Menopause Comprehensive Study

Menopause is the permanent cessation of ovarian function, resulting in amenorrhea. The average age of menopause is 51 years, meaning that women spend one-third of their lives in a postmenopausal state. Tobacco use and higher socioeconomic status are associated with an earlier onset of menopause, whereas greater parity predicts a later age of onset.

Hormonal changes that herald menopause begin with a decrease in ovarian inhibin production and an increase in follicle-stimulating hormone release from the pituitary gland, followed by a drop in ovarian estradiol production 6 to 12 months before menopause. Irregular menstrual bleeding typically occurs for 2 to 8 years before cessation of menses.

Perimenopause is the stage which precedes menopause. Peri-menopausal women still have their periods but often experience symptoms of menopause. These women are best treated with progesterone rather than estrogen since they often have adequate estrogen. Usually, bleeding becomes lighter and less frequent. The diagnosis of menopause can be established clinically, and a follicle-stimulating hormone level does not need to be obtained routinely.

Vasomotor symptoms such as hot flushes and night sweats represent the single most frequent menopause-related complaint.  Three-quarters of menopausal women in the United States experience hot flushes, but only a fraction of these women actually seek medical attention for this symptom. Hot flushes gradually diminish over time, but 26% to 50% of women continue to experience them for up to 10 years. Hot flushes are more common at night, often interfering with sleep. They typically last anywhere from 30 seconds to a few minutes and may be accompanied by palpitations or other symptoms of anxiety. Estrogen is the most effective treatment for the relief of hot flushes, with a 50% to 90% response rate, and evidence shows that even low doses provide effective symptom relief.

Do you experience hot flushes, night sweats, vaginal dryness, urinary incontinence, depression, mood swings, or changes in sleep patterns or appetite?

* Do you experience irritability, bloating, headaches, breast swelling or mood swings in the week prior to menstruation?

* Do you experience irregular menstrual cycles, spotting, or heavy bleeding?

* Is intercourse painful due to vaginal dryness?

Changes in women’s health may begin around age 40, such as hot flushes and night sweats, insomnia or disruption of sleep, decreased sex drive, night sweats, fatigue, dryness of the vagina, pain in the joints, urinary issues, and emotional problems. Estrogen is the most effective treatment for the relief of hot flushes, with a 50% to 90% response rate, and evidence shows that even low doses provide effective symptom relief. Hormone Replacement Therapy should be considered in nonsmokers without other significant cardiovascular risks, a history of thromboembolic disease, a personal history of breast cancer, or a first-degree relative with breast cancer. The North American Menopause Society (NAMS) reviewed the available evidence and concluded that the absolute risk of Hormone Replacement Therapy is low and that although the use of such therapy should be individualized, estrogen replacement (with progesterone ) is the most effective treatment for vasomotor symptoms. For women in whom Hormone Replacement Therapy is contraindicated, there is data suggesting some benefit from antidepressants (SSRIs, the serotonin-norepinephrine reuptake inhibitor venlafaxine), clonidine, and gabapentin. There is currently insufficient evidence for the effectiveness of either physical exercise or herbal remedies such as soy proteins, black cohosh, red clover, dong quai, evening primrose, or ginseng

Vaginal atrophy and dryness are common during menopause and may result in vaginal burning and pruritus, dyspareunia, and dysuria.  Vaginal estrogen therapy is the most effective treatment of vulvar and vaginal atrophy and  the preferred method of administration for women with primarily vaginal symptoms.

Systemic Risks and Benefits of Hormone Replacement Therapy

The Women’s Health Initiative (WHI) identified an increase in the risk of cardiovascular events (fatal and nonfatal myocardial infarction) during the first year of Hormone Replacement Therapy; while this risk declined over time, the magnitude of the initial increase led to persistence of the effect over a mean of 5.2 years of follow-up. However, the WHI design initiated Hormone Replacement Therapy in women ages 50 to 79 years, many of whom older than 60 already had significant coronary artery disease risks. In fact, subgroup analysis indicates that perimenopausal or recently menopausal women may actually get cardiovascular benefit from Hormone Replacement Therapy. Women ages 50 to 59 years in the estrogen-only arm of the WHI trial had a statistically significant decrease in a global coronary score  and a decrease in coronary events that was nearly significant .

The Heart and Estrogen/Progestin Replacement Study (HERS), as well as an additional follow-up study (HERS II), found no increased risk of cardiovascular events in an average of 6.8 years of follow-up. In addition, a meta-analysis of 23 randomized, controlled trials of Hormone Replacement Therapy found that women within 10 years of menopause had a significant reduction in coronary events.

Another controversial issue is the impact of Hormone Replacement Therapy on breast cancer. The WHI indicated that estrogen-progestin combination therapy appears to be associated with an increase in the risk of breast cancer. For the estrogen-only arm in the WHI, however, the overall risk of breast cancer was lower; more specifically, ductal and localized cancer decreased, while lobular or tubular cancers (which are typically small, slow growing, low grade, and well differentiated) were more common. Because unopposed estrogen increases the risk of endometrial cancer, it should only be used in women who have had a hysterectomy; otherwise, it should be combined with progesterone.

Estrogen has a significant positive impact on bone mineral density, and the onset of menopause accelerates bone loss, often bringing on osteoporosis and consequent increased risk of vertebral, hip, and distal forearm fractures.

In summary, Hormone Replacement Therapy provides symptomatic relief of hot flushes as well as vaginal atrophy and dryness, but the decision to treat must be individualized and weighed against potential risks, including thromboembolism and breast cancer. Overall, the risk-benefit ratio is much greater for women closer to the start of menopause than for women more than 10 years past menopause.

Bioidentical Hormone Replacement Therapy

Bioidentical Hormone Replacement Therapy is restoring hormones with prescriptions that are biologically identical to those produced by the human body. These are usually prepared by compounding pharmacies. There are several bioidentical pharmaceutical brands of estrogen and progesterone available (Elestrin, Climara, Vivelle, Divigel, Estrasorb, Femring, Evamist, Vagifem, Estrace and Prometrium).

Estrogen may influence cognitive function in multiple ways:

Estrogen supports cognitive function. Estrogen receptors have been identified throughout the brain and appear particularly concentrated in the basal forebrain. The basal forebrain is of special interest since it is the major source of cholinergic innervation to the hippocampus. The cholinergic system is a neurotransmitter system important for regulation of memory and learning, while the hippocampus is the primary region of the brain mediating cognitive function.

* Estrogen increases synthesis of acetylcholine  and the ability of  neurons  to communicate with other nerve cells.

* Estrogen influences the glutamate system, a second neurotransmitter system involved in learning and memory .

* Estrogen stimulates neurons and contributes to regulation of genes that influence neuron survival, regeneration, and plasticity.

Women taking hormones have better verbal memory. Maintenance of cognitive abilities, like maintenance of bone mineral density, may require high estrogen levels over many years. Amyloid plaques are one of the pathologic hallmarks of Alzheimer disease. Estrogen may be important in preventing amyloid deposition. Epidemiologic studies of estrogen for the prevention of  Alzheimer disease showed consistent benefits. Very long-term exposure to high estrogen levels reflected by high bone mineral density has been associated with better cognitive function.

Other possible benefits of estrogen include:

1. Improvement in lipid profiles with estrogens.
2. Enhanced endothelial function, which may occur in young healthy women starting estrogen therapy with menopause but not older postmenopausal women with coronary disease.
3. Improved insulin sensitivity.
4. Estrogen may protect nerve cells from excitotoxins and  act as an antioxidant to shield nerve cells from free radical damage.
5. Estrogen in various forms can provide relief of vasomotor symptoms, and the use of the transdermal or transvaginal route should be considered.

Potential adverse effects of oral estrogens include:

1. An increase in serum triglyceride concentrations.
2. Prothrombotic effects.
3. An increase in hepatic synthesis of vascular inflammatory markers such as C-reactive protein.

Women who started postmenopausal hormone therapy closer to menopause appeared to have a lower risk of CHD compared to women further from menopause. The low baseline risk and modest HR in women ages 50 to 59 years resulted in no absolute excess risk in stroke . In WHI-Coronary Artery Calcium Study, coronary-artery calcium, as measured by electron beam CT, was lower in women assigned to unopposed estrogen when compared to placebo. Additional clinical trials showed earlier initiation of estrogen therapy is associated with a decreased risk of CHD .

Type of estrogen — The type of estrogen may also be important in determining risk. Both the WHI and the HERS trials , employed conjugated equine estrogen-progestin therapy. In comparison, the Estrogen in Prevention of Atherosclerosis trial (EPAT) randomly assigned 222 healthy, postmenopausal women to unopposed oral 17-beta-estradiol (1 mg/day) or placebo . Estradiol therapy was associated with a decreased risk of atherosclerosis (as measured by carotid artery intima-media thickness )

There is a lower risk of MI and stroke with esterified estrogens when compared to conjugated estrogens .

Secondary prevention — Although a number of observational and angiographic studies have strongly suggested that women with CHD derive the greatest benefit for prevention of subsequent coronary events and survival, combined oral estrogen and progestin therapy appeared to reduce the risk of developing type 2 diabetes mellitus.

Transdermal estrogen — Transdermal estrogen has more favorable effects than oral estrogen on markers for cardiovascular risk, less thrombogenic, and may be associated with a lower risk of thromboembolism than oral estrogens. Observational studies evaluated the association between estrogen therapy and venous thromboembolism (VTE), and suggested that Hormone Therapy caused approximately a two-fold increase in VTE risk.

Although it is reasonable to believe that the transdermal route of administration of estrogen avoids the hepatic first-pass effect and therefore reduces thromboembolic risk. Likewise, local estrogen therapy may have vaginal and uterine benefits with less systemic absorption.

Many women have found that a personalized hormone replacement therapy has positive benefits before, during or after menopause. Optimal skin tone, easier weight management, and increased energy levels are just a few of the benefits for women in menopause and women close to menopause (perimenopause). Imbalanced hormones also affect sleep, metabolic rate and immune system function, and contribute to the development of osteoporosis, breast and endometrial cancer, and heart disease.

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