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Wednesday, November 23, 2011

How to Manage Polycythemia Caused by Testosterone Replacement Therapy

Testosterone Replacement Therapy and Polycythemia

November 16, 2011

Testosterone Replacement Therapy and Polycythemia in HIV-Infected Patients


A research letter recently published in the journal AIDS by Vorkas et al determined that testosterone use was associated with polycythemia, and intramuscular administration demonstrated a stronger association than topical (testosterone patch) use. No adverse cardiovascular or thrombotic events were observed. HIV-infected patients taking testosterone should undergo routine hematologic monitoring with adjustment of therapy when appropriate.

Polycythemia is an excessive production of red blood cells. With polycythemia the blood becomes very viscous or "sticky," making it harder for the heart to pump. High blood pressure, strokes and heart attacks can occur.

The association between testosterone replacement therapy and polycythemia has been reported for the past few years as this therapy has become more mainstream. In addition to increasing muscle and sex drive, testosterone can increase the body's production of red blood cells. This hematopoietic (blood-building) effect could be a good thing for those with mild anemia.

Although all testosterone replacement products can increase the amount of red blood cells, the study showed a higher incidence of polycythemia in those using intramuscular testosterone than topical administration (testosterone patch was the main option used -- no gels). Smoking has also been associated with polycythemia and may contribute to the effects of other risk factors.

In the above mentioned study, twenty-five patients met the criteria for polycythemia (21 male; four female). Using the number of unique patients with five clinic visits during the time frame of the study as the denominator, the estimated prevalence of polycythemia was 0.42% (95% CI 0.27-0.61). Mean hemoglobin at the time of diagnosis of polycythemia was 18.9+/-0.42 g/dl in men and 17.0+/-0.83 g/dl in women. Among the four female cases, one was diagnosed with chronic obstructive pulmonary disease (COPD) and severe pulmonary hypertension, while the other three did not have a documented explanation for elevated hemoglobin. Because of the relatively small number of female cases and the fact that the primary hypothesis is related to testosterone use, this case-control study focused on the 21 male patients.

Five of the 21 cases (24%) did not use testosterone, but had other explanations for their polycythemia: pulmonary hypertension, COPD and plasma volume contraction. In two of the 21 cases (10%) there was no documented reason for elevated hemoglobin. No cases met the criteria for polycythemia vera, and no adverse cardiovascular or thrombotic events were noted among the cases or controls.

The letter recommends that all HIV-infected patients taking testosterone should undergo routine hematologic monitoring and adjustment of testosterone dose or cessation of testosterone therapy as appropriate based on hemoglobin values. Unfortunately, no mention is made of therapeutic phlebotomy as a management strategy for this problem. Considering that stopping testosterone replacement would affect patients' quality of life and leave their hypothalamic-pituitary-gonadal axis in a dysfunctional state for weeks, months or permanently, other ways to manage polycythemia besides treatment cessation need to be discussed.

Below is an excerpt from my book, Testosterone: A Man's Guide, further detailing the prevention and management of polycythemia.


Preventing and Managing Polycythemia

It's important to check patients' hemoglobin and hematocrit blood levels while on testosterone replacement therapy. As we all know, hemoglobin is the substance that makes blood red and helps transport oxygen in the blood. Hematocrit reflects the proportion of red cells to total blood volume. A hematocrit of over 52 percent should be evaluated. Decreasing testosterone dose or stopping it are options that may not be the best for assuring patients' best quality of life, however. Switching from injectable to transdermal testosterone may decrease hematocrit, but in many cases not to the degree needed.

The following table shows the different guideline groups that recommend monitoring for testosterone replacement therapy. They all agree about measuring hematocrit at month 3, and then annually, with some also recommending measurements at month 6 after starting testosterone (it is good to remember that there is a ban on gay blood donors in the United States).
Monitoring testosterone therapy: What the consensus guidelines say
Many patients on testosterone replacement who experience polycythemia do not want to stop the therapy due to fears of re-experiencing the depression, fatigue and low sex-drive they had before starting treatment. For those patients, therapeutic phlebotomy may be the answer. Therapeutic phlebotomy is very similar to what happens when donating blood, but this procedure is prescribed by physicians as a way to bring down blood hematocrit and viscosity.

A phlebotomy of one pint of blood will generally lower hematocrit by about 3 percent. I have seen phlebotomy given weekly for several weeks bring hematocrit from 56 percent to a healthy 46 percent. I know physicians who prescribe phlebotomy once every 8-12 weeks because of an unusual response to testosterone replacement therapy. This simple procedure is done in a hospital blood draw or a blood bank facility and can reduce hematocrit, hemoglobin, and blood iron easily and in less than one hour.

Unfortunately, therapeutic phlebotomy can be a difficult option to get reimbursed or covered by insurance companies. The reimbursement codes for therapeutic phlebotomy are CPT 39107, icd9 code 289.0.
Unless a local blood bank is willing to help, some physicians may need to write a letter of medical necessity for phlebotomy if requested by insurance companies. If the patient is healthy and without HIV, hepatitis B, C, or other infections, they could donate blood at a blood bank.

The approximate amount of blood volume that needs to be withdrawn to restore normal values can be calculated by the following formula, courtesy of Dr. Michael Scally, an expert on testosterone side effect management. The use of the formula includes the assumption that whole blood is withdrawn. The duration over which the blood volume is withdrawn is affected by whether concurrent fluid replacement occurs.

Volume of Withdrawn Blood (cc)=
Weight (kg) × ABV×[Hgbi - Hgbf]/[(Hgbi +Hgbf)/2]
Where:
ABV = Average Blood Volume (default = 70)
Hgbi (Hcti) = Hemoglobin initial
Hgbf (Hctf) = Hemoglobin final (desired);
So, for a 70 kg (154 lbs) man (multiply lbs x 0.45359237 to get kilogram) with an initial high hemoglobin of 20 mg/mL who needs to have it brought down to a normal hemoglobin of 14 mg/mL, the calculation would be:
CC of blood volume to be withdrawn = 75 x 70 x [20 - l4]/[(20 + l4)/2] = 75 x 70 x (6/17) = approximately 1850 cc;
One unit of whole blood is around 350 to 450 cc; approximately 4 units of blood need to be withdrawn to decrease this man's hemoglobin from 20 mg/mL to 14 mg/mL.

The frequency of the phlebotomy depends on individual factors, but most men can do one every two to three months to manage their hemoglobin this way. Sometimes red blood cell production normalizes without any specific reason. It is impossible to predict exactly who is more prone to developing polycythemia, but men who use higher doses, men with higher fat percentage, and older men may have a higher incidence.

Some doctors recommend the use of a baby aspirin (81 mg) a day and 2,000 to 4,000 mg a day of omega-3 fatty acids (fish oil capsules) to help lower blood viscosity and prevent heart attacks. These can be an important part of most people's health regimen but they are not alternatives for therapeutic phlebotomy if the patient has polycythemia and does not want to stop testosterone therapy. It is concerning that many people assume that they are completely free of stroke/heart attack risks by taking aspirin and omega-3 supplements when they have a high hematocrit.

Although some people may have more headaches induced by high blood pressure or get extremely red when they exercise, most do not feel any different when they have polycythemia. This does not make it any less dangerous.


Friday, October 28, 2011

Monitoring Testosterone Replacement Therapy (TRT)

Monitoring Testosterone Replacement Therapy (TRT)


by Nelson Vergel
Nelson Vergel is the author of "Testosterone: A Man's Guide" and co-author of the book 'Built to Survive" , the founder of the Body Positive Wellness Clinic in Houston, and an expert speaker on exercise, nutrition, testosterone replacement, metabolism , sexual function and therapies to increase lean body mass and decrease fat. He has provided over 500 lectures in the past 15 years in the U.S. and overseas. He provides patient-friendly information accessible to all, no matter of their knowledge base.

Testosterone: A Man's GuideExcerpted from  "Testosterone: A Man's Guide".
Testosterone replacement therapy is not without side effects, although most are manageable. I’ve been taking testosterone replacement for 16 years and for the most part have had few side effects thanks to careful monitoring. It’s critical that you are monitored for side effects in addition to your testosterone level. Some men may experience one or more side effects that sometimes go unnoticed until it is too late. In part it is the underground, unmonitored use of testosterone that creates so much bad publicity for a very helpful product.
The first step in the proper monitoring of replacement therapy is providing your doctor with a thorough medical history. Appendix A shows a simple and comprehensive medical history form (courtesy of Dr John Crisler, allthingsmale.com). Patients who would like to be proactive can fill out this form and give a copy to their doctor. It is expected that every doctor have a similar form, although most do not ask questions pertinent to sexual function or on the use of androgens. Let your doctor know about all the medications you take so that medication-induced sexual dysfunction can be ruled out before starting testosterone.
I also strongly believe that if a patient goes to the doctor to obtain a Viagra, Cialis or Levitra prescription, the doctor should check the patient’s testosterone blood levels to ensure that it is not the root of the problem. Hypogonadal men may not respond as well to these drugs if their testosterone is not normalized first. Studies combining testosterone and oral sexual enhancement drugs have shown a synergistic effect on sexual benefits. The following suggested guidelines for monitoring testosterone replacement is recommended by several physician groups and practices:
You should be evaluated after the first month of therapy to measure your testosterone blood levels. If your doctor doesn’t ask, let him know about your quality of life. Make sure your doctor is aware of your energy level, mood, and sexual function, as well as any potential side effects (tender breasts, urinary flow decrease, moodiness, and acne).
When using testosterone, your doctor will want to measure total blood testosterone levels right before the next corresponding injection after the first month (it takes a while for the blood levels to stabilize). If testosterone is >700 ng/dl (24.5 nmol/liter) or <350 ng/dl (12.3 nmol/liter), your doctor will adjust the amount or the frequency of your dose. I mentioned this earlier in the book but it bears repeating here: Some men need to have levels above 500 ng/dl to experience any of the expected sexual function benefits from testosterone. It is important to be honest about when your doctor asks you about your sexual performance.
Your doctor will check your hematocrit before starting testosterone, after 3 months and then every year after that. If your hematocrit is above 54%, you may need a therapeutic phlebotomy (read the section "Checking for Increased Blood Thickness (Polycythemia)" for more details.
Be ready to have a digital rectal examination done and a prostatic specific antigen (PSA) blood test drawn prior to starting testosterone, and after 3 months. Once every 6 months after that may not be unreasonable, especially in older men. A PSA over 4 ng/ml can be reason for concern and referral to an urologist. Testosterone replacement needs to be stopped if increases in PSA above normal are observed. Note: at the start of testosterone replacement in older men, when testosterone blood levels are rapidly rising, PSA may also increase. This is especially true when testosterone gels are employed, because they elevate DHT more relative to other options. Once testosterone levels have stabilized PSA drops back down to roughly baseline. It is important to allow "steady state" for testosterone fluctuations to stabilize before measuring PSA; a month or so should be sufficient.
If you start experiencing breast tenderness, pain or growth, ask your doctor to measure your estradiol blood level using the sensitive assay (not the regular test used for women). Normal range for estradiol in men is 14–54 pg/ml (50–200 pmol/liter). Men who have high estradiol can be prescribed estrogen receptor inhibitors (more details in "Avoiding enlarged breasts (gynecomastia)"

Ensuring Prostate Health—No Link Found Between Androgen Levels and Risk for Prostate Cancer

The prostate is a gland that is part of the male reproductive system. Its function is to store and secrete a slightly alkaline (pH 7.29) a milky fluid which usually constitutes 25-30% of the volume of the semen along with spermatozoa. This alkaline fluid seems to neutralize the acidity in the vagina, prolonging the life span of the sperm. Also, the prostate contains some smooth muscles that help expel semen during ejaculation. It also helps control the flow of urine during ejaculation.
A healthy human prostate is classically said to be slightly larger than a walnut. In actuality, it is approximately the size of a kiwi fruit. It surrounds the urethra just below the urinary bladder and can be felt during a rectal exam.
Prostate cancerThis little gland attracts a great deal of attention in men’s health. One of the major issues is related to cancer. Prostate cancer is one of the leading causes of death in men in the United States. As men age, small hidden prostatic lesions become increasingly common. These may or may not become cancerous. These lesions occur in 30 percent of American men over the age of 45, with the prevalence rising to more than 80 percent for men over the age of 80. Genetic factors and life style conditions such as diet are believed to contribute to this transformation. [Figure 14.The prostate and surrounding organs (Courtesy of Wikipedia.com)]
.
Doctors use different methods to detect prostate cancer, including prostate-specific antigen (PSA) assays, digital rectal examination (DRE), and transrectal ultrasound. A DRE before starting testosterone replacement therapy and every six months is recommended, especially for men with a family history of prostate cancer or those older than 40 years. Nobody likes having a DRE but your continued good health is worth a few seconds of discomfort. An abnormal rectal exam, a confirmed increase in PSA greater than 2 ng/mL, or PSA of over 4 ng/mL will prompt a health care provider to refer you to a urologist for further evaluation (usually an ultrasound and prostate biopsies).
Admittedly the PSA and the DRE lack sensitivity and specificity. 25 percent of patients with prostate cancer have normal PSA levels (false negatives), while benign prostatic hyperplasia (BPH), a non-cancerous inflammation, may elevate them (false positives). Researchers have found hidden prostatic lesions with needle biopsies in some men with normal PSA level and normal transrectal ultrasound findings. Prostate biopsies are part of routine clinical use of testosterone therapy and are not justified unless a sharp rise in PSA is observed and infections have been ruled out.
There has some been confusion regarding testosterone replacement therapy’s role in PSA elevation or causing prostate cancer. Prostate cancer is initially androgen-dependent so testosterone therapy should not be used by men with prostatic cancer. This does not mean that it causes cancer. A huge pooled analysis of data from 18 studies (consisting of 3,886 men with prostate cancer and 6,438 controls), published in the February 6, 2008 issue of the Journal of the National Cancer Institute found that blood levels of androgens and other sex hormones do not seem to be related to an increased risk for prostate cancer. In short, testosterone therapy does not appear to cause prostate cancer but it can make it worse.
Prostate infectionAnother health concern is prostatitis or prostate infection. This is common in aging men and can be a leading cause of an elevated PSA. Your doctor will want to check you for an infection if your PSA unexpectedly increases by checking your urine for white blood cells. If they are high, he may refer you to an urologist who would induce a discharge from your penis to look at it under the microscope. Don’t ask me how the urologist does it, ask the urologist!
Benign prostatic hyperplasiaA common health condition is benign prostatic hyperplasia or BPH. It is estimated to occur in 50 percent of men older than 50 years. Increased frequency of urination, frequent trips to the bathroom at night, incomplete voiding, and urgency to urinate indicate possible prostatic inflammation. BPH does not necessarily lead to increased rates of prostate cancer. There have been no prospective, controlled, long-term studies on the effects of testosterone administration on either the development or the progression of BPH. One open label, one-year study that measured prostate size using ultrasound found no increase during testosterone replacement therapy, suggesting that the treatment does not cause BPH. Whether testosterone treatment worsens asymptomatic BPH has not been established. Some individuals are more prone to prostatic inflammation when using testosterone.
Another study was conducted by Dr. Michael D. Trifiro at Moores UCSD Cancer Center in San Diego. Dr. Trifiro observed 158 men for 20 years to determine the correlation between serum sex hormones and lower urinary tract symptoms (reduced urinary flow, urgency, and other symptoms associated with BPH). The researchers found no significant associations of total testosterone, estradiol (E2)), testosterone: E2 ratio, DHT, or dehydroepiandrosterone with lower urinary track symptoms or with any measured hormones(published in BJU International in December 2009).
Tesosterone replacement therapy is not contraindicated in those with BPH. Men with BPH who need to start testosterone replacement should be observed very closely. The first symptom that worsens with increased BPH is restricted urinary flow and urgency, especially during sleep hours. Many urologists are successfully prescribing medications to ease those symptoms and improve urinary flow in men with BPH. Finasteride (brand name: Proscar), which was approved by the FDA in 1992, inhibits production of dihydrotestosterone (DHT), which is involved with prostate enlargement. Its use can actually shrink the prostate in some men. However, many men using Proscar complain of erectile dysfunction (DHT receptors may be involved in healthy erctions). For men who experience this side effect, other medications may be of help. Proscar has also been found to decrease the risk of prostate cancer in men by 25 percent over aseven year period. More studies are ongoing.
The FDA approved the drugs terazosin (brand name: Hytrin) in 1993, doxazosin (Cardura) in 1995, and tamsulosin (Flomax) in 1997 for the treatment of BPH. All three belong to the class of drugs known as alpha blockers. They work by relaxing the smooth muscle of the prostate and bladder neck to improve urine flow and to reduce bladder outlet obstruction.
Terazosin and doxazosin were developed first to treat high blood pressure. Tamsulosin is the first alpha-blocker developed specifically to treat BPH. The main side effects of these drugs are nasal congestion, lowered blood pressure, and rash or itching. Most men using them report fast improvements in their urine flow within one to three days. They end up not having to get up in the middle of the night to urinate, so they sleep better and feel less fatigued during the day.
The most common nonprescription agent used to alleviate symptoms of BPH is the over-the-counter herb saw palmetto (Serenoa repens). Extracted from the berry of the saw palmetto shrub, this substance is thought to inhibit 5-alpha reductase (5-·R), thus blocking the conversion of testosterone into DHT, which is responsible for stimulating growth of the prostate gland.
Saw palmetto is generally well tolerated; side effects are infrequent, but include headache and gastrointestinal upset. No known drug interactions are associated with the use of this herb. Some studies found that saw palmetto led to an increase in urine flow rate in men with BPH compared with placebo, with effects comparable to finasteride.
One randomized, double-blind, placebo-controlled study followed men with BPH who took standardized saw palmetto extract 160 mg or placebo twice daily for one year. There was no significant difference found between the saw palmetto and placebo groups in standardized objective urinary symptoms. The incidence of side effects was similar in the two groups. These results cast considerable doubt on the effectiveness of saw palmetto for the treatment of BPH.
Patients who cannot tolerate BPH medications are now using emerging techniques like lasers to vaporize obstructing prostate tissue (www.greenlighthps.com). Talk to your urologist about this if you’re interested.
PERSONAL COMMENT: After using testosterone for 17 years, I started to develop a weak urine flow. My doctor gave me prescriptions for several alpha blockers (Uroxatral, Flomax, etc). They worked great but I experienced a rash with each one. My urologist found a prostate infection, which he treated with antibiotics. The infection seemed to linger for months. I then received an ultrasound of my prostate. This test showed that my prostate was not enlarged. Instead it showed that a calcification, caused by a chronic prostatic infection, was blocking my urine flow through my prostate. I got the green light laser procedure done to open up my urethra. It worked great. So, what may seem like BPH may not be! Prostatic infections often go untreated for months since in many cases we may not have symptoms.

Checking for Increased Blood Thickness (Polycythemia)

In addition to increasing muscle and sex drive, testosterone can increase your body’s production of red blood cells. This hemopoietic (blood building) effect could be a good thing for those with mild anemia. An excessive production of red blood cells is called polycythemia; it’s not a good thing. With polycythemia the blood becomes very viscous or "sticky" making it harder for the heart to pump. High blood pressure, strokes, and heart attacks can occur. This problem is not that common in men taking replacement doses of testosterone but more common in those taking higher bodybuilder doses.
It’s important to have your doctor check your blood’s hemoglobin and hematocrit.. Hemoglobin is the substance that makes blood red and helps transport oxygen in the blood. Hematocrit reflects the proportion of red cells to total blood volume. The hemoglobin and hematocrit should be checked before starting testosterone replacement therapy, at three to six months and then annually. A hematocrit of over 54 percent should be evaluated. Discontinuation of testosterone may be necessary but there is another option.
Many patients on testosterone replacement who experience polycythemia do not want to stop the therapy due to fears of re-experiencing the depression, fatigue and low sex-drive they had before starting treatment. For those patients, therapeutic phlebotomy may be the answer. Therapeutic phlebotomy is very similar to what happens when donating blood, but this procedure is prescribed by your physician as a way to bring down your blood levels of hematocrit and viscosity.
A phlebotomy of one pint of blood will generally lower hematocrit by about 3 percent. I have seen phlebotomy given weekly for several weeks bring hematocrit from 56 percent to a healthy 46 percent. I know physicians who prescribe phlebotomy once every six weeks because of an unusual response to testosterone replacement therapy. This simple procedure is done in a hospital blood draw facility and can reduce hematocrit, hemoglobin, and blood iron easily and in less than one hour. Unfortunately, therapeutic phlebotomy can be a difficult option to get reimbursed or covered by insurance companies. Your doctor may need to write a letter of medical necessity for it. If you are healthy and without HIV, hepatitis B, C, or other infections, you could also donate blood at a blood bank (a great way to help others!).
The approximate amount of blood volume that needs to be withdrawn to restore normal values can be calculated by the following formula, courtesy of Dr. Michael Scally, an expert on testosterone side effect management. The use of the formula includes the assumption that whole blood is withdrawn. The duration over which the blood volume is withdrawn is affected by whether concurrent fluid replacement occurs.
Volume of Withdrawn Blood (cc)=
Weight (kg) × ABV×[Hgbi - Hgbf]/[(Hgbi +Hgbf)/2]

Where:
ABV = Average Blood Volume (default = 70)
Hgbi (Hcti) = Hemoglobin initial
Hgbf (Hctf) = Hemoglobin final (desired);
So, for a 70 kg (154 lbs) man (multiply lbs x0.45359237 to get kilogram) with an initial high hemoglobin of 20 mg/mL who needs to have it brought down to a normal hemoglobin of 14 mg/mL, the calculation would be:
CC of blood volume to be withdrawn = 75 70 [20 l4]/[(20 + l4)/2]
= 75 70 (6/17) = approximately 1850cc;
One unit of whole blood is around 350 to 450 cc; approximately 4 units of blood need to be withdrawn to decrease this man’s hemoglobin from 20 mg/mL to 14 mg/mL.
The frequency of the phlebotomy depends on individual factors, but most men can do one every two to three months to manage their hemoglobin this way. Sometimes red blood cell production normalizes without any specific reason. It is impossible to predict exactly who is more prone to developing polycythemia, but men who use higher doses, men with higher fat percentage, and older men may have a higher incidence.
Some doctors recommend the use of a baby aspirin (81 mg) a day and 2,000 to 4,000 mg a day of omega-3 fatty acids (fish oil capsules) to help lower blood viscosity and prevent heart attacks. These can be an important part of most people’s health regimen but they are not a replacement for therapeutic phlebotomy if you have polycythemia and do not want to stop testosterone therapy. It amazes me how many people assume that they are completely free of stroke/heart attack risks by taking aspirin and omega-3 supplements when they have a high hematocrit.
Although some people may have more headaches induced by high blood pressure or get extremely red when they exercise, most do not feel any different when they have polycythemia. This does not make it any less dangerous. If you are using testosterone on your own you need to let your doctor know. Your physician may already suspect some sort of anabolic use if lab results reveal elevated hemoglobin and hematocrit.
PERSONAL COMMENT: I had polycythemia back in the mid-1990s when I was using supraphysiologic doses of testosterone and nandrolone to reverse my HIV-related weight loss. I required two phlebotomies in six months. My hematocrit and hemoglobin eventually normalized without any reason even when using the same doses of testosterone and nandrolone.

Ensuring Liver Health

I mentioned this before but it is well worth repeating. Contrary to what some physicians may think, injectable and transdermal testosterone have not been known to cause increased liver enzymes. The same cannot be said for over-the-counter supplements that claim to increase testosterone or growth hormone. Not only do most of them not work, but they could increase your liver enzymes to dangerous levels. This problem has been reported in the past to the FDA. I warn people all the time to be careful about their use. It is always good to check your liver enzymes when blood work is done since it is a cheap test and highly useful in detecting toxicities caused by medications or supplements you may be using.
It is the use of oral testosterone and anabolic formulations (except for oral testosterone undecanoate, commonly used in Canada) that can increase liver enzymes. Many men with hepatitis B or C can be safely treated with replacement doses of testosterone without any liver injury if gels, patches or injections are used. I am very concerned that some of these patients may be denied this important therapy due to potential fears and misconceptions. Some studies have shown an increased incidence of hypogonadism, fatigue, and sexual dysfunction in patients with hepatitis.
Some men like to take supplements to protect the liver against the damaging effects of medications, but very limited data is available on their use. Supplements potentially can interfere with medication blood levels; very little is known about supplement-drug interactions. However, I would like to bring up some supplements with data on liver protection:
  • Standardized silymarin (milk thistle herb)—160 mg/three timesday
  • Evening primrose oil—1,300 mg/three times/day
  • Alpha lipoic acid – 100 – 300 mg/three times/day Glycyrrhizinate Forte - Three or more capsules/day, but this may increase blood pressure.
  • N-acetyl cysteine – 600 mg/three times/day
  • Selenium – 200 mcg twice a day.
I trust the Jarrow and Super Nutrition brands for most of my supplements. Talk to your doctor before starting any supplements!

Monitoring Blood Pressure

High blood pressure or hypertension is another serious medical condition that can go undetected because it often has no symptoms. It’s referred to as "the silent killer" for this reason. High blood pressure can cause heart attacks, strokes, headaches, ruin your kidneys, erectile dysfunction and shrink your brain.
Before you start testosterone replacement or an exercise program, it is very important to get your blood pressure under control. This is done through diet, stress management, lowering your salt intake and/or the use of medications. It is a good idea to invest in a home-based blood pressure machine. One usually can be purchased at most pharmacy chains and cost under US$50. Some, like the OMRON HEM-780, can measure blood pressure easily and keep track of changes with time. Take measurements twice a day until you gain control of your blood pressure again.
It is important to have your blood pressure measured during the first month of treatment to ensure that it does not increase with testosterone. The good news is that replacement doses are much less associated with this problem. More serious risks for hypertension are associated with the high testosterone doses associated with performance-enhancing use.
NOTE: Some natural ways to decrease blood pressure are decreasing your salt intake, exercising, keeping a normal body weight for your height, managing stress, and engaging in meditation and yoga. "Erection-friendlier" blood pressure medications like ACE (angiotensin converting enzyme) inhibitors, renin inhibitors, ARB’s (angiotensin II receptor blockers), and combinations of them may be required for men who cannot maintain a blood pressure reading under 130/80 mm Hg.

Avoiding Enlarged Breast (Gynecomastia)

Yes, I am talking about breast appearance in men, not women. Gynecomastia is a benign enlargement of the male breast resulting from a growth of the glandular tissue of the breast. It is defined clinically by the presence of a rubbery or firm mass extending concentrically from the nipples. Men who start experiencing this problem complain of pain and tenderness around the nipple area. Gynecomastia is caused by higher than normal blood levels of estradiol, a metabolite of estrogen. As discussed earlier in the book, testosterone can convert into estradiol, DHT, and other metabolites. Men with higher amounts of the enzyme aromatase usually have this problem even at lower doses of testosterone. Growth of this glandular tissue is influenced by a higher fat percentage, older age, excessive alcohol intake, and the use of certain medications. Gynecomastia usually occurs early in testosterone replacement in those who experience this side effect.
In several studies on testosterone replacement, only a very small percentage of people receiving testosterone experience growth of breast tissue. In one HIV-specific study conducted by Dr. Judith Rabkin in New York, she reported that out of 150 men enrolled in the study, two men experienced this adverse reaction. Gynecomastia is much more common among those who use high testosterone doses, such as bodybuilders (they call this "gyno" or "bitch-tits").
How do you manage gynecomastia if it does occur? Lowering the testosterone dose had not proven helpful for the two patients in Dr. Rabkin’s study. The use of antiestrogens, such as tamoxifen 10 mg twice daily, with lower doses of testosterone has been effective. Gynecomastia can become permanent if the condition lasts very long although it may reduce in size when the androgen use is discontinued. In the absence of resolution, surgical correction may be necessary in severe cases.
For men who experience enlarged breast size, doctors usually check estradiol levels to determine whether too much testosterone is being converted into estrogen. I do not believe that routine measurement of estrogen is needed for men who have no symptoms of high estrogen (mainly breast tissue enlargement and water retention). For those who have higher than normal estrogen, doctors usually prescribe an antiestrogen medication. One such regimen is anastrozole at 1 mg/day during the first week until nipple soreness and breast enlargement disappear. The dose is then lowered to 0.25 mg a day, or 1 mg twice a week.
A warning: Bringing estrogen down to very low levels could cause health problems in men in the long run. Hair/skin quality and health, brain function, bone density, and other important factors may be greatly influenced by estrogen. However a 12-week study in men using anastrozole at 1 mg a day and 1 mg twice a week found no changes in bone metabolism markers.
The normal production ratio of testosterone to estrogen is approximately 100:1. The normal ratio of testosterone to estrogen in the circulation is approximately 300:1. Estrogen (measured as estradiol) should be kept at 30 picograms per milliliter (pg/mL) or lower. As men grow older or as they gain a lot of fat mass, their estrogen blood levels increase, even to levels higher than that of postmenopausal women.
Medications and Products That Can Cause GynecomastiaA number of medications have been reported in the medical literature to cause gynecomastia due to decreases in testosterone, increases in estradiol, or both. These include:
  • Antiandrogens. These include cyproterone, flutamide, and finasteride.used to treat prostate cancer and some other conditions.
  • HIV medications. Sustiva, Atripla, and Videx have been associated with gynecomastia.
  • Anti-anxiety medications such as diazepam (Valium).
  • Tricyclic antidepressants. These include amitriptyline.
  • Glucocorticoid steroids.
  • Antibiotics.
  • Ulcer medication such as cimetidine (Tagamet).
  • Cancer treatment (chemotherapy).
  • Heart medications such as digitalis and calcium channel blockers.
  • Anabolic steroids
Substances that have been reported to cause gynecomastia include:
  • Alcohol
  • Amphetamines
  • Marijuana
  • Heroin
  • Soy and flaxseed- There are conflicting studies but it is something to keep in mind
  • Exposure to pesticides and byproducts of plastic processing has also been linked to increased estrogen and decreased sperm count in men.

Does Testosterone Suppress the Immune System?

This question is raised out of the confusion over the use of the term "steroid." When somebody is having pain or inflammation and their physician prescribes them a "steroid" or something "steroidal", they are prescribing a corticosteroid (like prednisone) to decrease inflammation. These can have an immunosuppressive effect (sometimes its intended). The "steroid" that you hear about from the media when they are talking about use and abuse by athletes refers to an anabolic steroid (like testosterone). The similarities largely end with their street names.
Some in vitro and animal data do suggest that high dose testosterone could be immune suppressive. No such immunosuppressive effect is seen when testosterone was added at replacement concentrations. Several studies using testosterone alone or on combination with oxandrolone or nandrolone in HIV-positive immune compromised patients have found no immune suppressive effect.


Read more from this MESO-Rx article at:http://www.mesomorphosis.com/articles/vergel/testosterone-replacement-therapy.htm#ixzz1c6sBowuV

Testosterone: A Man's Guide- Introductory Lecture by Author Nelson Vergel

Testosterone therapy increases risk of red blood cell disorder for men with HIV

Nothing new that we did not know.

However, it bothers me how they do not mention therapeutic phlebotomy as a solution. Instead, they mention cessation of therapy. 

It also surprised me to see that they do not mention smoking as a risk factor for polycythemia.


Tuesday, October 25, 2011

New Genetic Associations For Testosterone Levels in Men

A study in male twins showed that genetics accounts for up to 65% of the variation in blood testosterone between individuals. However, up until this month, very little was known about the genetic factors responsible for this variation.
Read more:
http://spittoon.23andme.com/2011/10/24/snpwatch-new-genetic-associations-for-testosterone-levels-in-men/

Saturday, October 22, 2011

The Use of HCG to Increase Testicular Size and Sex Drive While on Testosterone Replacement Therapy

Human Chorionic Gonadotropin

Excerpt from the book “Testosterone: A Man’s Guide” by Nelson Vergel (available on http://amzn.to/qHtgrQ  or in different formats on www.TestosteroneWisdom.com ).  NelsonVergel@gmail.com




Human chorionic gonadotropin (HCG) (not to be confused with human growth hormone, or HGH) is a glycoprotein hormone that mimics LH (luteinizing hormone), produced in pregnancy by the developing embryo soon after conception, and later by part of the placenta. Its role is to prevent the disintegration of the corpus luteum of the ovary and to maintain the progesterone production critical for pregnancy in women. It supports the normal development of an egg in a woman’s ovary, and stimulates the release of the egg during ovulation. HCG is used to cause ovulation and to treat infertility in women.

HCG is also used in young boys when their testicles have not dropped down into the scrotum normally.  Additionally, HCG is used to increase testicular size after long-term testosterone or anabolic steroid use. However, the latter is an off-label use.

Testosterone replacement therapy triggers the hypothalamus to shut down its production of GnRH (gonadotropin releasing hormone). Without GnRH, the pituitary gland stops releasing LH. Without LH the testes (testicles or gonads) shut down their production of testosterone. For males HCG closely resembles LH. If the testicles have shrunken after long-term testosterone use, they will likely begin to enlarge and start their testosterone production shortly after HCG therapy is instituted. HCG jump-starts your testes to produce testosterone and to increase their size.

HCG can be extracted from pregnant women’s urine or through genetic modification. The product is available by prescription under the brand names Pregnyl, Follutein, Profasi, and Novarel. Novire is another brand but it is a product of recombinant DNA. Compounding pharmacies can also make HCG by prescription in different vial sizes. Brand names of HCG in regular pharmacies cost over $100 per 10,000 IUs.  The same amount of IUs cost around $50 in compounding pharmacies. Many insurance policies do not pay for HCG since they consider its use for testicular atrophy while on TRT an off label use. So, most men using it pay for it themselves and get it from compounding pharmacies that sell it a lot cheaper.

HCG is dispensed as a powder contained in vials of 3,500 IUs, 5, 000 IUs or 10, 000 IUs (depending on the compounding pharmacy, these amounts may vary). You can call compounding pharmacies and have them make vials for you with different IU amounts, though. These are usually accompanied by another vial of 1 mL (or cc) of bacteriostatic water to reconstitute the powder into a liquid solution. Bacteriostatic water (water with a preservative that is provided with the prescription) is mixed in with the powder to reconstitute, or dissolve, it before injection. This type of water can preserve the solution for up to 6 weeks when refrigerated. Some patients do not use the 1 mL water vials that come with the commercially (non compounded) available product and instead get their doctors to prescribe 30 cc bottles of bacteriostatic water so that they can dilute the HCG down to a more workable concentration that is more practical for men using lower doses of HCG weekly.

HCG is given as an injection under the skin or intramuscularly (there is still debate on which method is best). The number of IUs per injection will depend on how much bacteriostatic water you add to the dry powder vial. If you add 1 mL to a 5,000 IU powder vial, then you will have 5,000 IUs per mL, so 0.1 mL would be 500 IUs. If you add 2 mL to the 5,000 IU dry powder vial, then you will have 2,500 IUs/mL; 0.1 ml (or cc) in an insulin syringe will equal 250 IUs. If you need to inject 500 IUs, then you inject 0.2 ccs of this mixture. Table 3 provides dilution volumes at different HCG powder/water proportions.

Ultra-fine needle insulin syringes are used to inject HCG under the skin, making this very easy to take even for the needle-phobic. Typical sizes are:

•          1 ml, 12.7 mm long, 30 gauge and
•          0.5 ml, 8 mm, 31 gauge syringes.

Syringes require a separate prescription. Some compounding pharmacies will automatically include them with the shipment, but do not forget to ask them. Never use the syringe that you used for injecting the bacteriostatic water into the powder for injecting yourself; the needle will be dull (I usually use a regular 23 gauge, 1 inch, 3 ml syringe to load up the water). Remember that you also need alcohol pads to clean the injection area and the tip of the vial. Typical injection sites are the abdominal area close to the navel or in the pubic fat pad. Pinch a little of fat on your abdominals and inject into that pinched area, then massage with an alcohol pad. Discard syringes into the sharps container that can be provided by your pharmacy.

As I mentioned before, compounded HCG is a lot cheaper than the commercially available pharmaceutical products. Also, it is sometimes difficult to find commercially available HCG in regular pharmacies.

A review of the literature reveals a wide range of doses of HCG used and that there is very little agreement among physicians. For male infertility, doses range from 1250 IU three times weekly to 3000 IU twice weekly (these studies did not include men on testosterone replacement).
How long does the boost in testosterone last after an injection of HCG? A study looked into that and also tried to determine if high doses would be more effective at sustaining that boost. The profiles of plasma testosterone and HCG in normal adult men were studied after the administration of 6000 IU HCG under two different protocols. In the first protocol, seven subjects received a single intramuscular injection. Plasma testosterone increased sharply (1.6 ± 0.1-fold) within 4 hours. Then testosterone decreased slightly and remained at a plateau level for at least 24 hours. A delayed peak of testosterone (2.4 ± 0.3-fold) was seen between 72–96 hours. Thereafter, testosterone declined and reached the initial levels at 144 hours. In the second protocol, six subjects received two intravenous (IV) injections of HCG (5-8 times the dose given by injection to the first group) at 24-hour intervals. The initial increment of plasma testosterone after the first injection was similar to that seen in the first protocol despite the fact that plasma HCG levels were 5–8 times higher in this case. At 24 hours, testosterone levels were again lower than those observed at 2–4 hours and a second IV injection of HCG did not induce a significant increase. The delayed peak of plasma testosterone (2.2 ± 0.2-fold of control) was seen about 24 hour later than that in the first protocol. So, this study shows that more is not better when dosing HCG. In fact, high doses may desensitize Leydig cells in the testicles.  It also showed that testosterone blood levels peak not once but twice after HCG injections.  I wish they had studied a lower dose than 6000 IU since very few physicians prescribe this high dose.

HCG may not only boost testosterone but also increase the number of Leydig cells in the testicles. It is well known that Leydig cell clusters in adult testes enlarge considerably under treatment with HCG. However, it has been uncertain in the past whether this expansion involves an increase in the number of Leydig cells or merely an enlargement of the individual cells. A study was performed in which adult male Sprague-Dawley rats were injected subcutaneously daily with 100 IU HCG for up to 5 weeks. The volume of Leydig cell clusters increased by a factor of 4.7 during the 5 weeks of HCG treatment. The number of Leydig cells (initially averaging 18.6 x 106/cm3 testis) increased to 3 times the control value by 5 weeks of treatment (P<0.001), while the average volume of individual Leydig cells (initially  ~2200 µm3) enlarged only 1.6 times. They concluded that chronic treatment with HCG increases the number of Leydig cells in the testes of adult rats. We do not know if these results can be extrapolated to men.

Currently there are no HCG guidelines for men who need to be on testosterone replacement therapy and want to maintain normal testicular size. A study that used 200 mg per week of testosterone enanthate injections with HCG at doses of 125, 250, or 500 IU every other day in healthy younger men showed that the 250 IU dose every other day preserved normal testicular function (no testicular size measurements were taken, however). Whether this dose is effective in older men is yet to be proven. Also, there are no long-term studies using HCG for more than 2 years.

Due to its effect on testosterone, HCG use can also increase estradiol and DHT, although I have not seen data that shows if this increase is proportional to the dose used.
So, the best dose of HCG to sustain normal testicular function while keeping estradiol and DHT conversion to a minimum has not been established.

Some doctors are recommending using 200–500 IUs twice a week for men who are concerned about testicular size or who want to preserve fertility while on testosterone replacement. Higher doses, such as 1,000–5,000 IUs twice a week, have been used but I believe that these higher doses could cause more estrogen and DHT-related side effects, and possibly desensitize the testicles for HCG in the long term. Some doctors check estradiol levels a month after this protocol is started to determine whether the use of the estrogen receptor modulators tamoxifen (brand name: Nolvadex) or anaztrozole (brand name: Arimidex), is needed to counteract any increases in estradiol levels. High estradiol can cause breast enlargement and water retention in men but it is important at the right blood levels to maintain bone and brain health.

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Shippen’s Chorionic Gonadotrophin Stimulation Test (for males under 75 years of age)


Even though there seems not be an accepted and clinically proven protocol to dose HCG, Dr. Eugene Shippen (author of the book “The Testosterone Syndrome”), has developed his own after his own experiences. Most doctors do not follow this protocol but I am showing it here since I get a lot of questions about it. I have never used this protocol myself since I have been on testosterone replacement for over 15 years.

Dr. Shippen has found that a typical treatment course for three weeks is best for determining those individuals who will respond well to HCG treatment. It is administered daily by injection 500 units subcutaneously, Monday through Friday for three weeks. The patient is taught to self administer with 50 Unit insulin syringes with 30 gauge needles in anterior thigh, seated with both hands free to perform the injection.

Testosterone, total and free, plus E2 (estradiol) are measured before starting the protocol and on the third Saturday after 3 weeks of stimulation (he claims that salivary testing may be more accurate for adjusting doses). Studies have shown that subcutaneous injections are equal in efficacy to intramuscular administration.

By measuring the effect on his HCG protocol on total testosterone, he identifies candidates that require testosterone replacement versus those who just require having their testicles “awaken” with HCG to produce normal testosterone. I am yet to see any data that substantiates his approach, however.

Here is how he determines Leydig (testicular) cell function:

1. If the HCG protocol causes less than a 20% rise in total testosterone he suggests poor testicular reserve of Leydig cell function (primary hypogonadism or eugonadotrophic hypogonadism indicating combined central and peripheral factors).

2. 20-50% increase in total testosterone indicates adequate reserve but slightly depressed response, mostly central inhibition but possibly decreased testicular response as well.

3. More than 50% increase in total testosterone suggests primarily centrally mediated depression of testicular function.

He then offers these options for treatment for patients depending on the response to HCG and patient determined choices.

1. If there is an inadequate response, then replacement with testosterone will be indicated.

2. The area in between 20-50% will usually require HCG boosting for a period of time, plus natural boosting or “partial” replacement options.


I am yet to see what he means with natural boosting!


Dr. Shippen believes that full replacement with testosterone is always the last option in borderline cases since improvement over time may frequently occur as the testicles’ Leydig cell regeneration may actually happen. He claims that much of this is age dependent. Up to age 60, boosting is almost always successful. In the age range 60-75 is variable, but will usually be clear by the results of the stimulation test. Also, disease related depression of testosterone output might be reversible with adequate treatment of the underlying process (depression, obesity, alcohol, deficiency, etc.) He claims that this positive effect will not occur if suppressive therapy is instituted in the form of full testosterone replacement.

3. If there is an adequate response of more than 50% rise in testosterone, there is very good Leydig cell reserve. HCG therapy will probably be successful in restoring full testosterone output without replacement, a better option over the long term and a more natural restoration of biologic fluctuations for optimal response. But I am yet to see any data on long term use of HCG used in this approach! (I invite researchers to do such studies)

4-. Chorionic HCG can be self-administered and adjusted according to response. In younger, high output responders (T &gt; 1100ng/dl), HCG can be given every third or fourth day. This also minimizes estrogen conversion. In lower level responders (600-800ng/dl), or those with a higher estradiol output associated with full dose HCG, 300- 500 units can be given Mon-Wed-Fri. At times, sluggish responders may require a higher dose to achieve full testosterone response.

Dr. Shippen believes in checking salivary levels of free testosterone on the day of the next injection, but before the next injection to determine effecacy and to adjust the dose accordingly. He claims that later as Leydig cell restoration occurs, a reduction in dose or frequency of administration may be later needed.

5. He recommends to monitor both testosterone and estradiol levels to assess response to treatment after 2 - 3 weeks after change in dose of HCG as well as periodic intervals during chronic administration. He claims that salivary testing will better reflect the true free levels of both estrogens and testosterone. (Pharmasan.com and others) Most insurance companies do not pay for salivary testing. Blood testing is the standard way to test for testosterone and estradiol.

6. Except for reports of antibodies developing against HCG (he mentions that he has never seen this problem), the claims that there are no adverse effects of chronic HCG administration.

Dr.Shippen’s book was published in the late 90’s. I know of no physician that uses his protocol. I have no opinion on its validity. The idea that testicular function can be improved with cycles of HCG in men with low testosterone caused by sluggish yet functioning Leydig cells is an interesting concept that needs to be studied. I guess that since this protocol requires very close monitoring, many doctors have avoided using it. The off label nature of the protocol’s use of HCG can also make it expensive for patients who will have to pay cash for its use and monitoring.





A very well known doctor in the field of testosterone replacement, Dr. John Crisler (www.allthingsmale.com), recommends 250  IU of HCG twice per week for all TRT patients, taken the day of, along with the day before, the weekly testosterone cypionate injection. After looking at countless lab printouts, listening to subjective reports from patients, and learning more about HCG, he reports to be shifting that regimen forward one day. In other words, his patients who inject testosterone cypionate now take their HCG at 250 IU two days before, as well as the day immediately previous to, their weekly intramuscular shot. All administer their HCG subcutaneously, and dosage may be adjusted as necessary (he reports that rarely more than 350 IU twice weekly dose is required).

For men using testosterone gels, the same dose every third day has anecdotally helps to preserve testicular size (the dose of the gel has to be adjusted after a month of HCG to compensate for the increased testosterone caused by HCG).

Some doctors believe that stopping TRT for a few weeks in which only 1000- 2000 IU HCG weekly is used provides a good way to stimulate testicular function without having to use HCG continuously. I have not seen any data to support this approach. Others believe that cycling HCG on and off while maintaining TRT may prevent any desentization of testicular Leydig cells to HCG.  Again, no data or reports have been published on this approach.

Some men have asked me why we cannot use HCG solely to make our own testicles produce testosterone without the use of TRT along with it. According to Dr. Crisler, using HCG as sole testosterone replacement option does not bring the same subjective benefit on sexual function as pure testosterone delivery systems do—even when similar serum androgen levels are produced from comparable baseline values. However, supplementing the more “traditional” transdermal, or injected options, testosterone with the correct doses of HCG stabilizes blood levels, prevents testicular atrophy, helps rebalance expression of other hormones, and brings reports of greatly increased sense of well-being and libido.  But in excess, HCG can cause acne, water retention, moodiness, and gynecomastia (breast enlargement in men).

Many men have complained that their doctors do not know about HCG and how to use it (I do not blame doctors for being confused!). Some spend a lot of time trying to find doctors to feel comfortable prescribing it. One good way to find out what doctor in your area may be currently prescribing it is to call your local compounding pharmacies to ask them what doctors call them for their patients’ prescriptions.

If you decide (with the agreement of your doctor) that you want to use HCG with your TRT regimen at 500 IU per week, then you will need 2000 IU per month. I personally do not like to have diluted HCG sitting in my fridge for over six weeks (HCG may degrade with time after mixed in with bacteriostatic water even when refrigerated). So, a 3000 or 35000 IU vial should suffice for 6 weeks.

Your doctor can call in the following prescription to a compounding pharmacy:

Human Chorionic Gonadotropin, 3500 IU (or any other IU amount) vial, #1, 3 refills, as directed

Every 5 weeks, remember to call the compounding pharmacy to get the next shipment of HCG so that you do not run out.

After reading this section, you probably agree with me that using HCG requires a lot of discipline since you have to remember to inject it weekly in addition to your weekly or bi-weekly testosterone injection. But I know of many men who have that type of commitment since they do not want testicular size reduction. And many of us may just be fine with our reduced testicular size as long as testosterone is actually doing its job in improving our sex drive. And some lucky men do not get testicular atrophy at all on testosterone (those with large testicles to start with usually do not seem to complain about shrinkage as much as men starting with smaller testicular size before TRT). So it is a personal decision at the end!

As you will read in the section “HPGA dysfunction” HCG is also used in a protocol in combination with clomiphene and tamoxifen to attempt to bring the body’s own testosterone production back to normal when someone needs to stop testosterone or anabolic steroids after long-term use. This protocol only works for those who started testosterone or anabolic steroids at normal baseline testosterone levels (bodybuilders and athletes) and it is not intended to work in those of us who had testosterone deficiency (hypogonadism) to start with.

As you can tell, there is no agreement on the correct dose and frequency of HCG.   I really hope that researchers in the endocrine field compare different protocols in a controlled manner so that we can settle this issue once and for all. I encourage pharmaceutical companies to seek approval for using HCG for prevention of testicular atrophy in men using TRT. This new indication can prove to be lucrative as the TRT market grows over 2 billion dollars a year in the United States as more men become aware of hypogonadism treatment options.

PERSONAL COMMENT: I have used HCG to reverse testicular shrinkage and it works extremely well not only for that purpose but also for boosting sex drive. I do have to remind myself that as soon as I stop using it, testicular atrophy will recur.  I have recently started using it in small doses (250 IU twice a week subcutaneously) which seems to be a good maintenance regimen for me.  I get my HCG from compounding pharmacies at $70 per 10,000 IUs since the pharmaceutical commercial products are too expensive and rarely paid by insurance for testicular atrophy. I remind men that HCG can increase your estradiol and DHT blood levels, so it is important to have your doctor retest you for both of these values after you start. Lowering testosterone dosage may be required when using HCG along side with TRT since HCG can have an additive effect on testosterone blood levels. But we need so much more data on HCG to stop making assumptions and using protocols that are endorsed by anecdotal information.

Patient Price for HCG is $30-$70 depending on the number of IUs.

To get information from a reliable and economical compounding pharmacy about HCG , testosterone, anastrozole (estradiol blocker), Sermorelin, TRIMIX (erectile dysfunction) and other medications, fill out this form: INFORMATION REQUEST

For more information on HCG and other options, read: Testosterone: A Man's Guide

For more articles on HCG: Other articles on HCG use in men

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