Estrogen

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Estrogens (U.S., otherwise oestrogens or œstrogens) are a group of steroid compounds, named for their importance in the estrous cycle, and functioning as the primary female sex hormone, their name comes from estrus/oistros (period of fertility for female mammals) + gen/gonos = to generate.

Estrogens are used as part of some oral contraceptives, in estrogen replacement therapy for postmenopausal women, and in hormone replacement therapy for trans women.

Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors which in turn up-regulate the expression of many genes.[1] Additionally, estrogens have been shown to activate a G protein-coupled receptor, GPR30.[2]

Contents

Typical Estrogens, Chemical and Tradenames

There are a number of common forms of estrogen (steroid sex hormones) used within MTF hormonal re-assignment. They are all derived from cholesterol. The exact type and dosage of estrogen for HRT must be determined and discussed with your MD, endocrinologist or therapist. The chosen levels will be a function of your initial blood chemistry with changes, as necessary, based on ongoing monitoring of a defined frequency, often 3 to 6 months apart.

The initial dosages of estrogen are normally higher in pre-operative MTF transsexuals because of the need to overcome the high level of testosterone in the body. They are then reduced post operatively. Both pre- and postoperatively the dosage should be discussed with your physician.

Estrogens are available in a number of forms: tablets, patches, injectables and gels. One, or a combination of these, will normally be used for any hormonal re-assignment. They come in naturally occuring or chemically synthesized forms and they can be modified further to alter the way they are incorporated into the body, changing the rate of release and their effectiveness. The practice of increasing the hormone's uptake into the body by chemically altering the base molecule is well established, but this can also lead to an increased risk of side effects and complications.

There are three main routes of entry of chemicals into the body. These are oral (taken by mouth), absorbtion (as in through the skin) or direct (as in injection into the body).

Most estrogens are not administered in their pure chemical form, but come as an active ingredient within a carrier or binder. Commonly used are: lactose, starch, titanium dioxide, colourants or a miscible oil in injectibles


Steroidal

The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3). Estradiol (E2) is the predominate form in nonpregnant females, estrone is produced during menopause, and estriol is the primary estrogen of pregnancy. In the body these are all produced from androgens through actions of enzymes.

  • From menarche to menopause the primary estrogen is 17β-estradiol. In postmenopausal women more estrone is present than estradiol.
  • Estradiol is produced from testosterone and estrone from androstenedione by aromatase.
  • Estrone is weaker than estradiol.

Premarin, a commonly prescribed estrogenic drug, contains the steroidal estrogens equilin and equilenin, in addition to estrone sulfate but due to its health risk, more genetic estrogen named Progynova (estradiol valerate) are now more often prescribed.[citation needed]

Nonsteroidal

A range of synthetic and natural substances have been identified that also possess estrogenic activity.[3]

  • Synthetic substances of this kind are known as xenoestrogens.
  • Plant products with estrogenic activity are called phytoestrogens.
  • Those produced by fungi are known as mycoestrogens.

Unlike estrogens produced by mammals, these substances are not necessarily steroids.

Conjugated Estrogens

Conjugated Estrogens are naturally occuring compounds. They are found in all female animals and can be obtained by reducing and distilling the urine of pregnant females. They are manufactured to be water soluble and carried in a base which is easily dissolved in the gastrointestinal tract. Estradiol, Estrone and Estirol are basically the same molecule with different functional groups and only differ slightly chemically.

Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionised in body fluids, which favour excretion through the kidneys.

The most commonly used conjugated estrogen is available in tablet form with the trade name PREMARIN. This is a mixture of estrogens, obtained exclusively from natural sources, blended to represent the average composition of material derived from pregnant mares' urine. It contains the sodium salts of water-soluble sulphate esters of estrone, equilin, and 17 alpha-dihydroequilin, together with minor levels of other derivatives.

The dosage is commonally given in milligrams (mg).

Estradiol

Estradiol(17β-estradiol) is one of the naturally occuring sex hormones used in hormone replacement and MTF Hormonal re-assignment therapy. It is available in a number of forms as oral/sublingual tablets, transdermal patches, injections and as creams or gels.

- Oral versions

  • Estrace in 0.5, 1 and 2mg tablets
  • Activella (a tablet combined with progestin)0.5 or 1mg tablets
  • Estrofem 1mg or 2mg tablets

- Transdermal preparation

Transdermal application of hormones in hormonal reassignment is well established and is used widely to deliver estrogens into the blood stream via the direct absorbtion of the active ingredient. The low dosages are "relatively safe" compared to other means of HRT addition, as the majority of the active ingredient is utilized in the body without undergoing a first pass through the liver, reducing the impact on this vital organs.

Transdermal patches are normally worn for up to three days while the active ingredient is released at a steady daily rate into the bloodstream. They are used both pre and post operatively.

  • Alora in a delivery rate of 0.05, 0.075 and 0.1 mg per day
  • Climara in 3.8, 5.9 or 7.6mg patches
  • Vivelle in delivery rates of 0.025, 0.0375, 0.05, 0.075 and 0.1 mg/day.
  • Etraderm in 50 or 100 mcg
  • Menostar in 14mcg per day (Available US only)

- Ointments

Topical Ointments and gels are becoming increasingly popular as hormone delivery methods in hormonal reassignment. Both naturally ocurring estrogens and synthetics can be applied this way. They are applied to the skin and the active ingredient is absorbed directly into the bloodstream. The ointment or gel is typically supplied in a sachet and applied to the thigh area as direct application to the breast or genital region is NOT recommended.

- Injection

Injections can be used to directly add estrogen into the body either as a monthly or three monthly injection. It is not usual to use injectable pellets as now commonly used in birth control for women.

Needles offer a particular health hazard of their own and good hygiene practices must always be observed. Injectible estrogens are more commonly used in the North American continent than Europe.

  • Lunelle is one such example of an injectible estrogen and contains estradiol cypionate, as does Depo-Estradiol

Ethinyl Estradiol

Ethinyl Estradiol (19-nor-17a-pregna-1,3,5(10)- trien -20-yne-3,17-diol) is the most potent form of estrogen synthesised by man. It's major use is in the contraceptive pill where combined with Levonorgestrel. It prevents pregnancy by preventing ovulation (egg release). It is extremely effective and as such the prescribed dosage is much lower than conjugated estrogens and is prescribed in micrograms (mcg or µg)

It is available in tablet form, normally under the name of Ethinyl Estradiol, although a variety of trade names exist when combined with other steroid chemicals in the contraceptive pill

Estradiol Valerate

Estradiol Valerate; designated chemically as estra-1,3,5(10)-triene-3, 17-diol(17b)-, 17-pentanoate is a chemically modified version of naturally occuring estradiol and is used extensively as HRT in post menopausal women.

It is available in both tablet, transdermal patches or injectable forms under trade names such as Progynova or Delestrogen. Tablets are normally available in 1 or 2 mg blister packs, patches in 50 or 100 mg (which release into the blood stream over a time period) and injectibles in 40mg active ingredient vials.

Biosynthesis

Estrogens are produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries. Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts. These secondary sources of estrogens are especially important in postmenopausal women.

In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of moderate androgenic activity. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted to estrone or estradiol, either immediately or through testosterone. The conversion of testosterone to estradiol, and of androstenedione to estrone, is catalyzed by the enzyme aromatase.

Estradiol levels vary through the menstrual cycle, with levels highest just before ovulation.

Function

While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. They promote the development of female secondary sexual characteristics, such as breasts, and are also involved in the thickening of the endometrium and other aspects of regulating the menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important to the maturation of sperm[4][5][6] and may be necessary for a healthy libido.[7][8] Furthermore, there are several other structural changes induced by estrogen in addition to other functions. In dentistry, it reduces hyperkeratinization of the gingiva and increase vascular permeability, exudation, and edema.[citation needed]

  • Structural
    • promote formation of female secondary sex characteristics
    • decelerate height growth[9]
    • accelerate metabolism (burn fat)
    • reduce muscle mass
    • stimulate endometrial growth
    • increase uterine growth
    • increase vaginal lubrication
    • thicken the vaginal wall
    • maintenance of vessel and skin
    • reduce bone resorption, increase bone formation
    • morphic change (endomorphic -> mesomorphic -> ectomorphic)
  • protein synthesis
    • increase hepatic production of binding proteins
    • increase circulating level of factors 2, 7, 9, 10, plasminogen
    • decrease antithrombin III
    • increase platelet adhesiveness
  • Lipid
    • increase HDL, triglyceride
    • decrease LDL, fat deposition
  • Fluid balance
    • salt (sodium) and water retention [citation needed]
  • Hormones
    • increase cortisol, SHBG
  • Gastrointestinal tract
    • reduce bowel motility
    • increase cholesterol in bile
  • Melanin
    • increase pheomelanin, reduce eumelanin
  • Cancer
  • Lung function
    • promotes lung function by supporting alveoli (in rodents but probably in humans).[10]

Sexual desire is dependent on androgen levels rather than estrogen levels.[11]

Fetal development

In mice, estrogens (which are locally aromatized from androgens in the brain) play an important role in psychosexual differentiation, for example, by masculinizing territorial behavior;[12] the same is not true in humans.[13] In humans, the masculinizaing effects of prenatal androgens on behavior (and other tissues, with the possible exception of effects on bone) appear to act exclusively through the androgen receptor.[14] As a result, the utility of rodent models for studying human psychosexual differentiation has been questioned.[15]

Mental health

Estrogen is considered to play a significant role in women’s mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlates with significant mood lowering. Clinical recovery from postpartum, perimenopause, and postmenopause depression has been shown to be effective after levels of estrogen were stabilized and/or restored.[16][17]

Low estrogen levels in male lab mice may be one cause of obsessive–compulsive disorder (OCD). When estrogen levels were raised through the increased activity of the enzyme aromatase in male lab mice, OCD rituals were dramatically decreased. Hypothalamic protein levels in the gene COMT are enhanced by increasing estrogen levels which is believed to return mice that displayed OCD rituals to normal activity. Aromatase deficiency is ultimately suspected which is involved in the synthesis of estrogen in humans and has therapeutic implications in humans having obsessive-compulsive disorder.[18]

Medical applications

Oral contraceptives

Since estrogen circulating in the blood can negatively feed-back to reduce circulating levels of FSH and LH, most oral contraceptives contain a synthetic estrogen, along with a synthetic progestin. Even in men, the major hormone involved in LH feedback is estradiol, not testosterone.

Hormone replacement therapy

As more fully discussed in the article on Hormone replacement therapy, estrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis as well as treat the symptoms of menopause such as hot flashes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50-70% and spinal bone density increases by ~5% in those women treated with estrogen within 3 years of the onset of menopause and for 5–10 years thereafter.

Before the specific dangers of conjugated equine estrogens were well understood, standard therapy was 0.625 mg/day of conjugated equine estrogens (such as Premarin). There are, however, risks associated with conjugated equine estrogen therapy. Among the older postmenopausal women studied as part of the Women's Health Initiative (WHI), an orally-administered conjugated equine estrogen supplement was found to be associated with an increased risk of dangerous blood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated equine estrogens (Premarin alone and with medroxyprogesterone acetate as PremPro).[19]

In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated equine estrogens. Hormone replacement therapy has favorable effects on serum cholesterol levels, and when initiated immediately upon menopause may reduce the incidence of cardiovascular disease, although this hypothesis has yet to be tested in randomized trials. Estrogen appears to have a protector effect on atherosclerosis : it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.

Research is underway to determine if risks of estrogen supplement use are the same for all methods of delivery. In particular, estrogen applied topically may have a different spectrum of side-effects than when administered orally,[20] and transdermal oestrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history of thrombo-embolic disease.

Estrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism, castration, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppress lactation after child birth.

Breast cancer

About 80% of breast cancers, once established, rely on supplies of the hormone estrogen to grow: they are known as hormone-sensitive or hormone-receptor-positive cancers. Suppression of production in the body of estrogen is a treatment for these cancers.

Recently researchers have discovered that the common table mushroom has anti-aromatase[21] properties and therefore possible anti-estrogen activity. Clinical trials have begun in the United States looking into whether the table mushroom can prevent breast cancer in people.[22] A recent study has highlighted the importance of this research. In 2009, a case-control study of the eating habits of 2,018 women, revealed that women who consumed mushrooms had an approximately 50% lower incidence of breast cancer. Women who consumed mushrooms and green tea had a 90% lower incidence of breast cancer.[23]

Hormone-receptor-positive breast cancers are treated with drugs which suppress production in the body of estrogen.[24] This technique, in the context of treatment of breast cancer, is known variously as hormonal therapy, hormone therapy, or anti-estrogen therapy (not to be confused with hormone replacement therapy). Certain foods such as soy may also suppress the proliferative effects of estrogen and are used as an alternative to hormone therapy.[25]

Prostate cancer

Under certain circumstances, estrogen may also be used in males for treatment of prostate cancer.[26]

Miscellaneous

In humans and mice, estrogen promotes wound healing.[27]

At one time, estrogen was used to induce growth attenuation in tall girls.[9] Recently, estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.[28]

Most recently, estrogen has been used in experimental research as a way to treat patients suffering from bulimia nervosa, in addition to Cognitive Behavioral Therapy, which is the established standard for treatment in bulimia cases. The estrogen research hypothesizes that the disease may be linked to a hormonal imbalance in the brain.[29]

Estrogen has also been used in studies which indicate that it may be an effective drug for use in the treatment of traumatic liver injury.[30]

Health risks and warning labels

Hyperestrogenemia (elevated levels of estrogen) may be a result of exogenous administration of estrogen or estrogen-like substances, or may be a result of physiologic conditions such as pregnancy. Any of these causes is linked with an increase in the risk of thrombosis. [31]

The labeling of estrogen-only products in the U.S. includes a boxed warning that unopposed estrogen (without progestagen) therapy increases the risk of endometrial cancer.

Based on a review of data from the WHI, on January 8, 2003 the FDA changed the labeling of all estrogen and estrogen with progestin products for use by postmenopausal women to include a new boxed warning about cardiovascular and other risks. The estrogen-alone substudy of the WHI reported an increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using 0.625 mg of Premarin conjugated equine estrogens (CEE). The estrogen-plus-progestin substudy of the WHI reported an increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and DVT in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using PremPro, which is 0.625 mg of CEE with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).[32][33][34]

Cosmetics

Some hair shampoos on the market include estrogens and placental extracts; others contain phytoestrogens. There are case reports of young children developing breasts after exposure to these shampoos.[35] On September 9, 1993, the FDA determined that not all topically-applied hormone-containing drug products for OTC human use are generally recognized as safe and effective and are misbranded. An accompanying proposed rule deals with cosmetics, concluding that any use of natural estrogens in a cosmetic product makes the product an unapproved new drug and that any cosmetic using the term "hormone" in the text of its labeling or in its ingredient statement makes an implied drug claim, subjecting such a product to regulatory action.[36]

In addition to being considered misbranded drugs, products claiming to contain placental extract may also be deemed to be misbranded cosmetics if the extract has been prepared from placentas from which the hormones and other biologically active substances have been removed and the extracted substance consists principally of protein. The FDA recommends that this substance be identified by a name other than "placental extract" and describing its composition more accurately because consumers associate the name "placental extract" with a therapeutic use of some biological activity.[36]

History

In 1929 Adolf Butenandt and Edward Adelbert Doisy independently isolated and determined the structure of estrogen.[37] Thereafter, the market for hormonal drug research opened up.

The “first orally effective estrogen”, Emmenin, derived from the late-pregnancy urine of Canadian women, was introduced in 1930 by Collip and Ayerst Laboratories. Estrogens are not water-soluble and cannot be given orally, but the urine was found to contain estriol glucuronide which is water soluble and becomes active in the body after hydrolization.

Scientists continued to search for new sources of estrogen because of concerns associated with the practicality of introducing the drug into the market. At the same time, a German pharmaceutical drug company, formulated a similar product as Emmenin that was introduced to German women to treat menopausal symptoms.

In 1938, British scientists obtained a patent on a newly formulated nonsteroidal estrogen, diethylstilbestrol (DES), that was cheaper and more powerful than the previously manufactured estrogens. Soon after, concerns over the side effects of DES were raised in scientific journals while the drug manufacturers came together to lobby for governmental approval of DES. It was only until 1941 when estrogen therapy was finally approved by the Food and Drug Administration (FDA) for the treatment of menopausal symptoms. [38]

See also

References

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