13 with adrenal neoplasms. Cancer 11: 1083-102, 1958.

43. Walden PD, Ruan W, Feldman M, Kleinberg DL: Evidence that the Mammary Fat Pad Mediated the Action of Growth Hormone in Mammary Gland Development, Endocrinology 139 (2): 659-62, 1998

44. Young S, Gooneratne S. Straus FH 2nd, Zeller WP, Bulun SE, Rosenthal IM: Feminizing Sertoli Cell Tumors in Boys with Peutz-Jehgers Syndrome. American Journal of Surgical Pathology 19 (1):50-58, 1995.

45. Zachmann M, Eiholzer U, Muritano M, et al: Treatment of pubertal gynaecomastia with testolactone. Acta Endocrinol supple (copenh) 279:218-26, 1986.

about_steroids

About Anabolic Steroids

picture of steroids

To briefly touch base on history of anabolic steroids, they were first discovered in…

 

Anabolic androgenic steroids (AAS) are members of a class of natural and synthetic steroid hormones that promote cell growth and division.These hormones result in growth of many types of body tissues, especially muscle and bone. Most anabolic androgenic steroids have varying combinations of androgenic and anabolic qualities, and are often referred to AAS (anabolic/androgenic steroids).

To briefly touch base on history of anabolic steroids, they were first discovered in 1930s. Anabolic steroids have been used for many medical purposes including stimulation of bone growth, appetite, puberty, and muscle growth. The most common use of anabolic steroids is their ability to deal with chronic wasting conditions including cancer and AIDS. As all hormones, anabolic steroids can produce numerous physiological effects including increased protein synthesis, muscle mass, strength, appetite and bone growth.