Estrogen Therapy

Content Written By: Irwin Goldstein, MD

There has been a great deal of controversy about the risks and benefits of estrogen therapy in peri-menopausal and post-menopausal women. At menopause your ovary ceases estradiol production. In some post-menopausal women, estrogen production continues in varying degrees through peripheral conversion of androgens to estrogen via the enzyme aromatase. The only way to determine if you still make estrogen is to measure your estradiol blood levels.

There are three different 18 carbon sex steroid, estrogens estrone (E1), estradiol (E2), and estriol (E3). The most biologically relevant estrogen as it concerns sexual health is estradiol (E2).

Estrogen, similar to androgen, is required for normal structure and function of genital tissues. Estradiol in the blood passes into the genital cells (typically a smooth muscle cell), acts on estrogen receptors in these genital cells, and induces the nucleus of these genital cells to synthesize proteins. The proteins direct messages to act on genital tissues to maintain structure and function. For example, an estrogenized vagina has a thick lining layer (epithelial layer), a blood vessel-rich middle layer (lamina propria), and a thick muscle layer (muscularis layer). It is also highly rugated or folded. During sexual arousal an estrogenized vagina widens and lengthens, releases lubrication, and has enhanced sensation. The pH is around 4 and, as such, provides great resistance to infections and discharge. Estrogen is also required for normal structure and function of many other tissues, including bone and skin.

At some point after menopause, most women will have some degree of genital atrophy due to low estradiol values. Diminished estrogen production, consistent with menopause, is associated with thinning of all three layers of the vagina, the lining, blood vessel, and muscle layers. With estrogen loss, the vagina becomes pale and all layers begin to thin. There is diminished ability of the vagina to stretch during sexual arousal and lubrication decreases. Vaginal dryness can lead to dyspareunia. Vaginal pH increases and inflammation, infections, and discharge are commonplace. The estrogen-deficient vagina is easily traumatized and can bleed during sexual activity. Low estrogen also contributes to other genital changes such as thinning of the hair of the mons and shrinkage of the labia minora. In addition, the labia majora flatten as the subcutaneous fat and elasticity of the structures diminish. Atrophic changes in many of the genital tissues can be detected within 6-8 weeks in an estrogen-reduced environment. Researchers found that vaginal dryness, burning, and dyspareunia were reported more often in women with levels of estradiol <50 pg/mL than in those with higher levels. Low estrogen values also affect bone and skin health, mood, cognition, and many more metabolic and bodily functions.

Does every woman have to undergo treatment with estrogen if blood test values are low? The answer is no. One alternative to estrogen treatment is to use non-estrogen vaginal lubricants and moisturizers on a regular basis. While these products do not treat the source of the problem, lubricants and moisturizers can be successfully used to manage vaginal itching, irritation, and dyspareunia. Furthermore, local use of vaginal lubricants can be used to ease penetration and facilitate intercourse and may help increase vaginal blood flow.

Lubricants should be pH neutral so the vaginal environment and flora are not altered. Water-based lubricants are easily absorbed while silicone-based lubricants are able to leave the skin with an oily texture. Where contraception is important, however, petroleum-based lubricants and oils can decrease condom integrity. Vaginal moisturizers can provide long-term relief of vaginal dryness, producing a longer duration of lubrication and a significantly lower vaginal pH than lubricants.

Estrogen therapy has been shown to lower vaginal pH, increase vaginal blood flow and lubrication, and restore clitoral and vaginal sensation. In an illustrative study, only 15% of women on systemic hormone therapy reported vaginal dryness after a 5-year follow up, compared to 30-40% of those who did not use hormone therapy. Dyspareunia, vaginal irritation, pain, dryness or burning were also observed less often among those who used systemic hormone therapy compared to those who did not use hormone therapy. Relief from these vaginal atrophy symptoms can often lead to more sexual desire and sexual arousal.

Vaginal atrophy symptoms can be treated by local or systemic estrogen therapy. Local therapy can be delivered via vaginal estradiol creams, vaginal estradiol rings, and local vaginal estradiol tablets. Estradiol creams are subject to irregular application intervals and can be absorbed into systemic circulation, increasing systemic estrogen concentrations. Estradiol creams are messy; intravaginal rings and tablets may be more convenient. The intravaginal ring is placed in the vagina for 3 months during which time the ring slowly releases the estradiol into the local vaginal environment. One caveat of the intravaginal ring, however, is the need to fit in the individual’s vagina and not be expelled if there is vaginal prolapse. The intravaginal estradiol (25 micrograms) tablet is placed in the vagina several times per week with a special applicator. The intravaginal tablet slowly releases estradiol into the local vaginal milieu and is not designed to help systemic symptoms of menopause. Many health care providers prefer bioidentical intravaginal estradiol since blood levels of estradiol can be measured as a safety precaution. Alternative local estrogens include conjugated equine estrogen and estriol, however these non-bioidentical forms of vaginal estradiol are not easily measured in the blood. Local estrogen therapy can be as effective as systemic estrogen for specific treatment of vaginal atrophy symptoms. In fact, local estrogen therapy can restore the vaginal lining layer to its normal state within a short time period. Intravaginal estradiol can partly or completely restore vaginal health to that of pre-menopausal function and improve or cure genital atrophy and dryness. Studies show estradiol released from a ring to have equivalent efficacy to estradiol in cream delivery form.

Systemic estrogen therapy for treatment of vaginal atrophy symptoms can be oral or topical. Oral estrogens have been around for many years and have been the most common route of estrogen replacement. They are usually well tolerated and cost-effective. There are several drawbacks to the oral administration of estrogen, however. The drug must pass to the liver after being absorbed in the gastro-intestinal tract. In some women, this may increase the sex-hormone binding globulin level and thus act to reduce the amount of biologically active testosterone. The reduction in biologically active testosterone in post-menopausal women on oral estrogen therapy is a common cause of decreased libido.

Transdermal topical estrogen therapy is more effective at lower doses compared with oral administration. It gets absorbed directly through the skin into the blood stream and thus may provide more consistent blood estradiol levels. Topical estrogen therapy also avoids being absorbed in the gastro-intestinal tract and passing to the liver.

A new choice of topical administration is through the vagina via a special vaginal ring administration designed for systemic absorption. The ring is placed intravaginally where it remains for 90 days. This ring has the added benefit of increasing both local and systemic estradiol levels.

Systemic estrogens, both oral and topical, can again be divided into bioidentical and non-bioidentical medications. Many health care providers prefer systemic bioidentical estradiol since blood levels can be measured as a safety precaution. One goal is to keep the values of estradiol at or around 50 pg/ml since researchers found less vaginal dryness, burning, and dyspareunia at this blood level compared to lower levels.

You have likely heard about the Women’s Health Initiative study. The use of systemic estrogen therapy declined abruptly since that study. The Women’s Health Initiative was designed to measure the rate of heart attacks in healthy post-menopausal (on average 12 years post-menopause), with a mean of 64 years of age. Participants were divided into 2 groups, a non-bioidentical estrogen-progesterone arm for those with an intact uterus and a non-bioidentical estrogen only arm for women with prior hysterectomy. The non-bioidentical estrogen-progesterone arm studied the use of conjugated equine estrogen plus medroxyprogesterone acetate versus placebo, while the non-bioidentical estrogen only arm studied conjugated equine estrogen versus placebo. The Women’s Health Initiative studies showed that the risks of non-bioidentical estrogen-progesterone therapy include breast cancer, heart attack, and stroke. Other risks of estrogen therapy include blood clots, deep vein thrombosis, and pulmonary embolus.

The data obtained from the Women’s Health Initiative are based on the use non-bioidentical estrogen therapy, conjugated equine estrogen with or without a non-bioidentical progesterone, in North American women on average 12 years post-menopause. These data do not provide information for women considering bioidentical estradiol therapy in the peri-menopause or early post-menopause. The Women’s Health Initiative trials tested only one drug regimen and did not provide information about the use of other estradiol doses, formulations, regimens and routes of administration, or doses and duration of other estrogen therapies.

The recent fear of estrogens has led many women to consider herbal therapies because they are advertised as “natural” and, therefore, safer. Herbal therapies are not overseen by any government agency and the manufacturing is not regulated. What is on the label is not necessarily in the jar, and what is in the jar is not necessarily on the label. Numerous claims are made for these products, especially when it comes to sexual improvement effects. Healthcare providers should caution women about use of such products and to be wary of the claims of effect on sexual function.

In summary, estrogen use should be individualized to each woman’s needs and expectations. There is no formula for all women. What holds for women 10 to 20 years post-menopausal cannot be extrapolated to women recently post-menopausal. What holds for oral estrogen therapy cannot be extrapolated to non-oral systemic estrogen or to local vaginal estrogen therapy. Systemic estrogen has been shown to significantly improve vasomotor symptoms, including hot flushes, night sweats, and sleep disturbance, all of which can impact a women’s body image, mood, and sexual desire. Alleviation of such symptoms can often help increase both quality of life and satisfaction during sexual activity. As in all sexual health care concerns, consider seeking additional information from sexual health care focused health care professionals.

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