Hormone Replacement Therapy

Hormone Replacement Therapy (HRT) consists of replacing lost or diminished hormones in the body. Though applicable for any form of hormones produced by the body, it remains synonymous for post menopausal hormone replacement.

HRT was first introduced in the 1950’s. At that time the post menopausal woman, despite the presence of a uterus was only given estrogen. When the lack of opposing progestogen was shown to increase the risk of endometrial hyperplasia, both estrogen and progestogen was then introduced. Women without a uterus require only estrogen.

Types of estrogen available:

• estradiol valerate, a synthetic natural estrogen given at a dose of 2mg/day
• estradiol, a micronised version of natural estrogen given at a dose of 2mg/day
• conjugated equine estrogens, estrogens distilled from the urine of pregnant mares given at the dose of 0.625ug/day

Progestogens (progestins) refer to all steroids used as a substitute for endogenous progesterone. Natural progesterones can be either micronised or in the form of dydrogesterone. Unfortunately, natural progesterones have low bioavailabilty and increasing its dose may lead to unpleasant side effects. The progestogens available are either derivatives of the 17 α-hydroxyprogesterone or the 19- nortestosterone.

Treatment modalities

Post menopausal women without a uterus only require estrogen replacement therapy (ERT). If the ovaries have been left behind at surgery, a woman does not require ERT until she reaches menopause. She could await the normal transitional symptoms or carry out a blood test to determine the levels of FSH and LH at this stage.

Women with a uterus require both estrogen and progestogen. Progestogens are added to reduce the risk of endometrial hyperplasia and endometrial carcinoma.  Progestogens given for ten days or more offers an endometrial protective effect with an odds ratio of less than 1.0.

Sequential HRT: Progestogens are added for at least 10-14 days of every cycle. This causes a withdrawal bleed every month. Sequential HRT is recommended for women who are in the perimenopausal phase when bleeding irregularities are common.
Continuous combined HRT: Progestogens and estrogen are given daily. This causes suppression of the endometrial lining of the uterus. This regime is recommended for women in the post menopause phase. Though irregular bleeding may be common in the first six months of use, thereafter this treatment regime does not cause any withdrawal bleeding if correctly taken.

For long term use, the continuous combined HRT regime is preferred to the sequential regime, as a higher rate of endometrial carcinoma was found in the latter when taken for more than 5 years.

Delivery systems

HRT may be delivered in various ways.

• Oral tablets are available in both estrogen (E) and estrogen and progestogen (E/P) combinations. Though widely accepted, they have a first pass effect through the liver which may contribute to certain side effects such as pigmentation and thrombosis. However oral tablets remain the most popular although different regimes, dosages and combinations are available.
• Transcutaneous patches are available both in E and E/P preparations. It produces similar effects as the oral form though metabolic changes related to it’s effect on the heart are said to be less.  A significant side effect is the irritation around the edge of the patch and premature detachment which is more common in the tropical climate. Transcutaneous estrogen gel is also available.
• Subdermal implants (estrogen only) are available in various sizes containing 20, 50, 100 mg of estradiol so as to provide different durations of action. Taccyphylaxis is the biggest disadvantage. Testosterone implants given in conjunction with estradiol implants help with lowered libido levels in post menopausal women.
• Transvaginal estrogen cream has very minimal systemic absorption and is recommended in women with vaginal drynes.

The action of estrogen

The action of estrogen is mediated through receptors. The two distinct types of receptors, ERα and ERβ are similar but functionally different as they are expressed differently in the various parts of the body.  ERα is predominant in the breast, uterus and vagina and is mainly involved in reproductive events. ERβ is more general and is found in the ovary, brain, cardiovascular system and skin. When estrogen or any other compound binds with these receptors, it causes a conformational change that then predicts the response in the various end organs. Depending on the predominant receptor found in the end organ, differing responses may then be obtained.

The principal aim of HRT is to restore healthy levels of estrogen so as to reduce the effects of estrogen deprivation. HRT can be started at the perimenopausal or post menopausal phase. Prior to starting HRT, a full examination which includes a detailed history, general examination, blood pressure reading, breast examination, Pap smear and a gynaecological examination is important. Screening mammograms should be encouraged in women over the age of fifty. Bone mineral density testing should be carried out in women with a high risk of osteoporosis. Every woman should be counseled in detail regarding HRT. Her individual benefits and risks towards HRT should be evaluated.

Benefits of HRT

Conventional benefits of HRT include:

• relief of vasomotor symptoms
• relief of urogenital arophy
• relief of skin atrophy
• prevention and treatment of osteoporosis
• improvement in mood and cognition

Newer benefits of HRT are:

• decreased risk of colo-rectal cancer by 37%
• decreased age related  tooth loss
• decreased age related  macular degeneration
• delay of onset and progression of Alzheimer’s Disease when started early post menopausal

Side effects of HRT

Breast tenderness and bloating are common when HRT is initiated. These initial side effects can be minimized by altering the dose and type of estrogen and progestogen. Allergic reactions are usually rare. An increase in pigmentation may occur.

Weight gain is always assumed to be due to HRT use. However no evidence exists that either ERT or HRT contributes towards body weight. The increase in weight is usually due to a decreased metabolic rate which occurs at perimenopause and menopause.

Present recommendations for HRT

The era of promoting ERT or HRT use in every woman is over. In light of the recent data i.e. mainly the Women’s Health Initiative, recommendations towards the use of estrogen  and estrogen/ progestin combination in the post menopausal woman is made with careful consideration of each individuals benefit and risk ratio. Though not directly comparable, the two arms of the WHI have shown interesting results.

Table 4: The Women’s Health Initiative (WHI)

Reference

1. Essentials of Gynecology. (2005) Chapter 29 Menopause and Hormone Replacement Therapy
2. Editors Sabaratnam Arulkumaran, V Sivanesaratnam,
3. Alokendu Chatterjee, Pratap Kumar. Jaypee Brothers

Dr. Premitha Damodaran, MBBS,MOG

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