Hormones and metabolic modulators are a group of substances that are not limited to hormones themselves. This group of substances often modifies how hormones work, either by blocking the action of a hormone or by increasing the activity of a hormone. There are many substances that fall into the category of “Hormone or Metabolic Modulator.” Some of these substances are discussed here.

Aromatase inhibitors are hormone modulators that bind to aromatase and stop it from working. The aromatase enzyme is responsible for synthesizing estrogen in the body by turning testosterone and other androgens into estrogen. Aromatase inhibitors like exemestane, anastrozole, and letrozole are FDA-approved drugs that are used to treat some kinds of breast cancer. Some cancers grow faster in the presence of estrogen. By blocking the synthesis of estrogen there is less estrogen circulating in the body.

Likewise, selective estrogen receptor modulators (SERMs) (like tamoxifen and raloxifene) bind to estrogen receptors in breast tissue and block the effect of estrogen. Athletes in strength sports, or athletes who are trying to prevent the effects of estrogen on their bodies, might abuse aromatase inhibitors or SERMs.

Clomiphene is prohibited at all times as an anti-estrogenic substance. A selective estrogen receptor modulator (SERM), clomiphene is used in female fertility brand name prescription medications, such as Clomid. In women, clomiphene acts on the pituitary gland to stimulate the release of specific hormones responsible for ovulation. In men, clomiphene can alter testosterone levels by interfering with the negative feedback loop of the hypothalamic–pituitary–gonadal axis. Clomiphene is not FDA-approved for use by men for any condition and TUEs are unlikely to be granted to men who receive off-label prescriptions for clomiphene.

Another group of metabolic modulators are agents that prevent activin receptor IIB activation.

Myostatin is a growth factor that controls and limits the amount of muscle a person makes. Myostatin inhibitors (substances that block the action of myostatin) can cause an increase in muscle mass. A number of experimental compounds that modify myostatin are being evaluated to treat muscle wasting diseases, but there are currently no FDA-approved medications that modulate myostatin.

Other metabolic modulators include substances that affect how the body processes energy. For example, substances that mimic the effects of insulin can change how the body processes sugar, causing a person to burn more or less glucose. Insulin is also anabolic (muscle building), so substances that mimic the effects of insulin could build muscle.

Substances that activate AMP-activated protein kinases, for example AICAR, show promise in protecting cells against oxidative damage during stroke or in certain diseases like diabetes. Similarly, substances that activate peroxisome proliferator activated receptor modulators (PPARs) like GW1516, GW0742, L1655041 are experimental drugs under study to treat diabetes, lipid disorders, and metabolic syndrome. AMP-activated protein kinases and PPARs are experimental drugs with no approved medical use at this time. Despite not being approved for human use, these substances are synthesized by clandestine laboratories around the world.

Meldonium is a drug registered for use in some Baltic countries, but it is not approved for use in the U.S., Canada, or Western Europe. Meldonium has very long urinary excretion times so it is especially difficult to estimate clearance times for this substance.

All of the substances discussed in this section are prohibited in sport at all times. Please consult the Prohibited List for more examples of substances this class.

What you should know: