16 June 2020


 dr 6 61620

Dr. Testosterone
By George Touliatos, MD


Aromatase Inhibitors and Side Effects


Aromatase inhibitors (AIs) are a class of drugs used in breast cancer. Inhibiting the action of the enzyme aromatase, which converts androgens into estrogens, AIs suppress estrogen production and are considered as potent anti-estrogens. The inactivation of the aromatase enzyme, found in high concentration in subcutaneous adipose tissue, is the mechanism of their action. AIs basically inhibit estrogen production, in contrast to the old generation of anti-estrogens, the selective estrogen receptors modulators (SERMs). SERMs occupy the estrogenic receptors, thus making the circulating estrogens unable to attach to the receptors.


The two types of AIs include suicidal steroidal inhibitors, such as exemestane and non-steroidal inhibitors, such as anastrozole and letrozole. Exemestane prevents the rise of estradiol (E2) for quite a while after it is being used. The drug almost suppresses plasma and tissue estrogen level (estradiol-E2) by 85% in vivo of total estrogen.


Aromatase inhibitors have several side effects, when abused on a daily basis (for aesthetic purposes).


1. AIs have a significant negative impact on atheromatic index, thus increasing the risk of cardiovascular disease. Studies have shown an increase in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels and a decrease in high-density lipoprotein (HDL) cholesterol levels.


2. They lower bone mineral density (BMD), by lowering osteoblastic activity, resulting in increased risk of skeletal fragility. Therefore, arthritis, osteoarthritis, arthralgias and osteopenia-osteoporosis are serious negative adverse events.


3. Estrogens and aromatization lead to edema that lubricate synovial cavity in joints. Therefore, estrogens deprivation would cause joint stiffness and joint pain.


4. Estrogens are linked to the feeling of well-being, due to their relation to serotonin, the hormone of joy. Therefore, AIs have a negative effect on mood.


5. Estrogens are necessary for sexual drive. Lowering beta-estradiol dramatically would cost in libido.


6. Estrogens lead to water retention, known as edema. Muscle glycogen synthesis is formed from starch and water. Consequently, without water retention, there is lack of muscle glycogen and pumping. This costs in terms of energy and muscle flexing.


7. Finally, estrogens improve androgen receptor (AR) affinity. This was demonstrated by scientists that castrated male rats. As a result of this, estrogens went sky high. Afterward, male rats were given methyltrienolone AAS (M3) and the bonding between the steroid molecule and the AR was 500 times stronger. In a study held by Greeks in Aretaion University Hospital, 1mg/day of anastrozole or 2.5 mg/day of letrozole for six months could elevate LH and TT, through lower beta-estradiol (E2). Letrozole is even more potent than anastrozole, while exemestane is considered to be a suicidal AI. However, AIs abuse will crush on E2, which will have reverse effects in libido. A small amount of estrogens is required for proper sexual drive. Besides, AIs abuse will have a negative impact on high-density lipoprotein (HDL) and bone mineral density (BMD). Joints also tend to ache, due to less lubrication.




Aromatase inhibitors (AIs) are an important component of the treatment of hormone receptor-positive breast cancer in females. At the same time, they are necessary to prevent aromatization (estrogenic activity) caused by androgenic-anabolic steroids (AAS).


The first class of anti-estrogenic drugs are selective estrogen receptor modulators (SERMs), which act selectively in certain tissues (tamoxifen, clomiphene), occupying the estrogenic receptors, thus making circulating estrogens unable to attach to the receptors.


Modern aromatase inhibitors include suicidal steroidal inhibitors (exemestane) and non-steroidal inhibitors (anastrozole, letrozole), which inhibit the action of aromatase enzyme that converts androgens to estrogens. Aromatization takes place in a variety of tissues, such as mammary gland, adipose tissue, liver and brain. These drugs have the ability to diminish peripheral-circulating estrogens and beta-estradiol (E2) in particular. E2 is the main representative of estrogens. During a pre-contest preparation or “cutting phase,” AIs are widely abused.


This leads to a plethora of different side effects, with “arthralgia of aromatase inhibitors” being a common toxicity. The symptoms include joint pain, with most frequent in the wrists, knees, ankles, elbows and shoulders. This discomfort is usually symmetrical. Other symptoms include morning stiffness, muscle pain, skull and neck aching, carpal tunnel syndrome and restricted mobility of the affected part. The average time of the appearance of symptoms is about four weeks. Studies showed significantly higher rates of carpal tunnel syndrome following the use of anastrozole and exemestane compared to tamoxifen. Laboratory tests and imaging examinations are normal and necessary to exclude conditions that require immediate attention, such as traumatic, inflammatory, autoimmune arthritis, fracture, mechanical derangement, or tumor.


The pathogenic mechanism of AIs-induced arthralgia has different origins:


-Firstly, we know that estrogens and aromatization particularly, are associated with water retention and edema. This is a beneficial environment for the synovial cavity, since joints are lubricated, and thus friction is diminished.


-Moreover, studies have shown that estrogens are natural pain inhibitory receptors, an evolutionary adaptation to help women to better tolerate the pain during childbirth, when estrogen levels are particularly high.


Thus, estrogen deprivation makes the body more vulnerable to pain sensation and decreases threshold for painful stimuli. The perception of pain is more intense. Scientific evidence shows that AIs do not cause actual harm to the joint destruction of articular surfaces, cartilage, ligaments and muscles surrounding. Therefore, discontinuation of the AIs leads to prompt relief of symptoms.


The most appropriate intervention for pain management in AIs-associated arthralgia may be a combination of pharmacologic approaches in conjunction with dietary supplements for bone protection.


As an alternative treatment the use of SERMs is proposed, since these drugs act as a selective estrogenic on the liver and as an anti-estrogenic on the breast tissue. Tamoxifen occupies the estradiol receptor, without blocking the action of aromatase enzyme in the breast and subcutaneous tissues.


Estrogens still can circulate in blood, therefore synovial cavity of joints do not become dry.


The use of hyaluronic acid in liquid form acts as a moisturizer, when combined with hydrolyzed collagen.


Also, glucosamine-chondroitin-MSM complex helps. These are glycoproteins, which moisturize the articular surfaces and the hyaline cartilage. The use of ascorbic acid in ester form of vitamin C contributes to the biosynthesis of collagen protein.


Non-steroidal anti-inflammatory drugs (NSAIDs), on the one hand, suppress the inflammation and pain, since they inhibit inflammatory cytokines (prostaglandins). On the contrary, they sabotage the phenomenon of muscle inflammation and also account for increased risk of upper gastrointestinal bleeding (stomach, duodenum). As an alternative, omega-3 PUFAs (DHA/EPA) coming from fish oil may be used.




Estrogens directly affect a wide range of bodily functions, with positive and negative effects depending on the targeted organ. Estrogen receptors exist in various organs, including the anterior and posterior segment of the eye and lacrimal gland. Thus, changes in estrogenic activity affect the visual function both centrally (optic nerve) and distally.


Selective estrogen receptor modulators (SERMs) such as tamoxifen and clomiphene act on the estrogen receptors and may exert agonistic or antagonistic activity, depending on the targeted tissue. In the eye, they have the ability to inhibit the action of estrogens, causing various symptoms.


These include flashing lights (photopsia), blurred vision, color perception changes (dyschromatopsia), increased sensitivity to light (photophobia), and images in the visual field, reduced peripheral vision and scotomas.


A rare but serious complication is “tamoxifen retinopathy,” a disturbance that depends on the total cumulative dose of the drug. It is characterized by bilateral presence of crystalline deposits in the retina with or without macular edema. Tamoxifen can also induce cataracts.


As known, aromatase inhibitors (AIs) are a class of drugs that inhibit the action of the enzyme aromatase, which converts androgens into estrogens. Thus, AIs suppress estrogenic production and are considered potent anti-estrogens in the peripheral tissues. The two types of AIs include suicidal steroidal inhibitors, such as exemestane and non-steroidal inhibitors, such as anastrozole and letrozole.


Ocular side effects occur rarely and are linked to retinal hemorrhage, retinal detachment and disorders in color vision, similar to those caused by SERMs. The side effects of SERMs and AI in the eye are dose- and time-dependent. It should be noted that the ocular toxicities of tamoxifen, such as macular edema or retinal deposits, are often reversible, if the drug is discontinued or the dosage reduced.


But, as with all medicines, every individual’s susceptibility also plays a role, just like the rest of the concurrent eye problems (dry eye, myopia-short sighted, increased intraocular pressure) do too. Therefore, the use of SERMs and AI should be stopped immediately after the occurrence of visual disturbances and a full ophthalmologic monitoring should follow.


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8. Final results of the randomized trial of exercise intervention vs. usual care for breast cancer patients with aromatase inhibitor to prevent and improve the aromatase inhibitor induced arthralgia. Tamaki, M Takaesu, S Nagamine, S Terukina, Y Kamada, K Uehara, N Takigami, M Arakaki, K Yamashiro, M Miyashita, T Ishida, KM McNamara, N Tamaki and H Sasano. Cancer Research Feb 2018Volume 78, Issue 4 Supplement


9. Breast Cancer Medications and Vision: Effects of Treatments for Early-stage Disease. Alvin Eisner and Shiuh-Wen LuohCurr Eye Res. 2011 Oct; 36(10): 867-885.


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11. A rare case: Branch retinal vein occlusion associated with the use of tamoxifen. Demirci NS, Erdem GU, Uçgun N&, Bozkaya Y, Ozdemir NY, Dogan M, Zengin N. J Can Res Ther 2019;15:722-4


George Touliatos, MD is an author, lecturer, champion competitive bodybuilder and expert in medical prevention regarding PED use in sports. Dr. Touliatos specializes in medical biopathology and is the medical associate of Orthobiotiki.gr and Medihall.gr, Age Management and Preventive Clinics in Athens, Greece. Heis the author of four Greek books on bodybuilding, has extensively developed articles for www.anabolic.org and is the medical associate for the book Anabolics, 11th Edition (2017). Dr. Touliatos has been a columnist for the Greek editions of MuscleMag and Muscular Development magazines, and has participated in several seminars across Greece and Cyprus, making numerous TV and radio appearances, doing interviews in print and online. His personal website is https://gtoul.com/



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