Estrogens

Role of estrogen

Estrogen is the main female sex hormone produced primarily by the ovaries but it is also synthesised in smaller amounts in the adrenal glands and adipose (fat) tissue from androgens in these cells.  Estrogen is responsible for the development of female secondary sexual characteristics, including breast development and body shape and also the regulation of the menstrual cycle, including ovulation, endometrial thickening, and vaginal thickening and secretions. 

Estrogen has actions in various other metabolic processes including maintaining bone density, which is why it protects against osteoporosis in post-menopausal women.  Estrogen also regulates lipid (fat) metabolism to maintain cholesterol levels within normal levels, by reducing LDL cholesterol and increasing HDL cholesterol, thereby offering some protection against cardiovascular disease in post-menopausal women.  

Estrogen is a steroid hormone and works by entering cells of the target tissues, such as ovary, breast and uterus, and binding to its receptor.  The hormone-receptor complex then binds to DNA within the nucleus of the cell to regulate expression of certain genes involved in the production of proteins required for estrogen-dependent processes. 

Different forms of estrogen

Estrogen is not a single hormone but is classed as a group of hormones that exists in various different forms and with different potencies.   They are all synthesised from androgens, particularly androsteinedione, by the enzyme aromatase.

• Estradiol, specifically 17-beta-estradiol or E2, is the major and most active form of natural estrogen in the body.  It is responsible for the main actions of estrogen.  The level of estradiol rises through the first half of the menstrual cycle, reaching a peak just before ovulation and then begins to fall, but reaches another peak during the luteal phase of the menstrual cycle, falling again during the follicular stage before menstruation.  At menopause the production of estradiol ceases and levels drop to a low but constant level.
• Estrone or E1 becomes the most prominent form of natural estrogen during menopause, as estradiol drops, and is produced primarily in the adrenal glands.  Estrone is readily converted into a long lasting form estrone sulphate which concentrates in breast tissue of post-menopausal women and is thought to be involved the development of breast cancer, by being converted to estradiol.  Estrone can also cause breast tenderness or pain, nausea, headache, hypertension, and leg cramps.¹
• Estriol or E3, which is the weakest of the three natural forms of oestrogen.  It is the prominent form of estogen during pregnancy and is produced by the placenta, but plays no significant role in non-pregnant women as it is mild, short acting and normally present in small amounts.
• Conjugated oestrogens are a mixture of several different forms of estrogen (at least 10) isolated from horse urine.  They contain mainly forms of estrogen that are in the sulphate form and can be easily absorbed and converted to the active form estradiol.²
• oestradiol valerate is a prodrug (or precursor) of natural human oestradiol and is converted to 17-beta-estradiol by esterase enzymes in the blood and liver.  It is an effective form of estrogen used for intramuscular administration as it is absorbed slowly and lasts longer that estradiol itself. 
• Ethinyloestradiol is a synthetic form of 17-beta-estradiol that is more resistant to metabolism in the liver than natural estradiol but has the same biological activity. 

Delivery methods of oestrogen for HRT

Estrogen hormone replacement therapy is available in several different preparations and routes of administration.  These include:

• Oral preparations which are subjected to metabolism by the liver and this can cause problems in women with liver problems.  Also the amount of estrogen remaining in the blood after first pass through the liver may not actually correlate with the amount taken due to problems with absorption in some women.  Oral estrogen is associated with side effects, such as painful swollen breasts, nausea, headache and vaginal discharge.   There are also risks associated with estrogen therapy, including risk of stroke, heart attack, blood clots and breast and endometrial cancer.  For these reasons oral estrogen therapy is usually combined with a progestagen.
• Skin patches allow oestrogen to diffuse through the skin and into the blood.  This form of administration allows for lower doses to be used, as estrogen bypasses liver and is therefore, not subject to first pass metabolism by the liver.  It also provides more constant blood levels as it diffuses into the blood at a steady rate.  Also since estrogen in skin patches bypasses the liver they can be used in women with liver problems.  Various forms of estrogen can be used including estradiol, the natural and most active form of estrogen, and estradiol valerate.
• Topical creams containing oestriol or conjugated estrogens are applied into the vagina and used for topical treatment of urogenital symptoms of menopause such as atrophic vaginitis, as it is released slowly and acts directly on the vaginal skin, with little absorption into the blood.
• Topical transdermal gel containing estradiol, which is rubbed into the skin so that the estrogen diffused through the skin directly into the blood circulation.
• Pessaries containing estradiol inserted into the vagina, where it dissolves slowly releasing estradiol to act locally on the vaginal skin.  

References

1. Bhavnani BR. Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism.  Proc Soc Exp Biol Med 1998: 217; 6-16
2. Pasqualini JR, Chetrite G, Nguyen B-L, Maloche C et al.  Estrone sulfate-sulfatase and 17β-hydroxysteroid dehydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence.  J Steroid biochem Mol Biol 1995: 53; 407-412.