Uses of Estrogens

USES

 

Currently, the two most common uses of estrogens are as contraceptives and for hormone replacement therapy in postmenopausal women, but there are some other indications as well.

 

Hormone Replacement Therapy (HRT)

 

Due to cessation of ovarian function at menopause women suffer a number of physical, psychological and emotional consequences.

 

Medical problems related to menopause are:

 

·   Vasomotor Disturbances Hot flushes, chilly sensation, inappropriate sweating, faintness, paresthesias, aches and pains.

·    Urogenital Atrophy Change in vaginal cytology and pH, vaginal dryness, vulval shrinkage, dyspareunia, vaginitis, itching, urinary urgency, predisposition to urinary tract infection.

·    Osteoporosis Loss of osteoid as well as calcium → thinning and weakening of bone → minimal trauma fractures especially of femur, hip, radius, vertebrae.

·        Dermatological Changes Thinning, drying and loss of elasticity of skin, wrinkles, thin and listless hairs.

·      Psychological/Cognitive Disturbances Irritability, depressed mood, loss of libido and self confidence, anxiety and dementia.

·     Increased Risk Of Cardiovascular Diseases Coronary artery disease, myocardial infarction, stroke.

 

The vasomotor symptoms tend to subside over a few years, but the other changes progress continuously.

 

Estrogen ± progestin HRT or ‘menopausal hormone therapy’ (MHT) is highly efficacious in suppressing the perimenopausal syndrome of vasomotor instability, psychological disturbances and atrophic changes, but several recent findings have emphasized a number of risks and limitations of long-term HRT, so that the whole outlook has changed.

 

The dose of estrogen used in HRT is substantially lower than that for contraception. Typically conjugated estrogens are used 0.625 mg/day (equivalent to ethinylestradiol 10 μg) either cyclically (3 weeks treatment 1 week gap) or continuously, but there is a trend now to use lower doses (0.3–0.45 mg/day). A progestin (medroxy progesterone acetate/norethisterone 2.5 mg daily) is added for 10–12 days each month. Though the progestin may attenuate the metabolic and cardiovascular benefits of estrogen, it is needed to block the increased risk of dysfunctional uterine bleeding and endometrial carcinoma due to continuous estrogenic stimulation of endometrium. Estrogen alone is used in hysterectomised women and when a progestin is not tolerated or is contraindicated. Transdermal estradiol (with oral or transdermal progestin) appears to have certain advantages (see above) and is preferred by some.

 

The benefits and risks of HRT are considered below:

 

a. Menopausal Symptoms And Atrophic Changes

 

The vasomotor symptoms respond promptly and almost completely. They are the primary indication for using HRT which improves general physical, mental and sexual well being as well. Genital and dermal atrophic changes are arrested; vulval and urinary problems resolve. Vaginal application of estrogen is effective in relieving local symptoms.

 

b. Osteoporosis And Fractures

 

HRT restores Ca²⁺ balance; further bone loss is prevented and the excess fracture risk is nullified. When used for this purpose, HRT should be initiated before significant bone loss has occurred, because reversal of osteoporosis is none or slight. Calcium + vit D supplements and exercise aid the beneficial effect of HRT. However, accelerated bone loss starts again on cessation of HRT. The ‘Women’s health, osteoporosis, progestin-estrogen’ trial (2002) has shown that even lower doses of conjugated estrogens (0.3, 0.45 mg/day) increased bone mineral density in postmenopausal women, though 0.625 mg/day was more effective.

 

Not withstanding the above, appreciation of the other risks of HRT (see below) has dislodged estrogen from its prime position in the treatment of osteoporosis compared to raloxifen and bisphosphonates.

 

c. Cardiovascular Events

 

Since hypertension and cardiovascular disease are rare in premenopausal women, and estrogens improve HDL : LDL ratio, retard atherogenesis, reduce arterial impedance, increase NO and PGI₂ production and prevent hyper insulinaemia, it was believed that estrogen therapy in postmenopausal women will have a protective cardiovascular influence. This was supported by early reports relying mainly on retrospective/ epidemiological studies and those using surrogate markers to indicate that HRT in otherwise healthy women reduced risk of coronary artery disease (CAD), myocardial infarction (MI) and stroke. This lead to the extensive use of HRT; a segment of doctors contended that menopausal women should take HRT for the rest of their lives.

 

In the past decade many large scale placebo controlled randomized interventional trials and cohort studies have yielded opposite results. The ‘Heart and estrogen/ progestin replacement study’ (HERS and HERS II) conducted in older women with preexisting cardiovascular disease found that HRT triples the risk of venous thromboembolism, initially increases risk of MI and affords no secondary prophylaxis of CAD in the long-term. The larger ‘women’s health initiative’ (WHI) study conducted in over 16000 younger women without CAD found 24% increase in CAD, 40% increase in stroke and doubling of venous thromboembolism with the use of combined HRT. It was terminated prematurely in 2002. The increased risk of MI was attributed to the progestin component, since women who took estrogen alone had no increase in the incidence of MI. The committee on safety of medicines (CSM) of UK has estimated that ~20 out of 1000 women aged 60–69 years and not using HRT develop venous thromboembolism over 5 years; 4 extra cases occur in those taking estrogen alone, while 9 extra cases occur in those taking combined HRT. Thus, progestin use adds to the risk.

 

d. Cognitive Function And Dementia:

 

Contrary to earlier belief, the ‘women’s health initiative memory study’ (WHIMS) conducted among older women (65–79 years) has failed to detect any protection against cognitive decline by ether estrogen alone or combined HRT. There was infact slight global deterioration. Surprisingly, the incidence of dementia (Alzheimer’s) was doubled.

 

e. Cancer:

 

That estrogens enhance the growth of breast cancer has been well recognized. However, it was contended that small replacement doses of estrogens will not induce new cancer. This appears to be supported by the estrogen alone arm of WHI study in hysterectomized women, as the occurrence of breast cancer was actually lower (but insignificantly). However, in the combined HRT group, a significantly higher incidence of cancer breast occurred, indicating that medroxyprogesterone was the culprit. The prospective observational cohort ‘Million women study’ (MWS) in the UK found a marginally higher incidence of breast cancer with estrogen alone, but a clearly higher one with estrogen + progestin. Some other studies have also implicated the progestin, and the CSM of UK has drawn similar conclusions. Thus, the protective effect of progestin on endometrial cancer appears to be counter balanced by the pro-carcinogenic effect on the breast.

 

Estrogen is well known to induce endometrial hyperplasia and its continuous use unopposed by progestin results in irregular uterine bleeding. In the long-term it predisposes to endometrial carcinoma. The MWS has supported this contention. The standard practice is to give combined HRT to women with an intact uterus. However, a Cochrane Database Review has concluded that lower dose unopposed estrogen does not increase endometrial carcinoma risk; may be used in women with intact uterus when a progestin is contraindicated.

 

A small protective effect of combined HRT on colorectal carcinoma has been detected by the WHI study, but this needs to be confirmed.

 

a)   Gallstone, Migraine:

 

Estrogens slightly increase the risk of developing gallstones, while progestins may trigger migraine.

 

Tibolone

 

It is a 19-norsteroid developed specifically to be used for HRT, which combines estrogenic and progestational properties with weak androgenic activity. In a dose of 2.5 mg daily, it suppresses menopausal symptoms and lowers the raised Gn levels. No endometrial stimulation has been noted. Urogenital atrophy, psychological symptoms, libido and osteoporosis are improved similar to other forms of HRT. Contraindications are the same as for conventional HRT, but increase in breast cancer risk appears to be less than with combined HRT.

 

Weight gain, increased facial hair and occasional vaginal spotting may be noted.

 

LIVIAL 2.5 mg tab, one tab daily without interruption; institute therapy only after the women has been menopausal for atleast 12 months.

Current conclusions regarding HRT

Current Conclusions Regarding HRT

 

Ø The main indication of HRT is vasomotor and other symptoms in the perimenopausal period. It should be used at the smallest effective dose and for the shortest duration.

Ø Young women with premature menopause clearly deserve HRT.

Ø Hysterectomized women should receive estrogen alone, while those with intact uterus be given estrogen + progestin.

Ø Perimenopausal women should be given cyclic HRT rather than continuous HRT.

Ø HRT is not the best option to prevent osteoporosis and fractures.

Ø HRT affords no protection against cardiovascular disease; conventional dose combined HRT may even increase the risk of venous thromboembolism, MI and stroke.

Ø HRT does not protect against cognitive decline; may increase the risk of dementia.

Ø Combined HRT increases the risk of breast cancer, gallstones and migraine.

Ø Transdermal HRT may have certain advantages over oral HRT.

Ø The need for HRT should be assessed in individual women, and not prescribed routinely.