Estrogen Vaginal Cream

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. Additionally, estrogens have been shown to activate a G protein-coupled receptor, GPR30.

Types

Steroidal

The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3). Estradiol (E2) is the predominant 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.

Nonsteroidal

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

  • 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.

Biosynthesis

Estrogens are produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta. 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. Fat cells also produce estrogen, potentially being the reason why underweight or overweight are risk factors for infertility.

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 and may be necessary for a healthy libido. 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.

  • Structural
    • promote formation of female secondary sex characteristics
    • decelerate height growth
    • 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
  • coagulation
    • 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
  • Hormones
    • increase cortisol, SHBG
  • Gastrointestinal tract
    • reduce bowel motility
    • increase cholesterol in bile
  • Melanin
    • increase pheomelanin, reduce eumelanin
  • Cancer
    • support hormone-sensitive breast cancers (see section below)
  • Lung function
    • promotes lung function by supporting alveoli (in rodents but probably in humans).

Sexual desire is dependent on androgen levels rather than estrogen levels.

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; the same is not true in humans. In humans, the masculinizing 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. As a result, the utility of rodent models for studying human psychosexual differentiation has been questioned.

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.

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.

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 ).

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 men

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