Estrogen Replacement Therapy (ERT)

By Meryl Glassman

 

What is ERT?

Estrogen replacement therapy is the use of commercial estrogen preparations in women who are not producing normal (pre-menopausal) levels of estrogen. Because ERT can have certain undesirable side effects (which will be described in more detail later), Hormone Replacement Therapy (HRT) is more commonly used. The only difference between ERT and HRT is the addition of a synthetic progesterone to counteract these undesirable side effects.

ERT is most commonly prescribed to the following populations:

 

What is the role of estrogen in the body and the reproductive system?

The reproductive system of the female consists of the ovaries (the organs that house the eggs, or ovum), the uterus, and the vagina, as seen below. (diagram to come)

The ovaries contain follicles, in which the ovum develop. Each month, one ovum is released into the fallopian tubes at ovulation, which occurs at day 14 in a woman's menstrual cycle (pictured below)(diagram to come). If the ovum is fertilized by a sperm in the fallopian tube, it becomes implanted in the lining of the uterus and begins to grow and develop. If the ovum is not fertilized, it is washed away with the uterine lining (the endometrium) during menstruation, which occurs from days 1-5 of the cycle.

There are three phases of the menstrual cycle: the follicular phase, the luteal phase, and menstruation. During the follicular phase, which lasts from days 1 to 13, the hypothalamus secretes Follicle Stimulating Releasing Factor (FSRH) and Leutinizing Hormone Releasing Factor (LRH), which induce the anterior pituitary gland to secrete Follicle-Stimulating Hormone (FSH) and Leutinizing Hormone (LH).

 

FSH and LH stimulate development of the ovum, and induce the ovaries to release estradiol, a form of estrogen. This presence of estradiol acts on the hypothalamus and pituitary to cause the release of more estradiol. When the ovary begins to release progesterone in the luteal phase, the anterior pituitary halts secretion of LH and FSH. When estrogen and progesterone levels fall on day 28, menstruation begins.

There are three different types of estrogens:

 

 

During puberty, estrogens induce the development of the uterus, the fallopian tubes, and the breasts. Estrogens cause the cells of the endometrial surface of the uterus to proliferate rapidly, and a sudden decrease in estrogens (and progesterone) cause the uterus to shed its lining during menstruation. Estrogens also induce deposition of calcium and phosphate in the bones, and therefore help to maintain bone density.

Menopause

Menopause is normally broken down into three stages:

Perimenopause: This is the period immediately before menopause in which the ovarian function begins to decrease, estrogen secretion is reduced, and menstruation occurs less frequently. It often spans three to five years.

Menopause: This is the permanent cessation of menstruation due to loss of ovarian function; it is marked by the last menstrual period and can only be assessed in retrospect. The average age of menopause is 51 years.

Postmenopause: The period spanning from menopause until death, when many menopausal symptoms may continue.

Although not considered a part of menopause itself, Premenopause is the time between menarche (the first menstrual period) and the onset of perimenopause, when normal ovarian function occurs.

During perimenopause, the number of follicles in the ovaries decreases and less estrogen is synthesized. This disrupts the feedback loop to the hypothalamus and the anterior pituitary, and as a result, levels of FSH and LH rise. In premenopausal women, LH is present in greater amounts than FSH; in postmenopausal women, FSH is present in greater amounts than LH.

Symptoms of Perimenopause, Menopause and Postmenopause

There are physiological and psychological symptoms associated with perimenopause and postmenopause (and are also associated with hysterectomy). They are an indication of the importance of b-estradiol in many organs and systems of the body.

Physiological symptoms

 

Psychological symptoms

 

Considering the undesirable side effects of menopause and decreased estrogen secretion, it is not surprising that much research has been devoted to developing an effective estrogen replacement regimen.

The History of ERT

In the 1920's, most clinicians were aware that menopause was associated with a sharp decline in estrogen secretion by the ovaries. The first research to show that estrogen replacement could alleviate some of the symptoms of menopause was performed in the 1940's. In the 1960's and 1970's, it was discovered that estrogen therapy could reduce the risk of osteoporosis in postmenopausal women.

In 1975, it was announced that ERT was associated with an increased risk of endometrial cancer. Doctors then began prescribing lower levels of estrogen in conjunction with progestins (synthetic progesterones) because this combination was shown not to increase a woman's risk of endometrial cancer. This combination of estrogen and progestin, which is used almost universally to treat menopausal women, is also known as Hormone Replacement Therapy, or HRT.

Each year, over 3 million women in the United States alone take some form of ERT or HRT.

ERT Regimens

Today, most physicians prescribe either continuous (both estrogen and progestin every day) or cyclical (estrogen every day, progestin for 10-12 days each month) HRT. Although cyclical HRT produces withdrawal bleeding for about 5 days each month (similar to a menstrual period), it is prescribed more often because continuous HRT is associated with irregular bleeding which can decrease the likelihood of patient compliance. Estrogens and progestins can be administered transdermally (through a skin patch), subcutaneously (by injection), intravaginally (as a cream), and orally. Oral administration is the most common. Three classes of estrogens are used for estrogen replacement therapy in the Unites States.

Natural estrogens: these are the estrogens as they are found in the human body; they include b-estradiol and estrone (estrone sulfate)

Conjugated estrogens: these are a combination of several different estrogens, including estradiol and estrone

Synthetic estrogens: these are estrogens that are engineered to act more effectively upon estrogen receptors that the naturally occurring estrogens. These include ethinyl estradiol and diethylstilbestrol.

The most commonly used progestins are medroxyprogesterone acetate and megestrol acetate, given cyclically or continuously.

Advantages and Disadvantages of ERT

Although ERT is very effective in treating menopausal women, it can have some undesirable and dangerous side effects. For this reason, ERT is not normally prescribed for more than 5 to 7 years.

Advantages of ERT

 

Disadvantages of ERT

 

More Web Resources on ERT, HRT and Menopause

Brigham and Women's Hospital

Brigham and Women's Hospital provides more basic information on all aspects of ERT

The Foundation for Better Health Care

The Foundation for Better Health Care provides resources on various topics of women's health

Information on estradiol

This page provides information on risks involved with ERT and other issues concerning hormone replacement

 

References

Ettinger, B. (1998). Overview of estrogen replacement therapy: a historical perspective. Proceedings of the Society for Experimental Biology and Medicine, 217(10): 2-5.

Grenant, H.K. (1989). Estrogens in the prevention of osteoporosis in postmenopausal women. American Journal of Obstetrics and Gynecology, 161(6): 1842-1846.

Jones, J.M. (1996) The Pearls and Perils of Perimenopause. Journal of the American Academy of Nurse Practitioners, 8(11): 531-535.

McNagy, S.E. (1999) Prescribing hormone replacement therapy for menopausal symptoms. Annals of Internal Medicine, 131: 605-616.

Mishell, D. R. Jr. (1989). Estrogen replacement therapy: an overview. American Journal of Obstetrics and Gynecology, 161(6): 1825-18-27.

Notelovitz, M. (1989). Estrogen replacement therapy: indications, contraindications and agent selection. American Journal of Obstetrics and Gynecology, 161(6): 1832-18-41.

Thompson, W. (1995). Estrogen replacement therapy in practice: trends and issues. American Journal of Obstetrics and Gynecology, 173: 990-993.

Utian, W. H. (1989). Biosynthesis and physiologic effects of estrogen and pathophysiologic effects of estrogen deficiency: a review. American Journal of Obstetrics and Gynecology, 161(6): 1828-1831.