Ethynylestradiol (EE2) ELISA kit

One of the more popular modern medications is a synthetic hormone called ethynylestradiol (EE2). It is mostly used for oral contraceptives, hormone replacement therapy (HRT), and in the treatment of a variety of hormone-dependent disorders like endometriosis and polycystic ovary syndrome (PCOS). The chemical formula for EE2 is an abridged form of estradiol, the natural ovarian steroid, and has a 17-alpha extra ethinyl group. This change drastically increases the bioavailability and stability of the compound when taken in the mouth, even in low dosages. EE2 was a game changer in pharmacology as it solved the problem of oral estrogen therapy while offering an effective long-acting replacement for natural estrogens. But as use of the substance has grown, so too have concerns about its environmental and health hazards.

Figure 1. Structures of 17-estradiol (E2) and 17-ethinylestradiol (EE2). (Sources: Rohn KJ, et al. 2012)

Ethynylestradiol, a synthetic steroid with similar structure to natural oestrogens, but modified to improve stability and effectiveness. This is due to an ethynyl group (CC) added to the 17-alpha carbon of the estradiol backbone, and this is the main distinction between EE2 and the natural form. This change of structure stops its liver-mediated degrading of the drug very quickly, making it more bioavailable, allowing less drug to do the desired biological effects. Its produced compound is more stable against enzymatic metabolism, and can be used efficiently through the mouth without regular doses. Its characteristic is crucial for its use in oral contraceptives, for which it is convenient to dose daily and necessary for success. EE2 is biologically active because it binds to estrogen receptors (ER and ER) in every body tissue, from the reproductive system to the breast to the brain and bones. Once bound to these receptors, EE2 engages the estrogen receptor signaling network and can cause a range of physiological effects. Estrogen receptor – activated by EE2, gene transcription controlling cell proliferation, metabolism and reproduction. As an oral contraceptive, EE2 causes ovulation to be halted, cervical mucus modified to make it less permeabilised by sperm and endometrial lining thinned so it's less responsive to a fertilised egg. This three-pronged strategy works really well to prevent pregnancy. EE2 is also involved in the regulation of menopausal symptoms like hot flashes and vaginal dryness, by compensating for low levels of estrogen in the body at menopause. Although EE2 is best known as a contraceptive and a therapeutic agent, it's the powerful estrogenic action that makes it effective for treating PCOS and endometriosis (both disorders often related to hormonal deficiencies). Also, EE2 is sometimes combined with other drugs to cure hormone-responsive cancers like prostate and breast cancer, where its regulation of oestrogen pathways can control the disease. Clinically flexible and long-acting, EE2 is a medicine in everyday use. But even though it's been well-studied, the side effects and long-term effects of synthetic oestrogen use are an ongoing issue. The biggest usage of Ethynylestradiol is in birth control products along with the synthetic progestins. This combination is common in oral contraceptives pills (OCPs). The EE2 and progestin pair in a way that helps to prevent pregnancy. EE2 does more than stop ovulation, it also thickens cervical mucus and thus puts sperm at a disadvantage. It also changes the lining of the endometrium so it becomes infelicitous to implantation if fertilisation takes place. A combination oral contraceptive (COC) isn't just for getting pregnant – it's also used for managing menstruation, menstrual cramping, and acne. The other uses of EE2 in hormone replacement therapy (HRT) are as contraception, especially for women who are menopausal. Oestrogen naturally stalls after menopause and can lead to everything from hot flashes and night sweats to vagina dryness. As an alternative to oestrogen, EE2 diminishes these symptoms and makes menopausal women's lives easier. EE2 is also occasionally prescribed in low doses to treat other hormone-related disorders like PCOS and endometriosis. EE2 regulates menstrual cycles in these cases and decreases the symptoms of excess oestrogen secretion (ovarian cysts, pain in the pelvis). In the treatment of hormone-responsive cancers, like some types of breast and prostate cancer, EE2 could be administered to reduce the effects of oestrogen on cancer cells. As oestrogen is implicated in these cancers, by modulating oestrogen signalling, EE2 can slow or prevent the development of tumours. But the cancer therapy with EE2 is very specific, and typically only in a limited number of patients in whom the cancer cells are estrogen receptor positive.

EE2's medical effects are known but, because it is used so much, there are real worries about its environment, especially in aquatic systems. Since EE2 is a synthetic, it is difficult to eliminate in the environment, and it has been found in rivers, lakes and groundwater. It does this in the natural world because it's chemically inert, resistant to natural degradation. EE2 diffuses into the environment from unused medications and in the faeces of patients who've used oral contraceptives. Once EE2 gets into wastewater, it can enter municipal treatment plants, and eventually river and stream where it can be harmful to aquatic life. The effects of EE2 exposure in the environment can also be profound, with fish and amphibian reproductive systems among those that have been documented. Low-EE2 fish were found to have reduced sex ratios, feminisation of males, and decreased fertility. These changes happen because EE2 acts just like natural oestrogens by interacting with oestrogen receptors in these animals and interfering with their reproduction. This is particularly a problem in places where estrogenic pollutants accumulate, as it will create an asymmetric sex ratio, which can hamper species. Even amphibians like frogs can develop abnormal sexual behaviour in EE2-infested water. And bioaccumulation of EE2 through the food chain can be toxic to other animals and humans. While EE2 concentrations in drinking water are relatively small, high doses of estrogenic chemicals can be cumulative. A few have proposed a causal connection between chronic low-dose EE2 exposure and infertility, breast cancer and other hormone-related human disorders. The issue is especially acute because EE2 is ubiquitous in water supply – researchers have found levels of the chemical in surface and groundwater around the world. The effects of EE2 on the environment are hugely important, but the compound's health effects have also been much studied and debated. As an active oestrogen, EE2 has the potential to interfere with the body's natural hormonal balance, and it has been worried about the potential long-term effects on humans, particularly when regularly administered. Although EE2 is typically safe and effective when used as directed, the potential hormonal interference can have side effects. In the presence of EE2-containing contraceptives, some have experienced blood clots, strokes and some forms of cancer (most commonly breast and cervical cancers). But these are generally regarded as minimal and are offset by the use of birth control and alleviation of symptoms for hormone-dysfunction patients. The other problem is that EE2 may be connected to endocrine disorders. EE2 is an endocrine disruptor and can mess with the body's natural hormone systems, altering normal reproduction. Research has shown that even EE2 at low levels can be significant for reproductive health in humans and animals. These effects are currently being investigated, but there are researchers who believe that long-term use of synthetic oestrogens such as EE2 can cause hormone-related cancers and other reproductive problems later in life. Because of these risks to human and natural health, the demand for greater control and surveillance of EE2 in drinking water and sewage systems has come in. To that, some countries and regulatory authorities have increased regulations for monitoring pharmaceuticals in water. These are all attempts to reduce exposures to EE2 from water, as well as other environmentally friendly forms of contraception and hormone therapy.

17α-Ethynylestradiol
Ethinylestradiol
EE2
17α-Ethynylestradiol
Ethynyl estradiol
3,17β-Dihydroxyestra-1,3,5(10)-trien-17-yl acetate
1,3,5(10)-Estratrien-3-ol, 17-ethynyl-17β-hydroxy