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by Michael C. Scally, M.D.
Author of "Anabolic Steroids - A Question of Muscle: Human Subject Abuses in Anabolic Steroid Research"
Harvard Medical School - M.D.; Harvard-M.I.T. Program In Health Science & Technology
Massachusetts Institute of Technology, B.S. Chemistry/Life Sciences
Dr. Scally early on recognized the lack of research and treatment for individuals using anabolic-androgenic steroids (AAS). He has remained as the sole physician by reputation and publication to actively pursue and advocate the proper use of AAS to optimize health. Dr. Scally has personally cared for thousands of individuals using AAS. His protocol for Anabolic Steroid Induced Hypogonadism has been presented before the Endocrine Society, American Association of Clinical Endocrinologists, American College of Sports Medicine, & International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV.
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Best Case Senario... clomid
Q: I just recently finished a 7 day treatment of Clomid at 100 mg a day. prescribed by my endocrinologist. What is the best case scenario of this protocol?
Can you tell me more about Clomid and how it works?
If the Clomid did raise my testosterone levels, then what is the doctor going to do next? I assume if it didn't raise my levels then he is going to put me on testosterone replacement therapy (TRT).
A: Clomiphene is classified as a selective-estrogen receptor-modulator (SERM).
Tamoxifen is classified as an estrogen receptor blocker.
Arimidex, Aromasin, Femara are aromatiziation enzyme inhibitors.
Clomiphene is classified as a selective-estrogen receptor-modulator (SERM) due to its ability to compete with estradiol for estrogen receptors at the level of the hypothalamus. Clomiphene blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of gonadotropin releasing hormone (GnRH). During clomiphene therapy, the frequency and amplitude of GnRH pulses increase and stimulate the pituitary gland to release more FSH and LH.
In turn, FSH and LH stimulate the testicles to produce more testosterone. LH and FSH then apparently stimulate the testicles to produce testosterone and sperm. Sperm volume and density are increased; however, clomiphene may not increase sperm maturation or motility. Testosterone is converted to estradiol as well as dihydrotestosterone (DHT). The estrogenic effects of clomiphene are secondary to the primary effects on HPTA function. Clomiphene exhibits no androgenic, anti-androgenic, or progestational effects, nor does it affect pituitary-thyroid or pituitary-adrenal function. In some clinical situations clomiphene citrate will produce negative feedback inhibition on The HPTA. This can usually be determined by clinical signs and laboratory profile.
Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate in a % of patients, but with a modest effect on sexual function.
It does appear that many men may have functional suppression of the central component of their hypothalamic–pituitary–testicular axis resulting from a variety of acute and chronic medical conditions and multiple drug use. The same is true for various types of anxiety.
Endurance Athlete:
Patients with an intact hypothalamic-pituitary-gonadal axis are most likely to respond to clomiphene citrate. To assess the efficacy of estrogen antagonist therapy on the function of the hypothalamic-pituitary-testicular axis in a young male runner with significant morbidity attributable to idiopathic hypogonadotropic hypogonadism. Clomiphene citrate (CC) at doses up to 50 mg two times per day over a 5-month period. Barely detectable levels of LH and FSH associated with hypogonadal levels of T were restored to the normal range with CC therapy. The patient experienced improved erectile function, increased testicular size and sexual hair growth, and an improved sense of well being. Exercise-induced hypogonadotropic hypogonadism exists as a clinical entity among male endurance athletes, and CC may provide a safe and effective treatment option for males with debilitating hypogonadism related to endurance exercise.
Long Term AAS Use:
Tan, R.S. and D. Vasudevan, Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril, 2003. 79(1): p. 203-5.
OBJECTIVE: To report a case of symptomatic hypogonadism induced by the abuse of multiple steroid preparations that was subsequently reversed by clomiphene.
DESIGN: Case report.
SETTING: University-affiliated andrology practice within family practice clinic.
PATIENT(S): A 30-year-old male.
INTERVENTION(S): Clomiphene citrate, 100-mg challenge for 5 days, followed by treatment at same dose for 2 months.
MAIN OUTCOME MEASURE(S): Clinical symptoms, androgen decline in aging male questionnaire, total T, FSH, LH.
RESULT(S): Reversal of symptoms, normalization of T levels with LH surge, restoration of pituitary-gonadal axis.
CONCLUSION(S): Clomiphene citrate is used typically in helping to restore fertility in females. This represents the first case report of the successful use of clomiphene to restore T levels and the pituitary-gonadal axis in a male patient. The axis was previously shut off with multiple anabolic steroid abuse.
Multiple Causes:
A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone and free testosterone occurred in all patients.
It was found clinically that if the primary cause of the problem is corrected, clomiphene can occasionally be tapered and stopped, and the testosterone level will remain normal (unpublished observations). In some patients the total treatment needs to be extended beyond 6 months. Quite frequently in men with ED and hypogonadism, correcting that the sexual problem may require additional methods of treatment. Nevertheless, correcting the testosterone deficit may have other beneficial effects. These may include increasing energy and well-being, as well as prevention of anemia or bone loss, depending on the severity of the hypogonadism. If patients cannot maintain their testosterone levels in the normal range after clomiphene is discontinued, permanent testosterone replacement with intramuscular injection, transdermal patches, or gels should be considered.
A minority, 39%, of the men will clinically respond to this treatment totally and this group will not have to consider artificial means of correcting their sexual dysfunction, or treatment of their comorbid medical or psychological factors. Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED. For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.
Clomiphene citrate is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Visual Symptoms - Blurred vision, lights, floaters, waves, unspecified visual complaints, photophobia, diplopia, scotomata, phosphenes and headaches are those most common I have encountered. Reducing the dosage or discontinuing the medication resolves these side effects.
Clomiphene is administered orally and is well absorbed from the GI tract. Clomiphene is a combination of racemic isomers, enclomiphene and zuclomiphene, which may have different pharmacokinetic and pharmacodynamic parameters that have not been completely elucidated. Zuclomiphene is thought to be the more estrogenic isomer. The metabolic fate of clomiphene has not been completely established, but the drug appears to undergo hepatic metabolism. Both unchanged drug and its metabolites are excreted in the feces via the bile. Stereo-specific enterohepatic recycling or sequestering seems to occur also, with the zuclomiphene isomer accumulating over several cycles of treatment. However, even with continued cycles of use, combined maximum plasma levels of enclomiphene and zuclomiphene do not appear to exceed 100 mmol/L. The half-life of clomiphene is reported to be 5 days, but studies with radiolabeled doses have demonstrated that the drug may be found in the feces for up to 6 weeks.
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HCG timing and dosing for shut down recovery....logic behind it all ??
Q: What's the logic behind all the different timing and dosing of HCG ?? We hear taking it every day, every other day, every 3rd, 4th, or 5th day. What's the logic or science behind all the different timings? Shouldn't HCG timing mimic the bodies natural pulsing of LH? What is that exactly? Where do all you guys get the timing from? Articles, studies, colleagues?
What about the dosing ? I hear to take it easy to prevent desensitizing the testes. With this you hear anywhere from 100 units to 250 units to play it safe. Others say anywhere from 500 to 2500 units at a time...Isn't that a bit much ?
What about the length of time? I hear two clinics suggest 10 days; others say 3-5 weeks. Where does all this come from and who's right? Help me! Does anyone have any hard info here ?
A: Almost everything you hear or read will be anecdotal and therefore subject to no verification. Experiences with hCG while on TRT are posted. The use of hCG for PCT is only partly related to its use on TRT.
hCG while on TRT is used for two reasons. One reason is cosmetic. While on TRT it is not unusual and more often expected to have testicular atrophy. This is variable from individual to individual. The other reason is to act as a stimulus so the testicles do not shut down and therefore will be easier to initiate independent function after AAS cessation.
Desensitization is a potential problem with hCG. I do not think you will experience it with doses of 500IU or less 3X/week. Studies have used this dose for considerably long periods. In my patients when hCG was used while on AAS the dose was 1000IU every 3 days with one month on hCG followed by one month off hCG.
hCG for PCT involves additional concepts. This is the timing of hCG in relation to other medications for return of HPTA functionality. Under normal conditions the HPTA is a tightly coupled dynamic feedback loop. It is this coupling that has to be achieved after AAS cessation to return to normal. The analogy I use is the starting of a car by pushing it from behind. Alone the care will not start but with pushing the clutch can be popped and the car started.
After AAS cessation the secretion of LH is nil. It will not be able to initiate T production until a certain stimulus LH level is reached. Studies have shown that the time for this to occur can be lengthy. Thus the idea is to ‘push’ the testicles with hCG and get them started. Once T production is initiated the dependent variable is LH. If the hCG is withdrawn without adequate LH to couple with the testicles return of HPTA functionality will fail.
The increased production of LH is achieved by a dual action of clomiphene citrate and tamoxifen. Clomiphene is a mixed agonist/antagonist (SERM) at the estradiol receptor. Clomiphene will increase the secretion of LH by action at the hypothalamo-pituitary area. Clomiphene will cause an increase in LH and secondarily increases in T and estradiol. Estradiol has a negative feedback influence on the HPTA. Estradiol is 200X the inhibitory effect of T per molar basis. Normal serum levels are the following:
Testosterone: 3-10 ng/ml (10-35 nM/L)
Estradiol: 15-65 pg/ml (55-240 pmol/L)
Tamoxifen will counteract the effect of the estradiol. Once the hCG is withdrawn the LH, initiated by clomiphene and tamoxifen, will couple with the testicles and take over production of T by the testicles. The levels of LH to maintain and couple with the testicles are maintained by clomiphene and tamoxifen. Clomiphene is continued for 15 days while Tamoxifen is continued for 30 days.
In healthy adult men, circulating levels of testosterone have a distinct pattern, with increasing levels during sleep toward a maximum around the time of awakening and a decrease during the day. In PCT hCG is administered every other day. I suggest the same time each injection in an attempt to simulate this rhythm. This is purely empirical but I recommend hCG at bedtime (2200). Clomiphene is taken in divided doses of 50mg 2X/day.
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Health Consequences of Long-Term TRT
Q: Dr. Scally,
With all the medical information on the benefits of healthy levels of testosterone (usually patients on testosterone), if a person can't restore their natural production thru proper therapy or doesn't want to try, is there really any harm on being on reasonable amounts of trt ongoing?
I'm talking mid fifties with no desire to procreate anymore or having to have daily sex. I don't consider shrunken testes, receding hairline, an occasional pimple to be problems. I'm asking about serious health concerns being caused by reasonable dose lifetime trt keeping testosterone in a normal to high normal range. I'm glad your on the forum-your reputation in this area is second to none. Thanks, Greg
A: The question opens up a 'bag of worms' regarding a patient's wishes. I understand your agreeing to certain side effects, etc. to be on TRT. But if there is a cause for the hypogonadism it first needs to be determined, if possible. When you state, "... a person can't restore their natural production thru proper therapy or doesn't want to try ..." I have to assume that the patient has no prior significant medical history - diagnosis PADAM or Andropause.
“TRT in Brief”
Frank hypogonadism is a clinical condition in which low levels of serum testosterone are found in association with specific signs and symptoms, including diminished libido and sense of vitality, erectile dysfunction, reduced muscle mass and bone density, depression, and anemia. It is associated with specific morbidity and mortality risks.
When relative hypogonadism occurs in an older man, the condition is often called andropause, or androgen deficiency of the aging male. The difference is whether or not a serum T level is compared to the same age or that of a younger age. BTW the same approach is taken for BMD. There we use comparison to a younger population. At this time there are no long term studies on the morbidity and mortality for TRT. The most controversial topic in the ongoing discussion of TRT is the issue of risk.
Testosterone supplementation in the United States has increased more than 500 percent in prescription sales of testosterone products since 1993. IMS Health (www.imshealth.com/ims/portal), which tracks prescription drug sales, has said the market for testosterone products in general jumped from $49 million in 1997 to $200+/2000, 250+ million/2001, and 400+/2002 The first testosterone gel on the market, Androgel, launched by the Belgian pharmaceutical company Solvay S.A. in 2000, posted about $196 million in U.S. sales last year, a 52 percent jump from 2001.
Coronary Artery Disease - Data supporting a causal relation between higher testosterone levels and heart disease is sparse. Several studies suggest that higher testosterone levels may actually have a favorable effect on the risk of cardiovascular disease. Studies of TRT have not demonstrated an increased incidence of cardiovascular disease or events such as myocardial infarction, stroke, or angina.
Lipid Profile - Available data regarding the relation of TRT to lipid profiles are inconsistent. Supraphysiologic doses of androgens, particularly oral nonaromatizable androgenic steroids lower high-density lipoprotein (HDL) levels. Numerous controlled studies using physiologic replacement doses of testosterone have shown no change, or minimal reduction, in HDL, often with a reduction in total cholesterol.
The limited information available suggest a neutral effect of TRT within the physiologic range is not associated with worsening of the lipid profile
Polycythemia - Men with hypogonadism have lower hemoglobin levels than age-matched controls, and TRT can restore their hemoglobin levels to the normal range. Injections appear to be associated with a greater risk of erythrocytosis than topical preparations. the H/H/ level should be monitored in men receiving TRT. Treatment may include the withholding of testosterone, therapeutic phlebotomy, or blood donation, may be instituted if erythrocytosis develops.
Benign Prostatic Hyperplasia - The development of BPH requires the presence of androgens and that the marked reduction in serum testosterone caused by chemical or surgical castration causes reduced prostate volume. Studies have failed to demonstrate exacerbation of voiding symptoms attributable to BPH during testosterone supplementation.
Prostate volume, as determined by ultrasonography, does increase significantly during testosterone-replacement therapy. Urine flow rates, postvoiding residual urine volumes, and prostate voiding symptoms did not change significantly in these studies. This is explained by the poor correlation between prostate volume and urinary symptoms. Individual men with hypogonadism may occasionally have increased voiding symptoms with TRT.
Prostate Cancer - There is no scientific peer-reviewed literature that definitely establishes a link between the administration of testosterone and the increasing the risk or development of prostate cancer. There is no compelling evidence that testosterone has a causative role in prostate cancer or to suggest men with higher testosterone levels are at greater risk of prostate cancer or that treating hypogonadism with exogenous androgens increases this risk. Just remember the incidence of prostate cancer rises with aging which is associated with declining testosterone levels. Prostate cancer becomes more prevalent exactly at the time of a man's life when testosterone levels decline.
Over 200,000 men are given a diagnosis of prostate cancer each year and most are first detected by a rise in the PSA level unrelated to testosterone therapy.
Interestingly the underlying prevalence of occult prostate cancer in men with low testosterone levels appears to be substantial. A history of prostate cancer has been considered an absolute contraindication to testosterone-replacement therapy which is now under active debate for men who are deemed cured.
PSA – The 2002 U.S. Preventative Services Task Force recommendations on the screening for prostatic cancer concludes that the evidence is insufficient to recommend for or against routine screening for prostate cancer using prostate-specific androgens (PSA) testing or digital rectal examination (DRE), "Screening is associated with important harms including frequent false-positive results and unnecessary anxiety, biopsies, and potential complications of treatment of some cases of cancer that have never affected a patient's health. The USPSTF concludes that evidence is insufficient to determine whether the benefits outweigh the harms for a screened population."
PSA values used to trigger prostate biopsy include an increase of 1.5 ng per milliliter within two years or a total increase of 2.0 ng per milliliter over any period. These recommendations have been based on observational population studies in untreated men.
Hepatic Effects - The use of oral preparations of testosterone has been reported to lead to hepatotoxic effects and neoplasia, including benign and malignant tumors. Intramuscular injections and transdermal preparations do not appear to be associated with hepatic dysfunction. Routine monitoring with liver-function tests is probably unnecessary but caution usually is better.
Sleep Apnea - Testosterone-replacement therapy has been associated with exacerbation of sleep apnea or with the development of sleep apnea.
Gynecomastia - A small number of men receiving testosterone-replacement therapy report breast tenderness and swelling.
Anabolic Steroid Induced Hypogonadism (ASIH) – Probably the most bothersome since this may cause problems in discontinuing TRT. Testicular size and consistency often diminish, fertility will be greatly decreased because of down-regulation of gonadotropins.
Skin - Transdermal TRT is associated with a variety of skin reactions, mainly erythema or pruritus, which are more common with patches than with gel preparations. Intramuscular injections of testosterone can cause local pain, soreness, bruising, erythema, swelling, nodules, or furuncles. Acne, oily skin, increased body hair, and flushing have also been observed but are generally considered only a minor inconvenience. There isn’t any data indicating acceleration of male-pattern baldness with TRT but seems reasonable it might.
Fluid retention is uncommon and generally mild, but testosterone-replacement therapy should be used cautiously in men with congestive heart failure or renal insufficiency.
Hypertension has rarely been reported.
There is no universal agreement regarding target levels of replacement therapy, although many experienced clinicians aim for the mid- to upper-normal range in order to optimize the response to treatment. Treatment to raise levels above the physiologic range is discouraged, although it should be recognized that peak serum testosterone levels generally do rise transiently above the upper limit of normal with standard injection-therapy dosages.
If the patient reports an adequate clinical response to testosterone supplementation, there is no need for dosage adjustment, even if levels are in the low-normal range. If the clinical response is suboptimal and testosterone levels are no higher than the low-normal range, the testosterone dosage should be increased. If the maximal recommended dose of transdermal therapy has been prescribed without the achievement of adequate serum testosterone levels, consideration should be given to changing to intramuscular-injection therapy. For men receiving injection therapy, clinicians must interpret the results of blood tests on the basis of the interval since the most recent injection, recognizing that peak serum levels are obtained 2 to 5 days after injection and that the levels often return to base line by 10 to 14 days after injection. If the hematocrit rises above the reference range, consideration should be given to temporarily withholding testosterone-replacement therapy, reducing the dosage, or performing phlebotomy. Subsequent monitoring visits are performed at three-to-six-month intervals for the first year and yearly thereafter. At each visit there should be an assessment of the symptomatic response to treatment.
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Why Use Both Clomid and Nolvadex Together?
Q: I have read that Clomid and Novadex are very similar products. Is this true? If so why would you need to take both?
A: The administration of antiestrogens is a common treatment because anti estrogens interfere with the normal negative feedback of sex steroids at hypothalamic and pituitary levels in order to increase endogenous gonadotropin-releasing hormone secretion from the hypothalamus and FSH and LH secretion directly from the pituitary. In turn, FSH and LH stimulate Leydig cells in the testes, and this has been claimed to lead to increased local testosterone production, thereby boosting spermatogenesis with a possible improvement in fertility. There may also be a direct effect of antiestrogens on testicular spermatogenesis or steroidogenesis.
Clomiphene is a synthetic derivative an estrogen. Clomid is a mixed agonist/antagonist for the estradiol receptor. Tamoxifen is a pure estradiol receptor antagonist. Clomid acts as an estrogen, rather than an antiestrogen, by sensitizing pituitary cells to the action of GnRH. Although tamoxifen is almost as effective as Clomid in binding to pituitary estrogen receptors, tamoxifen has little or no estrogenic activity in terms of its ability to enhance the GnRH-stimulated release of LH. The estrogenic action of Clomid at the pituitary represents a unique feature of this compound and that tamoxifen may be devoid of estrogenic activity at the pituitary level.
Perusal of the literature thus indicates that clomiphene acts in several ways in the human male; (a) due to its similarity of structure to stilbesterol it binds with receptor sites in the hypothalamus and pituitary, (b) It stimulates gonadotrophin secretion by acting on the hypothalamo-hypophyseal system, (c) the inhibitory effects of high levels of circulating estrogens (produced under the influence of clomiphene) on hypothalamo-hypophyseal axis are possibly prevented by its potent antiestrogenic behaviour. The result of these varied effects of clomiphene is an overall increase in gonadotrophin and estrogen secretion and accounts for their increase under clinical conditions.
In one study the administration of tamoxifen, 20 mg/day for 10 days, to normal males produced a moderate increase in luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol levels, comparable to the effect of 150 mg of clomiphene citrate (Clomid). Treatment of patients with "idiopathic" oligospermia for 6 to 9 months resulted in a significant increase in gonadotropin, testosterone, and estradiol levels.
Cochran database summary showed ten studies involving 738 men were included. Five of the trials did not specify method of randomization. Antiestrogens had a positive effect on endocrinal outcomes, such as serum testosterone levels. Antiestrogens appear to have a beneficial effect on endocrinal outcomes, but there is not enough evidence to evaluate the use of antiestrogens for increasing the fertility of males with idiopathic oligo-asthenospermia.
In the over one-thousand patients I have treated for HPTA normalization after AAS cessation i have used the combination of clomiphene citrate and tamoxifen. I have used clomiphene citrate alone in many cases. I added tamoxifen to the protocol to see if I could get a better clinical response. This seemed to be the case although I have not had the opportunity to evaluate the data. When both compounds are used the clomiphene citrate is discontinued first and the tamoxifen is continued for 2 more weeks. as I stated in the post on hCG injections it is imperative to be tested while on the medications. thus one would be tested ~3-5 days before the tamoxifen expires. In the 1st stage described in the hCG post one tests for testosterone only. the serum T level determines whether or not the hCG is halted. In the typical situation the hCG is stopped and the CC & tamoxifen continued. the lab tests at the end of the oral meds is LH & T.
Author of "Anabolic Steroids - A Question of Muscle: Human Subject Abuses in Anabolic Steroid Research"
Harvard Medical School - M.D.; Harvard-M.I.T. Program In Health Science & Technology
Massachusetts Institute of Technology, B.S. Chemistry/Life Sciences
Dr. Scally early on recognized the lack of research and treatment for individuals using anabolic-androgenic steroids (AAS). He has remained as the sole physician by reputation and publication to actively pursue and advocate the proper use of AAS to optimize health. Dr. Scally has personally cared for thousands of individuals using AAS. His protocol for Anabolic Steroid Induced Hypogonadism has been presented before the Endocrine Society, American Association of Clinical Endocrinologists, American College of Sports Medicine, & International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV.
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Best Case Senario... clomid
Q: I just recently finished a 7 day treatment of Clomid at 100 mg a day. prescribed by my endocrinologist. What is the best case scenario of this protocol?
Can you tell me more about Clomid and how it works?
If the Clomid did raise my testosterone levels, then what is the doctor going to do next? I assume if it didn't raise my levels then he is going to put me on testosterone replacement therapy (TRT).
A: Clomiphene is classified as a selective-estrogen receptor-modulator (SERM).
Tamoxifen is classified as an estrogen receptor blocker.
Arimidex, Aromasin, Femara are aromatiziation enzyme inhibitors.
Clomiphene is classified as a selective-estrogen receptor-modulator (SERM) due to its ability to compete with estradiol for estrogen receptors at the level of the hypothalamus. Clomiphene blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of gonadotropin releasing hormone (GnRH). During clomiphene therapy, the frequency and amplitude of GnRH pulses increase and stimulate the pituitary gland to release more FSH and LH.
In turn, FSH and LH stimulate the testicles to produce more testosterone. LH and FSH then apparently stimulate the testicles to produce testosterone and sperm. Sperm volume and density are increased; however, clomiphene may not increase sperm maturation or motility. Testosterone is converted to estradiol as well as dihydrotestosterone (DHT). The estrogenic effects of clomiphene are secondary to the primary effects on HPTA function. Clomiphene exhibits no androgenic, anti-androgenic, or progestational effects, nor does it affect pituitary-thyroid or pituitary-adrenal function. In some clinical situations clomiphene citrate will produce negative feedback inhibition on The HPTA. This can usually be determined by clinical signs and laboratory profile.
Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate in a % of patients, but with a modest effect on sexual function.
It does appear that many men may have functional suppression of the central component of their hypothalamic–pituitary–testicular axis resulting from a variety of acute and chronic medical conditions and multiple drug use. The same is true for various types of anxiety.
Endurance Athlete:
Patients with an intact hypothalamic-pituitary-gonadal axis are most likely to respond to clomiphene citrate. To assess the efficacy of estrogen antagonist therapy on the function of the hypothalamic-pituitary-testicular axis in a young male runner with significant morbidity attributable to idiopathic hypogonadotropic hypogonadism. Clomiphene citrate (CC) at doses up to 50 mg two times per day over a 5-month period. Barely detectable levels of LH and FSH associated with hypogonadal levels of T were restored to the normal range with CC therapy. The patient experienced improved erectile function, increased testicular size and sexual hair growth, and an improved sense of well being. Exercise-induced hypogonadotropic hypogonadism exists as a clinical entity among male endurance athletes, and CC may provide a safe and effective treatment option for males with debilitating hypogonadism related to endurance exercise.
Long Term AAS Use:
Tan, R.S. and D. Vasudevan, Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril, 2003. 79(1): p. 203-5.
OBJECTIVE: To report a case of symptomatic hypogonadism induced by the abuse of multiple steroid preparations that was subsequently reversed by clomiphene.
DESIGN: Case report.
SETTING: University-affiliated andrology practice within family practice clinic.
PATIENT(S): A 30-year-old male.
INTERVENTION(S): Clomiphene citrate, 100-mg challenge for 5 days, followed by treatment at same dose for 2 months.
MAIN OUTCOME MEASURE(S): Clinical symptoms, androgen decline in aging male questionnaire, total T, FSH, LH.
RESULT(S): Reversal of symptoms, normalization of T levels with LH surge, restoration of pituitary-gonadal axis.
CONCLUSION(S): Clomiphene citrate is used typically in helping to restore fertility in females. This represents the first case report of the successful use of clomiphene to restore T levels and the pituitary-gonadal axis in a male patient. The axis was previously shut off with multiple anabolic steroid abuse.
Multiple Causes:
A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone and free testosterone occurred in all patients.
It was found clinically that if the primary cause of the problem is corrected, clomiphene can occasionally be tapered and stopped, and the testosterone level will remain normal (unpublished observations). In some patients the total treatment needs to be extended beyond 6 months. Quite frequently in men with ED and hypogonadism, correcting that the sexual problem may require additional methods of treatment. Nevertheless, correcting the testosterone deficit may have other beneficial effects. These may include increasing energy and well-being, as well as prevention of anemia or bone loss, depending on the severity of the hypogonadism. If patients cannot maintain their testosterone levels in the normal range after clomiphene is discontinued, permanent testosterone replacement with intramuscular injection, transdermal patches, or gels should be considered.
A minority, 39%, of the men will clinically respond to this treatment totally and this group will not have to consider artificial means of correcting their sexual dysfunction, or treatment of their comorbid medical or psychological factors. Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED. For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.
Clomiphene citrate is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Visual Symptoms - Blurred vision, lights, floaters, waves, unspecified visual complaints, photophobia, diplopia, scotomata, phosphenes and headaches are those most common I have encountered. Reducing the dosage or discontinuing the medication resolves these side effects.
Clomiphene is administered orally and is well absorbed from the GI tract. Clomiphene is a combination of racemic isomers, enclomiphene and zuclomiphene, which may have different pharmacokinetic and pharmacodynamic parameters that have not been completely elucidated. Zuclomiphene is thought to be the more estrogenic isomer. The metabolic fate of clomiphene has not been completely established, but the drug appears to undergo hepatic metabolism. Both unchanged drug and its metabolites are excreted in the feces via the bile. Stereo-specific enterohepatic recycling or sequestering seems to occur also, with the zuclomiphene isomer accumulating over several cycles of treatment. However, even with continued cycles of use, combined maximum plasma levels of enclomiphene and zuclomiphene do not appear to exceed 100 mmol/L. The half-life of clomiphene is reported to be 5 days, but studies with radiolabeled doses have demonstrated that the drug may be found in the feces for up to 6 weeks.
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HCG timing and dosing for shut down recovery....logic behind it all ??
Q: What's the logic behind all the different timing and dosing of HCG ?? We hear taking it every day, every other day, every 3rd, 4th, or 5th day. What's the logic or science behind all the different timings? Shouldn't HCG timing mimic the bodies natural pulsing of LH? What is that exactly? Where do all you guys get the timing from? Articles, studies, colleagues?
What about the dosing ? I hear to take it easy to prevent desensitizing the testes. With this you hear anywhere from 100 units to 250 units to play it safe. Others say anywhere from 500 to 2500 units at a time...Isn't that a bit much ?
What about the length of time? I hear two clinics suggest 10 days; others say 3-5 weeks. Where does all this come from and who's right? Help me! Does anyone have any hard info here ?
A: Almost everything you hear or read will be anecdotal and therefore subject to no verification. Experiences with hCG while on TRT are posted. The use of hCG for PCT is only partly related to its use on TRT.
hCG while on TRT is used for two reasons. One reason is cosmetic. While on TRT it is not unusual and more often expected to have testicular atrophy. This is variable from individual to individual. The other reason is to act as a stimulus so the testicles do not shut down and therefore will be easier to initiate independent function after AAS cessation.
Desensitization is a potential problem with hCG. I do not think you will experience it with doses of 500IU or less 3X/week. Studies have used this dose for considerably long periods. In my patients when hCG was used while on AAS the dose was 1000IU every 3 days with one month on hCG followed by one month off hCG.
hCG for PCT involves additional concepts. This is the timing of hCG in relation to other medications for return of HPTA functionality. Under normal conditions the HPTA is a tightly coupled dynamic feedback loop. It is this coupling that has to be achieved after AAS cessation to return to normal. The analogy I use is the starting of a car by pushing it from behind. Alone the care will not start but with pushing the clutch can be popped and the car started.
After AAS cessation the secretion of LH is nil. It will not be able to initiate T production until a certain stimulus LH level is reached. Studies have shown that the time for this to occur can be lengthy. Thus the idea is to ‘push’ the testicles with hCG and get them started. Once T production is initiated the dependent variable is LH. If the hCG is withdrawn without adequate LH to couple with the testicles return of HPTA functionality will fail.
The increased production of LH is achieved by a dual action of clomiphene citrate and tamoxifen. Clomiphene is a mixed agonist/antagonist (SERM) at the estradiol receptor. Clomiphene will increase the secretion of LH by action at the hypothalamo-pituitary area. Clomiphene will cause an increase in LH and secondarily increases in T and estradiol. Estradiol has a negative feedback influence on the HPTA. Estradiol is 200X the inhibitory effect of T per molar basis. Normal serum levels are the following:
Testosterone: 3-10 ng/ml (10-35 nM/L)
Estradiol: 15-65 pg/ml (55-240 pmol/L)
Tamoxifen will counteract the effect of the estradiol. Once the hCG is withdrawn the LH, initiated by clomiphene and tamoxifen, will couple with the testicles and take over production of T by the testicles. The levels of LH to maintain and couple with the testicles are maintained by clomiphene and tamoxifen. Clomiphene is continued for 15 days while Tamoxifen is continued for 30 days.
In healthy adult men, circulating levels of testosterone have a distinct pattern, with increasing levels during sleep toward a maximum around the time of awakening and a decrease during the day. In PCT hCG is administered every other day. I suggest the same time each injection in an attempt to simulate this rhythm. This is purely empirical but I recommend hCG at bedtime (2200). Clomiphene is taken in divided doses of 50mg 2X/day.
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Health Consequences of Long-Term TRT
Q: Dr. Scally,
With all the medical information on the benefits of healthy levels of testosterone (usually patients on testosterone), if a person can't restore their natural production thru proper therapy or doesn't want to try, is there really any harm on being on reasonable amounts of trt ongoing?
I'm talking mid fifties with no desire to procreate anymore or having to have daily sex. I don't consider shrunken testes, receding hairline, an occasional pimple to be problems. I'm asking about serious health concerns being caused by reasonable dose lifetime trt keeping testosterone in a normal to high normal range. I'm glad your on the forum-your reputation in this area is second to none. Thanks, Greg
A: The question opens up a 'bag of worms' regarding a patient's wishes. I understand your agreeing to certain side effects, etc. to be on TRT. But if there is a cause for the hypogonadism it first needs to be determined, if possible. When you state, "... a person can't restore their natural production thru proper therapy or doesn't want to try ..." I have to assume that the patient has no prior significant medical history - diagnosis PADAM or Andropause.
“TRT in Brief”
Frank hypogonadism is a clinical condition in which low levels of serum testosterone are found in association with specific signs and symptoms, including diminished libido and sense of vitality, erectile dysfunction, reduced muscle mass and bone density, depression, and anemia. It is associated with specific morbidity and mortality risks.
When relative hypogonadism occurs in an older man, the condition is often called andropause, or androgen deficiency of the aging male. The difference is whether or not a serum T level is compared to the same age or that of a younger age. BTW the same approach is taken for BMD. There we use comparison to a younger population. At this time there are no long term studies on the morbidity and mortality for TRT. The most controversial topic in the ongoing discussion of TRT is the issue of risk.
Testosterone supplementation in the United States has increased more than 500 percent in prescription sales of testosterone products since 1993. IMS Health (www.imshealth.com/ims/portal), which tracks prescription drug sales, has said the market for testosterone products in general jumped from $49 million in 1997 to $200+/2000, 250+ million/2001, and 400+/2002 The first testosterone gel on the market, Androgel, launched by the Belgian pharmaceutical company Solvay S.A. in 2000, posted about $196 million in U.S. sales last year, a 52 percent jump from 2001.
Coronary Artery Disease - Data supporting a causal relation between higher testosterone levels and heart disease is sparse. Several studies suggest that higher testosterone levels may actually have a favorable effect on the risk of cardiovascular disease. Studies of TRT have not demonstrated an increased incidence of cardiovascular disease or events such as myocardial infarction, stroke, or angina.
Lipid Profile - Available data regarding the relation of TRT to lipid profiles are inconsistent. Supraphysiologic doses of androgens, particularly oral nonaromatizable androgenic steroids lower high-density lipoprotein (HDL) levels. Numerous controlled studies using physiologic replacement doses of testosterone have shown no change, or minimal reduction, in HDL, often with a reduction in total cholesterol.
The limited information available suggest a neutral effect of TRT within the physiologic range is not associated with worsening of the lipid profile
Polycythemia - Men with hypogonadism have lower hemoglobin levels than age-matched controls, and TRT can restore their hemoglobin levels to the normal range. Injections appear to be associated with a greater risk of erythrocytosis than topical preparations. the H/H/ level should be monitored in men receiving TRT. Treatment may include the withholding of testosterone, therapeutic phlebotomy, or blood donation, may be instituted if erythrocytosis develops.
Benign Prostatic Hyperplasia - The development of BPH requires the presence of androgens and that the marked reduction in serum testosterone caused by chemical or surgical castration causes reduced prostate volume. Studies have failed to demonstrate exacerbation of voiding symptoms attributable to BPH during testosterone supplementation.
Prostate volume, as determined by ultrasonography, does increase significantly during testosterone-replacement therapy. Urine flow rates, postvoiding residual urine volumes, and prostate voiding symptoms did not change significantly in these studies. This is explained by the poor correlation between prostate volume and urinary symptoms. Individual men with hypogonadism may occasionally have increased voiding symptoms with TRT.
Prostate Cancer - There is no scientific peer-reviewed literature that definitely establishes a link between the administration of testosterone and the increasing the risk or development of prostate cancer. There is no compelling evidence that testosterone has a causative role in prostate cancer or to suggest men with higher testosterone levels are at greater risk of prostate cancer or that treating hypogonadism with exogenous androgens increases this risk. Just remember the incidence of prostate cancer rises with aging which is associated with declining testosterone levels. Prostate cancer becomes more prevalent exactly at the time of a man's life when testosterone levels decline.
Over 200,000 men are given a diagnosis of prostate cancer each year and most are first detected by a rise in the PSA level unrelated to testosterone therapy.
Interestingly the underlying prevalence of occult prostate cancer in men with low testosterone levels appears to be substantial. A history of prostate cancer has been considered an absolute contraindication to testosterone-replacement therapy which is now under active debate for men who are deemed cured.
PSA – The 2002 U.S. Preventative Services Task Force recommendations on the screening for prostatic cancer concludes that the evidence is insufficient to recommend for or against routine screening for prostate cancer using prostate-specific androgens (PSA) testing or digital rectal examination (DRE), "Screening is associated with important harms including frequent false-positive results and unnecessary anxiety, biopsies, and potential complications of treatment of some cases of cancer that have never affected a patient's health. The USPSTF concludes that evidence is insufficient to determine whether the benefits outweigh the harms for a screened population."
PSA values used to trigger prostate biopsy include an increase of 1.5 ng per milliliter within two years or a total increase of 2.0 ng per milliliter over any period. These recommendations have been based on observational population studies in untreated men.
Hepatic Effects - The use of oral preparations of testosterone has been reported to lead to hepatotoxic effects and neoplasia, including benign and malignant tumors. Intramuscular injections and transdermal preparations do not appear to be associated with hepatic dysfunction. Routine monitoring with liver-function tests is probably unnecessary but caution usually is better.
Sleep Apnea - Testosterone-replacement therapy has been associated with exacerbation of sleep apnea or with the development of sleep apnea.
Gynecomastia - A small number of men receiving testosterone-replacement therapy report breast tenderness and swelling.
Anabolic Steroid Induced Hypogonadism (ASIH) – Probably the most bothersome since this may cause problems in discontinuing TRT. Testicular size and consistency often diminish, fertility will be greatly decreased because of down-regulation of gonadotropins.
Skin - Transdermal TRT is associated with a variety of skin reactions, mainly erythema or pruritus, which are more common with patches than with gel preparations. Intramuscular injections of testosterone can cause local pain, soreness, bruising, erythema, swelling, nodules, or furuncles. Acne, oily skin, increased body hair, and flushing have also been observed but are generally considered only a minor inconvenience. There isn’t any data indicating acceleration of male-pattern baldness with TRT but seems reasonable it might.
Fluid retention is uncommon and generally mild, but testosterone-replacement therapy should be used cautiously in men with congestive heart failure or renal insufficiency.
Hypertension has rarely been reported.
There is no universal agreement regarding target levels of replacement therapy, although many experienced clinicians aim for the mid- to upper-normal range in order to optimize the response to treatment. Treatment to raise levels above the physiologic range is discouraged, although it should be recognized that peak serum testosterone levels generally do rise transiently above the upper limit of normal with standard injection-therapy dosages.
If the patient reports an adequate clinical response to testosterone supplementation, there is no need for dosage adjustment, even if levels are in the low-normal range. If the clinical response is suboptimal and testosterone levels are no higher than the low-normal range, the testosterone dosage should be increased. If the maximal recommended dose of transdermal therapy has been prescribed without the achievement of adequate serum testosterone levels, consideration should be given to changing to intramuscular-injection therapy. For men receiving injection therapy, clinicians must interpret the results of blood tests on the basis of the interval since the most recent injection, recognizing that peak serum levels are obtained 2 to 5 days after injection and that the levels often return to base line by 10 to 14 days after injection. If the hematocrit rises above the reference range, consideration should be given to temporarily withholding testosterone-replacement therapy, reducing the dosage, or performing phlebotomy. Subsequent monitoring visits are performed at three-to-six-month intervals for the first year and yearly thereafter. At each visit there should be an assessment of the symptomatic response to treatment.
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Why Use Both Clomid and Nolvadex Together?
Q: I have read that Clomid and Novadex are very similar products. Is this true? If so why would you need to take both?
A: The administration of antiestrogens is a common treatment because anti estrogens interfere with the normal negative feedback of sex steroids at hypothalamic and pituitary levels in order to increase endogenous gonadotropin-releasing hormone secretion from the hypothalamus and FSH and LH secretion directly from the pituitary. In turn, FSH and LH stimulate Leydig cells in the testes, and this has been claimed to lead to increased local testosterone production, thereby boosting spermatogenesis with a possible improvement in fertility. There may also be a direct effect of antiestrogens on testicular spermatogenesis or steroidogenesis.
Clomiphene is a synthetic derivative an estrogen. Clomid is a mixed agonist/antagonist for the estradiol receptor. Tamoxifen is a pure estradiol receptor antagonist. Clomid acts as an estrogen, rather than an antiestrogen, by sensitizing pituitary cells to the action of GnRH. Although tamoxifen is almost as effective as Clomid in binding to pituitary estrogen receptors, tamoxifen has little or no estrogenic activity in terms of its ability to enhance the GnRH-stimulated release of LH. The estrogenic action of Clomid at the pituitary represents a unique feature of this compound and that tamoxifen may be devoid of estrogenic activity at the pituitary level.
Perusal of the literature thus indicates that clomiphene acts in several ways in the human male; (a) due to its similarity of structure to stilbesterol it binds with receptor sites in the hypothalamus and pituitary, (b) It stimulates gonadotrophin secretion by acting on the hypothalamo-hypophyseal system, (c) the inhibitory effects of high levels of circulating estrogens (produced under the influence of clomiphene) on hypothalamo-hypophyseal axis are possibly prevented by its potent antiestrogenic behaviour. The result of these varied effects of clomiphene is an overall increase in gonadotrophin and estrogen secretion and accounts for their increase under clinical conditions.
In one study the administration of tamoxifen, 20 mg/day for 10 days, to normal males produced a moderate increase in luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol levels, comparable to the effect of 150 mg of clomiphene citrate (Clomid). Treatment of patients with "idiopathic" oligospermia for 6 to 9 months resulted in a significant increase in gonadotropin, testosterone, and estradiol levels.
Cochran database summary showed ten studies involving 738 men were included. Five of the trials did not specify method of randomization. Antiestrogens had a positive effect on endocrinal outcomes, such as serum testosterone levels. Antiestrogens appear to have a beneficial effect on endocrinal outcomes, but there is not enough evidence to evaluate the use of antiestrogens for increasing the fertility of males with idiopathic oligo-asthenospermia.
In the over one-thousand patients I have treated for HPTA normalization after AAS cessation i have used the combination of clomiphene citrate and tamoxifen. I have used clomiphene citrate alone in many cases. I added tamoxifen to the protocol to see if I could get a better clinical response. This seemed to be the case although I have not had the opportunity to evaluate the data. When both compounds are used the clomiphene citrate is discontinued first and the tamoxifen is continued for 2 more weeks. as I stated in the post on hCG injections it is imperative to be tested while on the medications. thus one would be tested ~3-5 days before the tamoxifen expires. In the 1st stage described in the hCG post one tests for testosterone only. the serum T level determines whether or not the hCG is halted. In the typical situation the hCG is stopped and the CC & tamoxifen continued. the lab tests at the end of the oral meds is LH & T.
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