Nelson Vergel
Founder, ExcelMale.com
Excerpt from
Available here: The Definitive Testosterone Replacement Therapy MANual: How to Optimize Your Testosterone For Lifelong Health And Happiness: Campbell, Jay: 9781942761723: Amazon.com: Books
Chapter 9 - Mitigating and Avoiding Potential Side Effects
When undergoing TRT, it is IMPERATIVE your mindset is one of expecting and mitigating potential side effects. Sometimes the difference between successful lifelong TRT and crash-and-burn flameouts is both the patient and the TRT prescribing doctor knowing what to expect. As we age, our bodies change and often times quite rapidly. The side effects men may or may not experience are random and sometimes don’t manifest for years if not decades.
It is crucially important to recognize the majority of potential side effects are minor and easily treatable. It is an unfortunate circumstance many men have received (and continue to receive) ineffective care from their TRT-prescribing physicians. Often times the inability to alleviate side effects forces men to end their treatment altogether. There is no reason for this whatsoever especially when you utilize the services of a progressive and experienced TRT prescribing physicians.
[CLICK HERE TO FIND THE RIGHT DOCTOR FOR YOU]
As I have continued to stress throughout this book, it is CRUCIAL you keep detailed files on your blood panels in order to best understand your values as they change over time. Know thyself, compile blood panel data, and do your homework to ensure your TRT is successful over the long term. Become your own doctor. Study your reactions. Take notes. Be vigilant in knowing your body and what allows it to work optimally. Remember, doctors are said to have “practices” for a reason. They are human and do make mistakes. You are the only one who truly knows your body, but only if you’re paying attention.
Before discussing what I believe are the optimal ancillary medications, it’s important to have a brief discussion on the primary issues and potential side effects men often face when undergoing TRT.
Estradiol
Estradiol monitoring and management is an important topic in TRT and recent studies have highlighted estradiol as just as important to male brain and sexual function as testosterone itself.[SUP][SUP][1][/SUP][/SUP] Most of you know estrogen is the "female hormone" and what makes women “emotional”. Actually estrogen is composed of three different forms, including one that plays a huge role in how men feel: estradiol (E2). So why is estradiol so important? It has profound implications for general health and has the potential to cause very unpleasant symptoms if levels are unbalanced. As testosterone levels decrease and estradiol levels increase, the ratio of free testosterone to estradiol reaches a critical point and estrogenic suppressive effects predominate.[SUP][SUP][2][/SUP][/SUP]
In my experience, both personally and in consulting with many men on TRT, the single biggest reason why TRT doesn’t “work” is because of estradiol (E2) management. Usually it’s out of balance. Unfortunately, a man can have side effects when suffering from low or high estradiol. From personal observation the single biggest determinant of whether estradiol (E2) is out of balance is erectile strength. Another obvious and noticeable side effect is water retention. Some men genetically overproduce aromatase which ultimately leads to increased estrogen production and its potential side effects. This is discussed in further detail later in this chapter.
It is of paramount importance to work with a knowledgeable TRT prescribing physician so both of you can dial in your estradiol from the start. Normally it will take an initial baseline blood estradiol (known as E2) panel and then future readings after starting TRT to figure out what level is best for the patient. There is a narrow therapeutic window regarding estradiol/estrogen where it is important for both patient and doctor to understand the optimal estradiol value range. Most knowledgeable TRT physicians will specify a ‘sensitive’ or ‘enhanced’ estradiol assay after a patient initiates TRT. This often times is critically important because the standard estradiol test is designed for women and tends to greatly overestimate estrogen.
DHT
Even though the main androgen secreted by the testes is testosterone, the main androgenic signal comes from dihydrotestosterone (DHT). This includes the brain, central nervous system, skin and the genitals. Practically everything but muscle. Testosterone is converted to the active androgen DHT by the action of the enzyme 5 alpha reductase (5-AR). DHT because it binds about 3-5 times more strongly to the androgen receptor than testosterone, is much more anabolic in nature[SUP][SUP][3][/SUP][/SUP].
DHT (dihydrotestosterone) is largely responsible for male pattern baldness. DHT can also cause benign growth of the prostate, increased oiliness of the skin and acne[SUP][SUP][4][/SUP][/SUP].
When you understand DHT in this fashion it is easy to believe your goal should be its elimination or reduction. But DHT is essential for proper brain chemistry and proper sexual function-including libido. Because of this odd duality, DHT is NOT something you want to reduce or eliminate in the body. But due to varying biochemical individuality, some men, will have to keep DHT levels under control as a prudent course of action. As always, great care and attention should be provided by your physician in monitoring your individual DHT levels relative to your initial baseline blood panel and ongoing blood panels over time. If you utilize TRT transdermally, it is very important to monitor your DHT levels as transdermals and creams often convert to DHT and will elevate PSA (prostate specific antigen) values transiently-usually until an effective dose of T is established.
Prolactin
Prolactin is a hormone that can lower your testosterone and interfere with your sex life. Excessive prolactin is also associated with gynecomastia, i.e., "male boobs."[SUP][SUP][5][/SUP][/SUP] Studies have found high prolactin levels (known as hyperprolactinemia) in men are linked to low sexual desire and erectile dysfunction.[SUP][SUP][6][/SUP][/SUP] Men with severe hyperprolactinemia frequently show mild hypogonadism (low testosterone), and complain of a loss of libido and sexual dysfunction.[SUP][SUP][7][/SUP][/SUP]
If you are using TRT long term and start suffering a decline in libido, I encourage you to get your serum prolactin levels measured. A super high reading (> 300) may require your doctor to send for an MRI of the pituitary in case the issue is a pituitary adenoma. This is a non-cancerous pituitary tumor that can cause vision problems and headaches. It is either monitored (while tightly controlling estrogen and prolactin) or surgically removed through an amazingly routine procedure.
Many anti-aging clinics are using Cabergoline regularly in their practices with men to boost libido/and or improve sexual function[SUP][SUP][8][/SUP][/SUP]. Anecdotal studies show one 0.5-milligram cabergoline tablet twice a week improves the quality and intensity of sex drive, arousal, and orgasm. This is clearly an “off label” usage of this medication due to the lack of peer reviewed research data advocating it for this specific reason.
The author of this book has been prescribed and used almost every SERM (Selective Estrogen Receptor Modulator) and AI (Aromatase Inhibitor) available.
After many years of experience, I’ve chosen (what I feel) are the OPTIMAL ancillary medications for physicians to treat and safely correct potential TRT side effects. Some men, due to the uniqueness of their biochemical individuality, will need stronger side effect mediation than others.
Because these SERM’s and AI’s have not been FDA approved for use in males, TRT physicians prescribe them ‘off-label'. Due to the fact that some of them are now manufactured as generic medications in most markets, it is unlikely a drug company would pursue FDA approval for use in men now because of limited profit incentive, mostly due to the relatively small market potential (for now at least). It is important to understand these medications were designed to treat breast cancer in women and as such they must be closely monitored when used in male endocrine systems. They are usually well tolerated and a progressive and experienced TRT physician should be quite familiar with their pharma dynamics.
A progressive TRT-prescribing doctor will analyze your lab work and symptoms and prescribe you ancillary medications recommended in the chart below (when your symptoms and/or blood values warrant it necessary) and will discuss these potential side effects and their ramifications beforehand. This will make them easier to identify for both of you. It is even more important you are also learned in understanding and dealing with them as well. Again, do your homework and know thyself.
[TABLE=width:-780][TR][TD]
Drug Classification
[/TD]
[TD]
Name of Drug
[/TD]
[TD]
Normal Dosage and Side Effects Addressed
[/TD][/TR]
[TR][TD]
SERM (Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Nolvadex (Tamoxifen)
10–20 mg
Tablet
[/TD]
[TD]
Nolvadex actually has quite a few applications for TRT users. First and foremost, its most common use is for the prevention of gynecomastia or male breast tissue growth otherwise known in locker room culture as “bitch tits”. Nolvadex binds to the receptor site in breast tissue, safely preventing estrogen formation. The advantage of Nolvadex is it doesn't reduce estrogen in your body keeping some estrogen floating around. Estrogen is important for a properly functioning immune system and healthy joints. It has also been shown to improve lipid profiles (HDL and LDL) while using testosterone.[SUP][SUP][9][/SUP][/SUP] Normal dosage of Nolvadex is 10 mgs up to 40 mgs per day or EOD until symptoms disappear. Most progressive TRT physicians will taper the medication.
[/TD][/TR]
[TR][TD]
SERM (Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Clomid (Clomiphene Citrate or Omifin)
[/TD]
[TD]
Clomid works by blocking estrogen (E) action in the pituitary.[SUP][SUP][10][/SUP][/SUP] The pituitary thereby sees less estrogen and makes more luteinizing hormone (LH) due to removal of negative feedback inhibition. Increased LH levels in turn stimulate the Leydig cells in the testis to synthesize more testosterone. Clomid binds to estrogen receptors and also restores the body's natural production of testosterone[SUP][SUP][11][/SUP][/SUP]. Clomid is now preferred by a number of TRT Physicians like Jeffrey Dach MD, John Crisler DO, and Dr. Eugene Shippen to be the preferential SERM used as ‘mono-therapy’ for hypogonadal men looking to remain fertile (retain motile sperm). These doctors have had great results using Clomid at 12.5 to 25 mgs EOD (every other day) to restore normal T production. In some men however, clomid increases SHBG which ultimately decreases free testosterone. As always careful evaluation of blood work is paramount.
[/TD][/TR]
[TR][TD]
SERM
(Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Toremifene Citrate
(Fareston)
60 mg Tablet
[/TD]
[TD]
Toremifene while chemically similar to Nolvadex has several other well-known effects including acting as an estrogen antagonist in the hypothalamus and pituitary (HTPA). Because its androgenicity to estrogenicity ratio is 5x that of Nolvadex, toremifene is highly likely to be capable of increasing testosterone.[SUP][SUP][12][/SUP][/SUP] I find Toremifene as a good adjunct to dose with after long periods of TRT usage where an increase in libido is needed. It has been known to deliver a jolt to your HPTA improving sexual desire and intimacy feelings. A dosage of 30 mgs (half a tab) for two to three days in a row until libido and feelings of sexual desire are restored has been effective for some patients. This is another SERM rarely prescribed by TRT doctors.
[/TD][/TR]
[TR][TD]
SERM (Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Raloxifene (Evista) 60 mg Tablet
[/TD]
[TD]
Raloxifene is the newest SERM at the disposal of TRT physicians and their patients. Raloxifene is in the same family of compounds as Tamoxifen. Raloxifene has about 10x the binding affinity for the estrogen receptor in breast tissue than Tamoxifen[SUP][SUP][13][/SUP][/SUP]. It binds much more strongly to the receptor site, virtually eliminating the possibility of any estrogen reaching a receptor and exerting the undesired effect[SUP][SUP][14][/SUP][/SUP]. If you’re reading between the lines, you can see how effective Raloxifene might be in the treatment and prevention of gynecomastia. An optimal dosing protocol is 60 mgs daily until gyno is gone.
[/TD][/TR]
[TR][TD]
AI’s (Aromatase Inhibitors)
[/TD]
[TD]
Arimidex
(Anastrozole)
Tablet
1 mg Tablet
[/TD]
[TD]
Arimidex is considered a “competitive inhibitor” AI which means it competes with estrogen around the aromatase enzyme. Arimidex performs by actively blocking the aromatase enzyme which inhibits the body’s ability to produce estrogen. It is the most often doctor prescribed aromatase inhibitor (AI) due to its wide availability and effectiveness. An optimal dosing protocol of Arimidex while on TRT is 0.5 mg between once and 3 days a week. Some men will need to go as high as 1 mg EOD in order to prevent side effects such as moodiness, water retention and lowered libido. We feel men with higher body fat percentages will need 0.5 mg of Arimidex EOD when starting TRT as a good failsafe to prevent estrogenic side effects caused by elevated aromatase enzymes found in fat tissue. Arimidex does have the ability to reduce HDL cholesterol levels and needs to be monitored for this reason[SUP][SUP][15][/SUP][/SUP].
[/TD][/TR]
[TR][TD]
AI’s (Aromatase Inhibitors)
[/TD]
[TD]
Aromasin (Exemestane)
25 mg Tablets
[/TD]
[TD]
Aromasin is considered a “suicide inhibitor” AI which means it attaches to the aromatase enzyme and permanently disables it. Aromasin at 12.5–25 mgs a day, will raise testosterone levels by about 60%, and also help the free-to-bound testosterone ratio by lowering levels of sex hormone-binding globulin (SHBG) by 20%[SUP][SUP][16][/SUP][/SUP]. It’s also highly compatible with Nolvadex and has beneficial effects on bone mineral content and lipid profiles. It suppresses estrogen more strongly than Arimidex but as a Type 1 inhibiting AI, once it deactivates the aromatase enzyme, it is rendered inactive allowing other ancillaries to continue to work.[SUP][SUP][17][/SUP][/SUP] This medication is widely misunderstood and it’s rare for TRT physicians to prescribe it. It needs to be studied more closely due to its unique ability to raise testosterone levels via its reduction of SHBG.
[/TD][/TR]
[TR][TD]
AI’s (Aromatase Inhibitors)
[/TD]
[TD]
AIFM
[/TD]
[TD]
AIFM is an over-the-counter transdermal aromatase inhibitor that uses ATD, a natural steroidal aromatase inhibitor. Tested clinically in numerous animal and cell models, it is as effective as Aromasin but is not particularly well suited for oral administration as it has poor oral bioavailability.[SUP][SUP][18][/SUP][/SUP]
Men can apply 1–3 pumps (200 to 600 mcl) twice a day to clean dry skin. 1–2 pumps to reduce moderate to high estrogen and 3 pumps for very high estrogen levels.
You can apply it to inside of wrists and forearms, top of feet and upper vascular part of thigh/hip. I have known men to use it directly on sensitive excess estrogenic fat tissue around the breast/nipple area with good results. Even though this AI is not a pharmaceutical preparation, the active ingredient ATD is a pharmaceutical agent—just not scheduled/controlled by the DEA. It’s one of those loophole agents classified as a nutritional supplement rather than an aromatase inhibitor. I have used this product in the past and received estrogen suppression similar to that of Arimidex.
[/TD][/TR][/TABLE]
The Usage of Aromatase Inhibitors (AI’s) and Selective Estrogen Receptor Modulators (SERM’s) as Testosterone Replacement Therapy (TRT)
It is becoming more commonplace for physicians to use a SERM (selective estrogen receptor modulator) such as Clomid, Nolvadex or Toremifene, or even an AI (aromatase inhibitor), such as Arimidex, as sole “TRT”. These medications will elevate luteinizing hormone (LH) and overall total testosterone levels.[SUP][SUP][19][/SUP][/SUP] In our experience however, patients rarely report long term noticeable benefits (increased lean body mass, libido, less fatigue, etc.) from these strategies for the following reasons:
1. A major risk of using an AI alone is driving estrogen levels too low with potential deleterious consequences for the lipid profile, bone mineral density, libido, etc.
2. There is also a very narrow therapeutic window in regulating estrogen and estradiol levels that will impact on health and libido. Less, in terms of estrogen, is not necessarily better and these values need to be monitored on a regular basis with an experienced TRT physician. Remember, it is all about balance for the individual patient.
If your doctor has you on a SERM or AI as a form of TRT, we encourage you to show them this book so they can better understand why the usage of testosterone is much more effective
strategy. Often times the usage of TRT however, will need to be combined with a SERM to achieve balance (between T and E) for the individual patient. The noticeable exception is for younger TRT patients (30-50 years old) desiring to retain fertility. These patients (as written more than once in this book) should ONLY consider using clomid or hCG monotherapy to help restore and improve low natural T production.
TRT protocols are inaccurate when AI’s and SERM’s are dosed without any corresponding elevated blood values or noticeable symptoms to indicate the patient needs either medication. There are *sometimes* exceptions to this rule. Older men (usually over 50) and men with high body fat percentages (for reasons previously discussed) can reasonably start a TRT protocol with an AI such as Arimidex dosed at 0.5 mgs every other day (EOD). After 21-30 days, if a patient starts to exhibit symptoms of unbalanced T and E, prescribing a SERM or modulating the therapeutic dosage of an AI is warranted until balance is achieved. And obviously vigilant observation of further lab work is necessary.
There are no hard and fast rules in regard to dosing the aromatase inhibitors (AI’s) and selective estrogen receptor modulators (SERM’s) medications. The dosing of these medications is highly variable. All men are biochemically different and why it is crucial to have a competent TRT prescribing doctor who can evaluate lab assays and attend to symptoms when the need arises. Again, ongoing and regular blood draws and patient feedback are crucial for both patient and doctor to achieve and maintain balance. With some men, balance can take time to achieve.
Metabolic Syndrome, Obesity, Aromatase and Estrogen
Testosterone levels are lower in men with obesity, metabolic syndrome and type 2 diabetes[SUP][SUP][20][/SUP][/SUP]. As evidenced by just looking around, obesity is increasing at dramatic rates in most of the Western and Non-Western world. We all know the reasons. Poor diet, and a lack of exercise are the chief culprits.
Recent studies indicate TRT in men with type 2 diabetes has beneficial effects on insulin resistance and visceral adiposity[SUP][SUP][21][/SUP][/SUP]. Most clinicians are aware insulin resistance and visceral fat play a key role in cardiovascular disease.
Testosterone replacement therapy has recently been proven to increase lean body mass (LBM), reduce fat mass and produce sustained and significant weight loss, reduction in waist circumference and BMI[SUP][SUP][22][/SUP][/SUP]. Wouldn’t TRT in obese men with testosterone deficiency be a unique and effective therapeutic approach to the management of obesity? Of course it would.
Wouldn’t it also make a lot of theoretical sense for men with type 2 diabetes and metabolic syndrome to consider having their testosterone levels measured? If found to be low or low normal, wouldn’t a well designed TRT protocol (along with a proper diet and exercise program fully structured to reduce body fat) offer a reasonable strategy to optimize their health? Absolutely.
Aromatase (as previously discussed) is more abundant in fat tissue.[SUP][SUP][23][/SUP][/SUP] The higher your body fat percentage, the more Aromatase enzymes floating around and the more likely you are to convert supplemental testosterone into estradiol (E2). Especially in the stubborn body fat depot areas (Alpha Type 2A receptors) like the fat tissue found in the love handles, chest, and upper and lower back.
In other words, the higher your body fat percentage, the more likely you are to be susceptible to estradiol conversion and negative estrogenic side effects like moodiness, water retention, increased fat deposition, etc. A prudent course of action for high body fat percentage men starting TRT is to be put on a low dose AI like Arimidex to minimize the estrogen issues likely to arise.
If your body fat is above 20%, (and to make every effort to minimize potential aromatization and estrogenic side effects) you should prioritize losing body fat while undergoing TRT. I discuss strategies to optimize your fitness while on TRT in Chapter 13.
DO YOU HAVE ANY QUESTIONS ABOUT YOUR SPECIFIC SITUATION?
[CLICK HERE
[SUP][SUP][1][/SUP][/SUP]Jankowska, E.A., Rozentryt, P., and Ponikowska, B. (2009). Circulating estradiol and mortality in men with systolic chronic heart failure. Journal of the American Medical Association. 2009 May 13;301(18):1892-901.
[SUP][SUP][2][/SUP][/SUP]The role of estradiol in the maintenance of secondary hypogonadism in males in erectile dysfunction Cohen, P.G.Medical Hypotheses , Volume 50 , Issue 4 , 331 - 333
[SUP][SUP][3][/SUP][/SUP]Androgen receptor signaling induced by supraphysiological doses of dihydrotestosterone in human peripheral blood lymphocytes.Proteomics. 2010 Sep;10(17):3165-75.
[SUP][SUP][4][/SUP][/SUP]Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.Eur Urol. 2000 Apr;37(4):367-80.
[SUP][SUP][5][/SUP][/SUP]Bromocriptine monotherapy of a prolactinoma causing erectile dysfunction. Arch Esp Urol. 1997 Jun;50(5):526-8.
[SUP][SUP][6][/SUP][/SUP]Hyperprolactinemia and Erectile Dysfunction. Rev Urol, 2000 Winter, 2(1):39–42,
[SUP][SUP][7][/SUP][/SUP]Prolactin and testosterone: their role in male sexual function. Carani C1, Granata AR, Fustini MF, Marrama P.Int Androl.1996 Feb;19(1):48-54
[SUP][SUP][8][/SUP][/SUP]Six months of treatment with cabergoline restores sexual potency in hyperprolactinemic males: an open longitudinal study monitoring nocturnal penile tumescence. J Clin Endocrinol Metab. 2004 Feb;89(2):621-5.
[SUP][SUP][9][/SUP][/SUP]Furr BJ, Jordan VC (1984). "The pharmacology and clinical uses of tamoxifen". Pharmacol. Ther. 25 (2): 127–205. doi:10.1016/0163-7258(84)90043-3
[SUP][SUP][10][/SUP][/SUP]Kim, E.D., et al., The treatment of hypogonadism in men of reproductive age. Fertil Steril, 2013. 99(3): p. 718-24.
[SUP][SUP][11][/SUP][/SUP]Tan, RS; Vasudevan, D. (Jan 2003). "Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse". Fertil Steril 79 (1): 203–5.
[SUP][SUP][12][/SUP][/SUP]Price N, Sartor O, Hutson T, Mariani S. Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer 2005;3:211-4. PMID 15882476
[SUP][SUP][13][/SUP][/SUP]J Pediatr. 2004 Jul;145(1):71-6. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.Lawrence SE, Faught KA, Vethamuthu J, Lawson ML.SourceDepartment of Pediatrics, University of Ottawa, Ontario, Canada.
[SUP][SUP][14][/SUP][/SUP]Vogel, Victor; Joseph Constantino, Lawrence Wickerman et al. (2006-06-21). "Effects of Tamoxifen vs. Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes". The Journal of the American Medical Association 295 (23)
[SUP][SUP][15][/SUP][/SUP]Rubinow KB, Tang C, Hoofnagle AN, et al. Acute Sex Steroid Withdrawal Increases Cholesterol Efflux Capacity and HDL-Associated Clusterin in Men.Steroids 2012;77(5):454-460. doi:10.1016/j.steroids.2012.01.002.
[SUP][SUP][16][/SUP][/SUP]De Ronde W, de Jong FH. Aromatase inhibitors in men: effects and therapeutic options. Reproductive Biology and Endocrinology : RB&E 2011;9:93. doi:10.1186/1477-7827-9-93.
[SUP][SUP][17][/SUP][/SUP]Simpson ER (2003). "Sources of estrogen and their importance". The Journal of Steroid Biochemistry and Molecular Biology 86 (3–5): 225–30. doi:10.1016/S0960-0760(03)00360-1. PMID 14623515
[SUP][SUP][18][/SUP][/SUP]Steel E, Hutchinson JB. The aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD) blocks testosterone-induced olfactory behavior in the hamster. Cancer Res. 1981 Aug;42(8 Suppl): 3327s-3333s.
[SUP][SUP][19][/SUP][/SUP]Short-term aromatase-enzyme blockade unmasks impaired feedback adaptations in luteinizing hormone and testosterone secretion in older men. Veldhuis JD1, Iranmanesh A. J Clin Endocrinol Metab. 2005 Jan;90(1):211-8. Epub 2004 Oct 13.
[SUP][SUP][20][/SUP][/SUP]Wang C, Jackson G, Jones TH, et al. Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes. Diabetes Care2011;34(7):1669-1675. doi:10.2337/dc10-2339.
[SUP][SUP][21][/SUP][/SUP]Jones TH, Arver S, Behre HM, et al., TIMES2 Investigators. Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study). Diabetes Care 2011;34(4):828-837. doi:10.2337/dc10-1233.
[SUP][SUP][22][/SUP][/SUP]Traish AM. Testosterone and weight loss: the evidence. Current Opinion in Endocrinology, Diabetes, and Obesity 2014;21(5):313-322. doi:10.1097/MED.0000000000000086.
[SUP][SUP][23][/SUP][/SUP]The hypogonadal–obesity cycle: role of aromatase in modulating the testosterone–estradiol shunt – a major factor in the genesis of morbid obesity Cohen, P.G. Medical Hypotheses , Volume 52 , Issue 1 , 49 - 51
Available here: The Definitive Testosterone Replacement Therapy MANual: How to Optimize Your Testosterone For Lifelong Health And Happiness: Campbell, Jay: 9781942761723: Amazon.com: Books
Chapter 9 - Mitigating and Avoiding Potential Side Effects
When undergoing TRT, it is IMPERATIVE your mindset is one of expecting and mitigating potential side effects. Sometimes the difference between successful lifelong TRT and crash-and-burn flameouts is both the patient and the TRT prescribing doctor knowing what to expect. As we age, our bodies change and often times quite rapidly. The side effects men may or may not experience are random and sometimes don’t manifest for years if not decades.
It is crucially important to recognize the majority of potential side effects are minor and easily treatable. It is an unfortunate circumstance many men have received (and continue to receive) ineffective care from their TRT-prescribing physicians. Often times the inability to alleviate side effects forces men to end their treatment altogether. There is no reason for this whatsoever especially when you utilize the services of a progressive and experienced TRT prescribing physicians.
[CLICK HERE TO FIND THE RIGHT DOCTOR FOR YOU]
As I have continued to stress throughout this book, it is CRUCIAL you keep detailed files on your blood panels in order to best understand your values as they change over time. Know thyself, compile blood panel data, and do your homework to ensure your TRT is successful over the long term. Become your own doctor. Study your reactions. Take notes. Be vigilant in knowing your body and what allows it to work optimally. Remember, doctors are said to have “practices” for a reason. They are human and do make mistakes. You are the only one who truly knows your body, but only if you’re paying attention.
Before discussing what I believe are the optimal ancillary medications, it’s important to have a brief discussion on the primary issues and potential side effects men often face when undergoing TRT.
Estradiol
Estradiol monitoring and management is an important topic in TRT and recent studies have highlighted estradiol as just as important to male brain and sexual function as testosterone itself.[SUP][SUP][1][/SUP][/SUP] Most of you know estrogen is the "female hormone" and what makes women “emotional”. Actually estrogen is composed of three different forms, including one that plays a huge role in how men feel: estradiol (E2). So why is estradiol so important? It has profound implications for general health and has the potential to cause very unpleasant symptoms if levels are unbalanced. As testosterone levels decrease and estradiol levels increase, the ratio of free testosterone to estradiol reaches a critical point and estrogenic suppressive effects predominate.[SUP][SUP][2][/SUP][/SUP]
In my experience, both personally and in consulting with many men on TRT, the single biggest reason why TRT doesn’t “work” is because of estradiol (E2) management. Usually it’s out of balance. Unfortunately, a man can have side effects when suffering from low or high estradiol. From personal observation the single biggest determinant of whether estradiol (E2) is out of balance is erectile strength. Another obvious and noticeable side effect is water retention. Some men genetically overproduce aromatase which ultimately leads to increased estrogen production and its potential side effects. This is discussed in further detail later in this chapter.
It is of paramount importance to work with a knowledgeable TRT prescribing physician so both of you can dial in your estradiol from the start. Normally it will take an initial baseline blood estradiol (known as E2) panel and then future readings after starting TRT to figure out what level is best for the patient. There is a narrow therapeutic window regarding estradiol/estrogen where it is important for both patient and doctor to understand the optimal estradiol value range. Most knowledgeable TRT physicians will specify a ‘sensitive’ or ‘enhanced’ estradiol assay after a patient initiates TRT. This often times is critically important because the standard estradiol test is designed for women and tends to greatly overestimate estrogen.
DHT
Even though the main androgen secreted by the testes is testosterone, the main androgenic signal comes from dihydrotestosterone (DHT). This includes the brain, central nervous system, skin and the genitals. Practically everything but muscle. Testosterone is converted to the active androgen DHT by the action of the enzyme 5 alpha reductase (5-AR). DHT because it binds about 3-5 times more strongly to the androgen receptor than testosterone, is much more anabolic in nature[SUP][SUP][3][/SUP][/SUP].
DHT (dihydrotestosterone) is largely responsible for male pattern baldness. DHT can also cause benign growth of the prostate, increased oiliness of the skin and acne[SUP][SUP][4][/SUP][/SUP].
When you understand DHT in this fashion it is easy to believe your goal should be its elimination or reduction. But DHT is essential for proper brain chemistry and proper sexual function-including libido. Because of this odd duality, DHT is NOT something you want to reduce or eliminate in the body. But due to varying biochemical individuality, some men, will have to keep DHT levels under control as a prudent course of action. As always, great care and attention should be provided by your physician in monitoring your individual DHT levels relative to your initial baseline blood panel and ongoing blood panels over time. If you utilize TRT transdermally, it is very important to monitor your DHT levels as transdermals and creams often convert to DHT and will elevate PSA (prostate specific antigen) values transiently-usually until an effective dose of T is established.
Prolactin
Prolactin is a hormone that can lower your testosterone and interfere with your sex life. Excessive prolactin is also associated with gynecomastia, i.e., "male boobs."[SUP][SUP][5][/SUP][/SUP] Studies have found high prolactin levels (known as hyperprolactinemia) in men are linked to low sexual desire and erectile dysfunction.[SUP][SUP][6][/SUP][/SUP] Men with severe hyperprolactinemia frequently show mild hypogonadism (low testosterone), and complain of a loss of libido and sexual dysfunction.[SUP][SUP][7][/SUP][/SUP]
If you are using TRT long term and start suffering a decline in libido, I encourage you to get your serum prolactin levels measured. A super high reading (> 300) may require your doctor to send for an MRI of the pituitary in case the issue is a pituitary adenoma. This is a non-cancerous pituitary tumor that can cause vision problems and headaches. It is either monitored (while tightly controlling estrogen and prolactin) or surgically removed through an amazingly routine procedure.
Many anti-aging clinics are using Cabergoline regularly in their practices with men to boost libido/and or improve sexual function[SUP][SUP][8][/SUP][/SUP]. Anecdotal studies show one 0.5-milligram cabergoline tablet twice a week improves the quality and intensity of sex drive, arousal, and orgasm. This is clearly an “off label” usage of this medication due to the lack of peer reviewed research data advocating it for this specific reason.
The author of this book has been prescribed and used almost every SERM (Selective Estrogen Receptor Modulator) and AI (Aromatase Inhibitor) available.
After many years of experience, I’ve chosen (what I feel) are the OPTIMAL ancillary medications for physicians to treat and safely correct potential TRT side effects. Some men, due to the uniqueness of their biochemical individuality, will need stronger side effect mediation than others.
Because these SERM’s and AI’s have not been FDA approved for use in males, TRT physicians prescribe them ‘off-label'. Due to the fact that some of them are now manufactured as generic medications in most markets, it is unlikely a drug company would pursue FDA approval for use in men now because of limited profit incentive, mostly due to the relatively small market potential (for now at least). It is important to understand these medications were designed to treat breast cancer in women and as such they must be closely monitored when used in male endocrine systems. They are usually well tolerated and a progressive and experienced TRT physician should be quite familiar with their pharma dynamics.
A progressive TRT-prescribing doctor will analyze your lab work and symptoms and prescribe you ancillary medications recommended in the chart below (when your symptoms and/or blood values warrant it necessary) and will discuss these potential side effects and their ramifications beforehand. This will make them easier to identify for both of you. It is even more important you are also learned in understanding and dealing with them as well. Again, do your homework and know thyself.
[TABLE=width:-780][TR][TD]
Drug Classification
[/TD]
[TD]
Name of Drug
[/TD]
[TD]
Normal Dosage and Side Effects Addressed
[/TD][/TR]
[TR][TD]
SERM (Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Nolvadex (Tamoxifen)
10–20 mg
Tablet
[/TD]
[TD]
Nolvadex actually has quite a few applications for TRT users. First and foremost, its most common use is for the prevention of gynecomastia or male breast tissue growth otherwise known in locker room culture as “bitch tits”. Nolvadex binds to the receptor site in breast tissue, safely preventing estrogen formation. The advantage of Nolvadex is it doesn't reduce estrogen in your body keeping some estrogen floating around. Estrogen is important for a properly functioning immune system and healthy joints. It has also been shown to improve lipid profiles (HDL and LDL) while using testosterone.[SUP][SUP][9][/SUP][/SUP] Normal dosage of Nolvadex is 10 mgs up to 40 mgs per day or EOD until symptoms disappear. Most progressive TRT physicians will taper the medication.
[/TD][/TR]
[TR][TD]
SERM (Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Clomid (Clomiphene Citrate or Omifin)
[/TD]
[TD]
Clomid works by blocking estrogen (E) action in the pituitary.[SUP][SUP][10][/SUP][/SUP] The pituitary thereby sees less estrogen and makes more luteinizing hormone (LH) due to removal of negative feedback inhibition. Increased LH levels in turn stimulate the Leydig cells in the testis to synthesize more testosterone. Clomid binds to estrogen receptors and also restores the body's natural production of testosterone[SUP][SUP][11][/SUP][/SUP]. Clomid is now preferred by a number of TRT Physicians like Jeffrey Dach MD, John Crisler DO, and Dr. Eugene Shippen to be the preferential SERM used as ‘mono-therapy’ for hypogonadal men looking to remain fertile (retain motile sperm). These doctors have had great results using Clomid at 12.5 to 25 mgs EOD (every other day) to restore normal T production. In some men however, clomid increases SHBG which ultimately decreases free testosterone. As always careful evaluation of blood work is paramount.
[/TD][/TR]
[TR][TD]
SERM
(Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Toremifene Citrate
(Fareston)
60 mg Tablet
[/TD]
[TD]
Toremifene while chemically similar to Nolvadex has several other well-known effects including acting as an estrogen antagonist in the hypothalamus and pituitary (HTPA). Because its androgenicity to estrogenicity ratio is 5x that of Nolvadex, toremifene is highly likely to be capable of increasing testosterone.[SUP][SUP][12][/SUP][/SUP] I find Toremifene as a good adjunct to dose with after long periods of TRT usage where an increase in libido is needed. It has been known to deliver a jolt to your HPTA improving sexual desire and intimacy feelings. A dosage of 30 mgs (half a tab) for two to three days in a row until libido and feelings of sexual desire are restored has been effective for some patients. This is another SERM rarely prescribed by TRT doctors.
[/TD][/TR]
[TR][TD]
SERM (Selective Estrogen Receptor Modulator)
[/TD]
[TD]
Raloxifene (Evista) 60 mg Tablet
[/TD]
[TD]
Raloxifene is the newest SERM at the disposal of TRT physicians and their patients. Raloxifene is in the same family of compounds as Tamoxifen. Raloxifene has about 10x the binding affinity for the estrogen receptor in breast tissue than Tamoxifen[SUP][SUP][13][/SUP][/SUP]. It binds much more strongly to the receptor site, virtually eliminating the possibility of any estrogen reaching a receptor and exerting the undesired effect[SUP][SUP][14][/SUP][/SUP]. If you’re reading between the lines, you can see how effective Raloxifene might be in the treatment and prevention of gynecomastia. An optimal dosing protocol is 60 mgs daily until gyno is gone.
[/TD][/TR]
[TR][TD]
AI’s (Aromatase Inhibitors)
[/TD]
[TD]
Arimidex
(Anastrozole)
Tablet
1 mg Tablet
[/TD]
[TD]
Arimidex is considered a “competitive inhibitor” AI which means it competes with estrogen around the aromatase enzyme. Arimidex performs by actively blocking the aromatase enzyme which inhibits the body’s ability to produce estrogen. It is the most often doctor prescribed aromatase inhibitor (AI) due to its wide availability and effectiveness. An optimal dosing protocol of Arimidex while on TRT is 0.5 mg between once and 3 days a week. Some men will need to go as high as 1 mg EOD in order to prevent side effects such as moodiness, water retention and lowered libido. We feel men with higher body fat percentages will need 0.5 mg of Arimidex EOD when starting TRT as a good failsafe to prevent estrogenic side effects caused by elevated aromatase enzymes found in fat tissue. Arimidex does have the ability to reduce HDL cholesterol levels and needs to be monitored for this reason[SUP][SUP][15][/SUP][/SUP].
[/TD][/TR]
[TR][TD]
AI’s (Aromatase Inhibitors)
[/TD]
[TD]
Aromasin (Exemestane)
25 mg Tablets
[/TD]
[TD]
Aromasin is considered a “suicide inhibitor” AI which means it attaches to the aromatase enzyme and permanently disables it. Aromasin at 12.5–25 mgs a day, will raise testosterone levels by about 60%, and also help the free-to-bound testosterone ratio by lowering levels of sex hormone-binding globulin (SHBG) by 20%[SUP][SUP][16][/SUP][/SUP]. It’s also highly compatible with Nolvadex and has beneficial effects on bone mineral content and lipid profiles. It suppresses estrogen more strongly than Arimidex but as a Type 1 inhibiting AI, once it deactivates the aromatase enzyme, it is rendered inactive allowing other ancillaries to continue to work.[SUP][SUP][17][/SUP][/SUP] This medication is widely misunderstood and it’s rare for TRT physicians to prescribe it. It needs to be studied more closely due to its unique ability to raise testosterone levels via its reduction of SHBG.
[/TD][/TR]
[TR][TD]
AI’s (Aromatase Inhibitors)
[/TD]
[TD]
AIFM
[/TD]
[TD]
AIFM is an over-the-counter transdermal aromatase inhibitor that uses ATD, a natural steroidal aromatase inhibitor. Tested clinically in numerous animal and cell models, it is as effective as Aromasin but is not particularly well suited for oral administration as it has poor oral bioavailability.[SUP][SUP][18][/SUP][/SUP]
Men can apply 1–3 pumps (200 to 600 mcl) twice a day to clean dry skin. 1–2 pumps to reduce moderate to high estrogen and 3 pumps for very high estrogen levels.
You can apply it to inside of wrists and forearms, top of feet and upper vascular part of thigh/hip. I have known men to use it directly on sensitive excess estrogenic fat tissue around the breast/nipple area with good results. Even though this AI is not a pharmaceutical preparation, the active ingredient ATD is a pharmaceutical agent—just not scheduled/controlled by the DEA. It’s one of those loophole agents classified as a nutritional supplement rather than an aromatase inhibitor. I have used this product in the past and received estrogen suppression similar to that of Arimidex.
[/TD][/TR][/TABLE]
The Usage of Aromatase Inhibitors (AI’s) and Selective Estrogen Receptor Modulators (SERM’s) as Testosterone Replacement Therapy (TRT)
It is becoming more commonplace for physicians to use a SERM (selective estrogen receptor modulator) such as Clomid, Nolvadex or Toremifene, or even an AI (aromatase inhibitor), such as Arimidex, as sole “TRT”. These medications will elevate luteinizing hormone (LH) and overall total testosterone levels.[SUP][SUP][19][/SUP][/SUP] In our experience however, patients rarely report long term noticeable benefits (increased lean body mass, libido, less fatigue, etc.) from these strategies for the following reasons:
1. A major risk of using an AI alone is driving estrogen levels too low with potential deleterious consequences for the lipid profile, bone mineral density, libido, etc.
2. There is also a very narrow therapeutic window in regulating estrogen and estradiol levels that will impact on health and libido. Less, in terms of estrogen, is not necessarily better and these values need to be monitored on a regular basis with an experienced TRT physician. Remember, it is all about balance for the individual patient.
If your doctor has you on a SERM or AI as a form of TRT, we encourage you to show them this book so they can better understand why the usage of testosterone is much more effective
strategy. Often times the usage of TRT however, will need to be combined with a SERM to achieve balance (between T and E) for the individual patient. The noticeable exception is for younger TRT patients (30-50 years old) desiring to retain fertility. These patients (as written more than once in this book) should ONLY consider using clomid or hCG monotherapy to help restore and improve low natural T production.
TRT protocols are inaccurate when AI’s and SERM’s are dosed without any corresponding elevated blood values or noticeable symptoms to indicate the patient needs either medication. There are *sometimes* exceptions to this rule. Older men (usually over 50) and men with high body fat percentages (for reasons previously discussed) can reasonably start a TRT protocol with an AI such as Arimidex dosed at 0.5 mgs every other day (EOD). After 21-30 days, if a patient starts to exhibit symptoms of unbalanced T and E, prescribing a SERM or modulating the therapeutic dosage of an AI is warranted until balance is achieved. And obviously vigilant observation of further lab work is necessary.
There are no hard and fast rules in regard to dosing the aromatase inhibitors (AI’s) and selective estrogen receptor modulators (SERM’s) medications. The dosing of these medications is highly variable. All men are biochemically different and why it is crucial to have a competent TRT prescribing doctor who can evaluate lab assays and attend to symptoms when the need arises. Again, ongoing and regular blood draws and patient feedback are crucial for both patient and doctor to achieve and maintain balance. With some men, balance can take time to achieve.
Metabolic Syndrome, Obesity, Aromatase and Estrogen
Testosterone levels are lower in men with obesity, metabolic syndrome and type 2 diabetes[SUP][SUP][20][/SUP][/SUP]. As evidenced by just looking around, obesity is increasing at dramatic rates in most of the Western and Non-Western world. We all know the reasons. Poor diet, and a lack of exercise are the chief culprits.
Recent studies indicate TRT in men with type 2 diabetes has beneficial effects on insulin resistance and visceral adiposity[SUP][SUP][21][/SUP][/SUP]. Most clinicians are aware insulin resistance and visceral fat play a key role in cardiovascular disease.
Testosterone replacement therapy has recently been proven to increase lean body mass (LBM), reduce fat mass and produce sustained and significant weight loss, reduction in waist circumference and BMI[SUP][SUP][22][/SUP][/SUP]. Wouldn’t TRT in obese men with testosterone deficiency be a unique and effective therapeutic approach to the management of obesity? Of course it would.
Wouldn’t it also make a lot of theoretical sense for men with type 2 diabetes and metabolic syndrome to consider having their testosterone levels measured? If found to be low or low normal, wouldn’t a well designed TRT protocol (along with a proper diet and exercise program fully structured to reduce body fat) offer a reasonable strategy to optimize their health? Absolutely.
Aromatase (as previously discussed) is more abundant in fat tissue.[SUP][SUP][23][/SUP][/SUP] The higher your body fat percentage, the more Aromatase enzymes floating around and the more likely you are to convert supplemental testosterone into estradiol (E2). Especially in the stubborn body fat depot areas (Alpha Type 2A receptors) like the fat tissue found in the love handles, chest, and upper and lower back.
In other words, the higher your body fat percentage, the more likely you are to be susceptible to estradiol conversion and negative estrogenic side effects like moodiness, water retention, increased fat deposition, etc. A prudent course of action for high body fat percentage men starting TRT is to be put on a low dose AI like Arimidex to minimize the estrogen issues likely to arise.
If your body fat is above 20%, (and to make every effort to minimize potential aromatization and estrogenic side effects) you should prioritize losing body fat while undergoing TRT. I discuss strategies to optimize your fitness while on TRT in Chapter 13.
DO YOU HAVE ANY QUESTIONS ABOUT YOUR SPECIFIC SITUATION?
[CLICK HERE
[SUP][SUP][1][/SUP][/SUP]Jankowska, E.A., Rozentryt, P., and Ponikowska, B. (2009). Circulating estradiol and mortality in men with systolic chronic heart failure. Journal of the American Medical Association. 2009 May 13;301(18):1892-901.
[SUP][SUP][2][/SUP][/SUP]The role of estradiol in the maintenance of secondary hypogonadism in males in erectile dysfunction Cohen, P.G.Medical Hypotheses , Volume 50 , Issue 4 , 331 - 333
[SUP][SUP][3][/SUP][/SUP]Androgen receptor signaling induced by supraphysiological doses of dihydrotestosterone in human peripheral blood lymphocytes.Proteomics. 2010 Sep;10(17):3165-75.
[SUP][SUP][4][/SUP][/SUP]Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.Eur Urol. 2000 Apr;37(4):367-80.
[SUP][SUP][5][/SUP][/SUP]Bromocriptine monotherapy of a prolactinoma causing erectile dysfunction. Arch Esp Urol. 1997 Jun;50(5):526-8.
[SUP][SUP][6][/SUP][/SUP]Hyperprolactinemia and Erectile Dysfunction. Rev Urol, 2000 Winter, 2(1):39–42,
[SUP][SUP][7][/SUP][/SUP]Prolactin and testosterone: their role in male sexual function. Carani C1, Granata AR, Fustini MF, Marrama P.Int Androl.1996 Feb;19(1):48-54
[SUP][SUP][8][/SUP][/SUP]Six months of treatment with cabergoline restores sexual potency in hyperprolactinemic males: an open longitudinal study monitoring nocturnal penile tumescence. J Clin Endocrinol Metab. 2004 Feb;89(2):621-5.
[SUP][SUP][9][/SUP][/SUP]Furr BJ, Jordan VC (1984). "The pharmacology and clinical uses of tamoxifen". Pharmacol. Ther. 25 (2): 127–205. doi:10.1016/0163-7258(84)90043-3
[SUP][SUP][10][/SUP][/SUP]Kim, E.D., et al., The treatment of hypogonadism in men of reproductive age. Fertil Steril, 2013. 99(3): p. 718-24.
[SUP][SUP][11][/SUP][/SUP]Tan, RS; Vasudevan, D. (Jan 2003). "Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse". Fertil Steril 79 (1): 203–5.
[SUP][SUP][12][/SUP][/SUP]Price N, Sartor O, Hutson T, Mariani S. Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer 2005;3:211-4. PMID 15882476
[SUP][SUP][13][/SUP][/SUP]J Pediatr. 2004 Jul;145(1):71-6. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.Lawrence SE, Faught KA, Vethamuthu J, Lawson ML.SourceDepartment of Pediatrics, University of Ottawa, Ontario, Canada.
[SUP][SUP][14][/SUP][/SUP]Vogel, Victor; Joseph Constantino, Lawrence Wickerman et al. (2006-06-21). "Effects of Tamoxifen vs. Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes". The Journal of the American Medical Association 295 (23)
[SUP][SUP][15][/SUP][/SUP]Rubinow KB, Tang C, Hoofnagle AN, et al. Acute Sex Steroid Withdrawal Increases Cholesterol Efflux Capacity and HDL-Associated Clusterin in Men.Steroids 2012;77(5):454-460. doi:10.1016/j.steroids.2012.01.002.
[SUP][SUP][16][/SUP][/SUP]De Ronde W, de Jong FH. Aromatase inhibitors in men: effects and therapeutic options. Reproductive Biology and Endocrinology : RB&E 2011;9:93. doi:10.1186/1477-7827-9-93.
[SUP][SUP][17][/SUP][/SUP]Simpson ER (2003). "Sources of estrogen and their importance". The Journal of Steroid Biochemistry and Molecular Biology 86 (3–5): 225–30. doi:10.1016/S0960-0760(03)00360-1. PMID 14623515
[SUP][SUP][18][/SUP][/SUP]Steel E, Hutchinson JB. The aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD) blocks testosterone-induced olfactory behavior in the hamster. Cancer Res. 1981 Aug;42(8 Suppl): 3327s-3333s.
[SUP][SUP][19][/SUP][/SUP]Short-term aromatase-enzyme blockade unmasks impaired feedback adaptations in luteinizing hormone and testosterone secretion in older men. Veldhuis JD1, Iranmanesh A. J Clin Endocrinol Metab. 2005 Jan;90(1):211-8. Epub 2004 Oct 13.
[SUP][SUP][20][/SUP][/SUP]Wang C, Jackson G, Jones TH, et al. Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes. Diabetes Care2011;34(7):1669-1675. doi:10.2337/dc10-2339.
[SUP][SUP][21][/SUP][/SUP]Jones TH, Arver S, Behre HM, et al., TIMES2 Investigators. Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study). Diabetes Care 2011;34(4):828-837. doi:10.2337/dc10-1233.
[SUP][SUP][22][/SUP][/SUP]Traish AM. Testosterone and weight loss: the evidence. Current Opinion in Endocrinology, Diabetes, and Obesity 2014;21(5):313-322. doi:10.1097/MED.0000000000000086.
[SUP][SUP][23][/SUP][/SUP]The hypogonadal–obesity cycle: role of aromatase in modulating the testosterone–estradiol shunt – a major factor in the genesis of morbid obesity Cohen, P.G. Medical Hypotheses , Volume 52 , Issue 1 , 49 - 51
Last edited:
