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Will lowering my estrogen levels, while keeping my androgen levels constant, hurt or hinder my muscle gains? This is a question I see alot of...In the past AI's were a must have in almost every cycle...Some still think that way. The use of agents to lower estrogen levels (aromatase inhibitors), or to block estrogen action at the receptor (estrogen receptor antagonists), has become quite en vogue lately. Personally, I think they are overused and could hinder muscle mass gains. I have discussed before the potential suppressant effects of anti-estrogen compounds on GH and IGF-1 production. But beyond that, there may be direct beneficial effects of estrogen on androgen activity in muscle that may be blocked by anti-estrogens. One important mechanism involved in muscle growth is the formation of NADPH, which is used as the prime source of energy (reducing power) in anabolic processes. Androgens are well known to stimulate one of the key enzymes involved in the formation of NADPH, called glucose 6-phosphate dehydrogenase. Furthermore, glucose 6-phosphate dehydrogenase is also involved in the production of raw materials for nucleic acid synthesis. Nucleic acids biosynthesis is required at high rates in regenerating tissues. One of the most widely documented effects of androgens is stimulation of glucose 6-phosphate dehydrogenase, and this is thought to be key to their anabolic activity. A recent study found however that without estrogens, androgens are not able to fully exert their stimulatory activity on this enzyme. The authors conclude that androgens and estrogens may exert synergistic effects on skeletal muscle. (Max SR ,"Androgen-estrogen synergy in rat levator ani muscle: glucose-6-phosphate dehydrogenase", Mol Cell Endocrinol 1984 Dec;38(2-3):103-7) The same author also found another mechanism by which estrogens may increase the activity of androgens in skeletal muscle. He used rats that had their testes removed and then administered androgens to them, with and without estrogens. What he found was that estrogens caused a very substantial increase in the binding of androgens to their receptors. He hypothesized that this is due either to a greater synthesis, or a decreased degradation of, androgen receptors. (Rance NE, Max SR, "Modulation of the cytosolic androgen receptor in striated muscle by sex steroids", Endocrinology 1984 Sep;115(3):862-6) So you see that it may be time for bodybuilders to rethink the use of anti-estrogen compounds. I think that a risk to benefit determination has to be considered, and unless someone feels that he is a high-risk case for estrogen related side effects, he probably should pass on the anti-estrogens.