Overall Health Benefits of Estrogen

• Maintains Bone Strength and Quality [11-67]
• Relieves Menopause Symptoms [68-88]
• Improves Sexual Function [89-113]
• Reduces Overall Body Fat [116-137]
• Improves Muscle Mass and Strength [139-170]
• Improves Mood and Energy Levels [171-190]
• Reduces Wrinkles and Maintains Younger, Tighter Skin [192-245]
• Improves Cognitive Function [246-308]
• Improves Sleep Quality [310-331]
• Enhances Exercise Performance [332-340]
• Decreases Urinary Tract Infections (UTI) [341-356]
• Decreases Risk of Heart Disease [357-403]
• Improves Cholesterol Profile [404-423]
• Improves Blood Sugar Levels [424-440]
• Improves Blood Pressure [441-456]
• Decreases Risk of Stroke [458-490]
• Boosts Immune Function [491-507]

Estrogen in Women

Estrogen is crucial to a woman’s reproductive function and cycle. This powerful hormone affects the following body areas:

• Ovaries: Estrogen is responsible for stimulating the growth of an egg follicle.
• Vagina: Estrogen stimulates the growth of the vagina and its structures. It also increases vaginal acidity to help fight bacterial infections and it lubricates the vagina.
• Fallopian tubes: It also stimulates the growth of the muscular walls of the fallopian tubes, and for the muscular contractions that transport the egg cells.
• Uterus: It helps maintain the lining of the uterus (endometrium) and enhances blood flow and uterine contractions during childbirth. In addition, estrogen also helps get rid of dead tissue in the uterus during menstruation.
• Cervix: It aids in the fertilization process by enhancing the transport of a sperm cell to an egg.
• Mammary glands: During adolescence, estrogen stimulates the growth of breast tissue. It also regulates the flow of milk during breastfeeding.

Aside from its key role in maintaining the growth and development of the female reproductive system, estrogen also has the following important functions:

• During puberty, estrogen slows down the growth of females and enhances the body’s response to insulin.
• In the liver, estrogen works to regulate cholesterol production.
• It causes body hair to become finer.
• It creates the ideal female body frame by making the bones smaller and shorter, the shoulders narrower, and the pelvis broader.
• It enhances body contour by increasing fat storage around the hips and thighs.
• It enhances the effects of certain brain chemicals.
• It gives females a higher-pitched voice by making the voice box smaller and vocal cords shorter.
• It helps maintain bone strength and quality.
• It helps regulate body temperature.
• It improves skin thickness and quality by increasing the production of collagen.
• It reduces the incidence of acne and oily skin by suppressing the activity of the oil glands.
• It regulates the brain region that is linked to sexual development.

Estrogen in Men

Men also produce estrogen in smaller amounts. In order for this process to happen, an enzyme called aromatase converts testosterone into estradiol. Research indicates that certain cells in the testis known as Leydig cells, contain the aromatase enzyme and produce some estrogen. [1]The aromatase enzyme is also abundant in the brain and penis. However, as men age, their aromatase levels can sometimes spike, which causes their testosterone to be converted into excess estradiol. [2] This in turn results in low testosterone while spiking estradiol levels. In some men, their aromatase levels are insufficient and suffer from estrogen deficiency. Other men produce abnormally low levels of testosterone that there isn’t enough to convert into estrogen, thus, causing a deficiency in both testosterone and estradiol.

Just like women, men also need estrogen to perform at optimal levels. Estradiol, the predominant form of estrogen, is thought to play a major role in male sexual function. [3] Estradiol in men modulates libido, erectile function, and production of sperm cells. In the brain, estradiol production is increased in areas that regulate sexual arousal. Moreover, several estrogen receptors are distributed throughout the erectile tissues of the penis (corpus cavernosum) with high concentrations found in the nerves, arteries, veins, and other blood vessels.

Estrogen Deficiency

In women over age 40, estrogen levels will significantly decline due to approaching menopause, which is medically known as perimenopause. During this time of transition, a woman’s ovaries will still produce estrogen, however, in smaller amounts. By the time that estrogen production completely stopped, a woman has already reached menopause. This age-related decline in estrogen levels can lead to debilitating signs and symptoms such as:

• Breast tenderness
• Brittle bones
• Cognitive impairment (memory issues, difficulty concentrating, and thinking problems)
• Difficulty sleeping
• Frequently missed periods (amenorrhea)
• Hot flashes
• Low libido
• Mood swings
• Night sweats
• Painful intercourse
• Thin, dry, or wrinkled skin

In men, low estrogen levels can also lead to the following signs and symptoms:

• Anxiety
• Bone loss
• Depression
• Erectile dysfunction
• Joint pains
• Fat accumulation
• Fatigue
• Irritability
• Oversleeping or sleeping difficulties
• Sexual dysfunction
• Water retention
• Hot flashes

Aside from the natural process of aging, certain medical conditions, lifestyle choices, and processes can lead to estrogen deficiency. These include:

• An underactive pituitary gland
• Anorexia nervosa
• Breastfeeding
• Certain medications, such as clomiphene
• Childbirth
• Chronic kidney disease
• Fat and calorie restriction
• Genetics
• Ovarian failure
• Polycystic ovarian syndrome (PCOS)
• Pregnancy failure
• Strenuous exercise or training
• Toxins
• Turner syndrome

Estrogen Replacement Therapy (ERT)

Over time, the gradual decline in women’s estrogen levels can lead to debilitating signs and symptoms which can ultimately impair one’s quality of life. Women who had their uterus surgically removed (hysterectomy) can also experience these detrimental effects. Fortunately, for those suffering from estrogen deficiency, ERT can be used to increase estrogen levels, alleviate unpleasant symptoms, and improve overall quality of life.

There are different ways ERT is administered. These include:

• Oral – The oral route is the most frequently utilized method of ERT because it effectively delivers estrogen into the bloodstream. Estrogen tablets are relatively convenient and inexpensive for most women.
• Transdermal patches (Skin patches) – Skin patches bypass the liver and are recommended for patients who do not respond to estrogen tablets. This route of administration allows the estrogen to be gradually absorbed by the skin.
• Transdermal gels or creams – This method makes use of a measured amount of gel or cream that is applied on the skin. Application of transdermal gel also allows the estrogen to be gradually absorbed into the bloodstream.
• Sublingual – This route involves placing estrogen tablets under the tongue. It is absorbed through the lining of the mouth into the blood vessels and then into the bloodstream.
• Intramuscular injections – Injection of estrogen into the muscles is the most common method of ERT used by many physicians. The hormone is usually mixed with a substance to allow slow release into the bloodstream once injected.
• Subcutaneous implantations – This method involves implantation of estrogen pellets into the tissue layer between the skin and the muscle at 3-6-month interval. The most commonly used body areas are the abdomen or buttocks.

Potential candidates for ERT usually undergo measurement of estrogen levels first through   comprehensive saliva, blood, urine and serum test. By determining the baseline estrogen levels, the ERT physician will be able to customize a treatment plan that is tailored to the individual needs of the patient.

Proven Health Benefits of ERT

Compelling evidence indicates that restoring estrogen to youthful levels through ERT can help treat and prevent a wide range of medical conditions that can improve one’s quality of life. The following are among the diverse health benefits of ERT:

Maintains Bone Strength and Quality

The body constantly builds and remodels bone. However, after menopause, this process slows down causing women to lose as much as 20% of their bone mass. [4] As a result, postmenopausal women begin to experience osteoporosis, fractures, and other bone disorders.  [5-7] In aging men, low estrogen levels can also increase their risk of developing bone problems.  [8-10] An overwhelming body of clinical evidence suggests that this age-related bone loss can be prevented and treated with ERT:

1. In both men and women, estrogen regulates bone metabolism and maintains bone formation. [11-13]
2. In postmenopausal women, low-dose ERT as well as the standard dose ERT is associated with significant reduction in the incidence of osteoporosis and fractures. [14-23]
3. In postmenopausal women, ERT significantly increases bone mineral density (BMD) of different skeletal sites without any adverse side effects. [24-37]
4. In postmenopausal women, discontinuation of ERT results in acceleration of bone breakdown, decrease in BMD and eventual loss of anti-fracture efficacy. [38-44]
5. In early and late postmenopausal women, ERT slows bone breakdown and increases bone BMD at all skeletal sites. [45-46]
6. In postmenopausal women with osteoporosis and other bone disorders, ERT appears to be safe and effective in increasing bone mass. [47-55]
7. In humans and animals with bone fractures, ERT accelerates bone healing and prevents further bone breakdown. [56-67]

Relieves Menopause Symptoms

Menopause can bring in a number of physiological changes that can permanently affect a woman’s life. These significant changes include unpleasant symptoms that appear before, during and after the onset of menopause. In order to treat menopause symptoms and replace the declining estrogen levels, most doctors prescribe ERT. There is mounting clinical evidence that ERT is safe and effective in alleviating menopause symptoms:

1. In healthy women in the perimenopausal transition who are experiencing bothersome symptoms, very-low-dose estrogen therapy (0.3 mg daily) [68-69] or transdermal estradiol (0.025 mg weekly) [70] often is effective in alleviating hot flushes and is associated with minimal side effects.
2. In postmenopausal women, ERT appears to treat mood swings and other menopause symptoms without any adverse side effects. [71-88]

Improves Sexual Function

When estrogen levels decline, both men and women may experience reduced libido which can ultimately affect their self-confidence as well as quality of life. In women, estrogen deficiency can cause changes to the structures and pH of the vagina, which in turn leads to vaginal health issues such as vaginal dryness, inflammation of vaginal tissues, irritation, and painful sexual intercourse (dyspareunia). In men, low estrogen levels can cause erectile dysfunction and reduced sexual desire. Studies show that undergoing ERT can help treat a wide array of sexual health issues associated with age-related decline in estrogen levels:

1. In castrated men, elevations in estrogen help maintain some sexual function and do not appear to be harmful. [89]
2. In male rats, estrogen is considered essential for normal intromission and ejaculatory function. [90]
3. In postmenopausal women with dyspareunia due to vaginal dryness, ERT restores vaginal cells, pH, lubrication, and blood flow, which in turn improves sexual function.   [91-95]
4. In pre-menopausal women with estrogen deficiency on hemodialysis, transdermal estradiol treatment is associated with restoration of regular menses and a marked improvement in their sexual function. [96]
5. In postmenopausal women with decreased libido, ERT improves female sexual functioning by acting on the central nervous system to increase sexual desire. [97-101]
6. In women who had hysterectomy, ERT is associated with significant improvements in lubrication, orgasm, sexual satisfaction, and general well-being. [102-110]
7. In postmenopausal women, ERT is associated with higher frequency of sexual activity and improvements in various sexual parameters such as satisfaction, interest, enjoyment, desire, thoughts and fantasies, arousal, responsiveness, and pleasure. [111-113]

Reduces Overall Body Fat

In addition to diet, lifestyle, and genetic factors, the aging process can also contribute to weight gain. In fact, the older we get, the more difficult it is to lose weight. Not only does our metabolism slows down, but also the production of estrogen. In women, the age-related decline in estrogen levels causes their bodies to look for other sources of estrogen, which can be found in fat cells. [114] As a result, their bodies learn to convert more calories into fat, leading to weight gain. In men, the age-related decline in estrogen causes fat accumulation, which in turn results in weight gain. [115] While diet and lifestyle modifications are critical elements to weight loss, there is increasing evidence that restoring estrogen to youthful levels through ERT may help you achieve healthier weight:

1. In obese menopausal women, three months of ERT significantly reduces weight by increasing energy expenditure. [116]
2. In healthy postmenopausal women, both intranasal and oral estrogen therapy promotes weight loss by increasing the levels of leptin, a hormone that inhibits hunger. [117-127]
3. In menopausal women, ERT lowers visceral adipose tissue (fatty tissue) by improving the body’s response to insulin. [128-129]
4. In postmenopausal women, ERT reduces weight and abdominal fat by lowering cholesterol levels. [130-131]
5. In postmenopausal women, ERT is associated with a significant reduction in body mass index (BMI). [132-133]
6. In rats, estrogen prevents weight gain by regulating body adiposity and fat distribution. [134-137]

Improves Muscle Mass and Strength

One of the most undesirable consequences of aging is the loss of muscle mass and strength. Current research suggests that low sex hormone concentration, specifically estrogen, may be among the key mechanisms for muscle wasting (sarcopenia) and weakness. [138] Interestingly, a large body of scientific evidence suggests that restoring estrogen levels through ERT may help diminish age-associated muscle loss and improve overall muscle function:

1. In postmenopausal women, one-year ERT intervention appears to increase muscle size, vertical jump height and running speed. [139-140]
2. In older females, ERT increases isometric muscle strength. [141]
3. In women aged 55–56 years, ERT results in more muscle power, higher vertical jump, faster walking speed, greater lean body mass and less fat mass. [142]
4. In postmenopausal women, ERT significantly increases muscle mass and improves muscle function by increasing protein synthesis as well as growth factors. [143-146]
5. In older women with muscle weakness, ERT significantly increases muscle mass, muscle function, muscle force and power generation. [147-149]
6. In peri- and postmenopausal women, ERT prevents muscle strength loss by improving the function of the existing muscle. [150-153]
7. In premenopausal and postmenopausal women, ERT significantly increases quadriceps femoris muscle strength. [154-155]
8. In postmenopausal women, ERT improves performance, mass and composition of various muscle groups in the body. [156-165]
9. In rodents, estrogen administration reduces muscle structural damage and muscle membrane disruption following potentially damaging exercise. [166-170]

Improves Mood and Energy Levels

Women’s emotional symptoms as they approach menopause vary. Some may experience no symptoms at all while others may have mood swings, depression, anxiety, panic attacks, anger, short temper, snappiness, crying episodes, and irritation. These symptoms can be debilitating and may significantly impair one’s quality of life. In addition, menopausal women suffering from low mood and decreased energy levels may increase their risk of developing mood disorders. Thus, ERT has been proposed as a potentially effective therapeutic strategy for mood disorders experienced during menopause. A number of high quality studies support the mood-enhancing effects of ERT:

1. In perimenopausal women with DSM-IV-defined major depressive disorder who have minimal response to antidepressants, ERT significantly improves depressive symptoms and scores in the Hamilton Rating Scale for Depression (HAM-D). [171]
2. In younger mid-life women, 3 months of ERT is associated with significant improvements in mood, everyday memory, working memory, and delayed verbal memory. [172]
3. In women with postpartum depression, transdermal and sublingual estradiol therapy appears to be safe and effective in alleviating depressive symptoms. [173-174]
4. In perimenopausal and postmenopausal women, ERT reduces both physical and depressive symptoms while increasing energy levels. [175-187]
5. In depressed perimenopausal women, estrogen favorably influences neurotransmitters (brain chemicals) involved in mood regulation. [188-190]

Reduces Wrinkles and Maintains Younger, Tighter Skin

During the menopausal years, the age-related decline in skin thickness accelerates by as much as   1.13% per year. [191] The decline in estrogen during this stage results in gradual decrease in collagen, water, and glycosaminoglycans (GAGs) content, which ultimately leads to thinning and sagging of the skin. Fortunately, these age-related skin imperfections can be diminished with ERT. Studies show that estrogen exerts potent anti-aging effect on the skin by reducing wrinkles and improving skin elasticity, which helps maintain a younger, tighter skin:

1. In postmenopausal women, six months of oral estrogen administration results in an increase in skin thickness, volume, and number of skin cells (keratinocytes). [192-193]
2. In elderly men and women, application of estrogen on the skin increases keratinocyte proliferation and epidermal thickness after only two weeks. [194]
3. In postmenopausal women, one year of oral ERT increases dermal thickness by 30% while six months of treatment increases skin collagen by 6.49%. [195-196]
4. In elderly men and women, application of estrogen on the skin appears to increase levels of type I, II and type III procollagen. [197-211]
5. In women who were at least five years post-menopause, continuous oral estrogen therapy significantly reduces wrinkles. [212]
6. Estrogen appears to fight skin aging in both men and women by increasing collagen and moisture content and maintaining skin barrier function. [213-221]
7. In cultured human epidermal keratinocytes, estrogen stimulates proliferation and DNA synthesis. [222-227]
8. In cultured human epidermal keratinocytes, estrogen provides protection against photoaging. [228-230]
9. In postmenopausal women, estrogen administration alleviates skin atrophy (thinning of skin) and xerosis (abnormally dry skin). [231-233]
10. In postmenopausal women, ERT reverses progressive skin slackness, resulting in younger, tighter skin. [234-235]
11. In perimenopausal women, ERT reduces the number and depth of wrinkles. [236-238]
12. In early menopausal women, ERT mitigates age-related changes in tensile properties. [240-241]
13. In postmenopausal women with sagging skin, both transdermal and oral estrogen preparations increase forearm skin elasticity by 5.2%. [242-243]
14. In women with wrinkles caused by pregnancy and menopause, ERT use is associated with significant reduction in facial wrinkling as assessed by an eight-point photographic scale. [244]
15. In postmenopausal women, ERT mitigates the effects of skin aging as assessed by a computerized suction device measuring facial skin distensibility, viscosity and elasticity. [245]

Improves Cognitive Function

Evidence, accumulated over the past several decades, shows that estrogen plays a critical role in the modulation of cognitive function in animals and humans. Modulation begins in the womb when estrogens exert their effect on various brain regions involved in cognitive function. Estrogen influences the nervous system, and this continues through adulthood when its production reaches the highest levels. With aging, estrogen levels gradually decline and contribute to impairment in memory, learning, and thinking skills. Research in basic neuroscience and other clinical research shows that ERT protects against the age-related decline in cognitive function:

1. In postmenopausal women and women with Alzheimer’s disease (AD), ERT significantly improves memory and attention. [246]
2. In young surgically menopausal women, injection of 10 mg estradiol every month for 3 months improves verbal memory, abstract reasoning, speed and accuracy. [247]
3. In healthy postmenopausal women, ERT lowers the risk of Alzheimer’s disease by 29% to 34%. [248-250]
4. In patients with lesions in the frontal cortex of the brain, ERT use is associated with significant improvements in verbal memory. [251-254]
5. In patients with age-related cognitive decline, estrogen helps maintain cognitive functions mediated by the frontal lobes. [255-261]
6. In postmenopausal women, ERT enhances performance on certain tests of working memory and cognitive set-shifting. [262-273]
7. Neuroimaging studies reveal that estrogen enhances function of the frontal lobe of the brain in women during cognitive challenges. [274-281]
8. In postmenopausal women, estrogen enhances cognitive function by modulating information processing in the brain. [282-292]
9. Observational studies of menopausal women taking ERT show that the treatment is associated with better verbal memory, working memory, and visuospatial function, and with a lower risk of dementia. [293-302]
10. In naturally postmenopausal women, ERT is associated with better verbal fluency, working memory, and psychomotor speed. [303]
11. Studies show that estrogen exerts its cognition-enhancing efficacy by boosting the regeneration of brain neurons, protecting against programmed cell death (apoptosis), modulating transmission of electrical signals between each neuron, increasing blood flow to the brain, preventing formation of abnormal proteins in the brain (β-amyloid), and fighting inflammation and free radicals. [304-308]

Improves Sleep Quality

As women transition into menopause, sleep disorders become more common. They may have trouble falling asleep and staying asleep. In fact, studies show that menopausal women spend less time in one of the deepest cycles of sleep known as the rapid eye movement (REM) sleep. [309] This in turn results in fatigue or tiredness upon waking up. Interestingly, several lines of evidence show that ERT improves sleep quality, reduces time to fall asleep and number of times a patient awakens, and increases amount of REM sleep:

1. In postmenopausal women, ERT significantly improves sleep quality, facilitates falling asleep, and decreases nocturnal restlessness and awakenings. [310-313]
2. In postmenopausal women with sleep apnea syndrome (SAS), ERT increases REM sleep and decreases the number of waking episodes. [314-317]
3. In postmenopausal women with mild-to-moderate sleep-disordered breathing (SDB), ERT is associated with significant reduction in measures of sleep-related breathing abnormalities. [318-319]
4. In women suffering from menopausal symptoms, estrogen administration at a dose of 0.625 mg significantly improves time spent awake after sleep onset and subjective measures of sleep (questionnaires). [320-321]
5. In postmenopausal women with sleeping difficulties, ERT is associated with significant decrease in hot flushes associated with awakenings, as well as improvement in sleep efficiency and a reduction in the rate of cyclic alternating pattern (EEG marker of unstable sleep). [322]
6. In menopausal and postmenopausal women, ERT improves sleep by decreasing night time awakenings. [323]
7. In perimenopausal and postmenopausal women, ERT improves sleep quality by decreasing frequent nighttime awakenings as well as vasomotor symptoms (night sweats, hot flushes and headaches). [324-330]
8. Estrogen treatment after menopause restores the normal sleep electroencephalogram pattern in postmenopausal women. [331]

Enhances Exercise Performance

With aging, a person’s activity level can significantly decrease because of various changes in body composition. Older persons start to gain weight, lose muscle and bone mass, and become susceptible to a wide array of debilitating diseases that affect their daily routine as well as overall quality of life. Fortunately, aside from diet and lifestyle modifications, restoring estrogen to youthful levels can be beneficial for older people who want to engage in any form of exercise to keep them in shape. By restoring muscle mass and bone quality, studies show that ERT can help enhance one’s exercise performance so that they can become physically active again:

1. In sedentary overweight adults, ERT appears to improve exercise performance by reducing body fat and improving lipid levels. [332]
2. In early menopausal women, ERT improves knee extensor strength, vertical jump height, and running speed. [333-334]
3. In females with estrogen deficiency, ERT lowers risk of stress fracture, thereby allowing them to sustain a high level of physical training. [335]
4. In older females, ERT is associated with significantly better postural balance. [336]
5. In postmenopausal females, ERT enhances hand grip strength. [337]
6. In postmenopausal women with muscle wasting, ERT enhances intense resistance exercises by increasing muscle mass. [338-339]
7. In healthy postmenopausal women, ERT appears to have beneficial effects on body composition and muscle performance. [340]

Decreases Urinary Tract Infections (UTI)

Postmenopausal women are often vulnerable to bacterial infections such as UTI. During this stage, falling estrogen levels result in deterioration of the urinary tract and vagina, as well as alteration in vaginal flora (bacteria that live inside the vagina). These changes predispose postmenopausal women to recurrent rate of UTIs. A growing body of scientific evidence indicates that ERT can restore vaginal flora and acidic pH to its premenopausal state, thus reducing the prevalence of UTIs in postmenopausal women:

1. In postmenopausal women with a history of recurrent UTIs, high-dose ERT cures urinary stress and urge incontinence. [341]
2. In postmenopausal women with urogenital complaints related to estrogen deficiency, low-potency estrogens do not only improve urogenital complaints effectively but also prevent recurrent UTI. [342]
3. Estrogen prevents UTI by stimulating the proliferation of lactobacillus in the vaginal epithelium, reducing pH, preventing vaginal colonization with Enterobacteriaceae (causative agent of UTI), and maintaining vaginal structure. [343]
4. In women with atrophic vaginitis (chronic and progressive inflammation of the vagina), use of estriol orally or vaginally is safe and improves urogenital complaints. [344-345]
5. In elderly women, vaginal estrogen treatment for one month dramatically reduces the incidence of UTI by increasing Lactobacilli and restoring vaginal pH. [346-347]
6. In women without liver disease, application of 0.5 mg of estriol cream produces similar beneficial effects with that of oral estriol in treating UTI. [348-349]
7. In menopausal women with recurrent UTI, estrogen stimulates the production of the body’s own antibiotic and strengthens the cells in the urinary tract. [350]
8. In postmenopausal women with recurrent UTI, use of vaginal estrogen ring for nine months reduces the incidence of UTI by 45%.[351]
9. Oral estrogen administration at a dose of 3 mg of daily for 8 weeks and 1 mg thereafter also reduces the incidence of UTI in postmenopausal women. [352]
10. In postmenopausal incontinent women, short duration (3-6 months) of ERT has significant benefits on UTI, overactive bladder symptoms, and incontinence. [353-354]
11. In postmenopausal women with recurrent UTI, ERT is more effective than antibiotics at alleviating urinary symptoms. [355]
12. If administered preoperatively, estrogen can improve outcomes of incontinence repair procedures, thereby preventing UTI. [356]

Decreases Risk of Heart Disease

The age-related decline in estrogen increases one’s risk of heart disease. This is because estrogen is believed to play a crucial role in the maintenance of a healthy heart by keeping blood vessels flexible, thereby improving the heart’s pumping power and overall blood circulation. In addition, falling estrogen levels increase blood pressure, blood sugar and cholesterol levels – all of which are major risk factors for heart disease! Recent research adds to the evidence that estrogen protects against heart attack and other adverse cardiovascular events:

1. Transdermal ERT may actually reduce the risk of heart disease among smokers and obese patients. [357-358]
2. Results from observational studies assessing the safety and benefit of ERT in young menopausal women show that local administration of estrogen in the form of vaginal creams, vaginal rings and transdermal patches is not associated with any adverse cardiovascular events. [359-360]
3. Observational studies also show that postmenopausal women who receive ERT have a lower rate of cardiovascular disease and cardiac death than those not receiving ERT. [361-362]
4. Estrogen helps activate nitric oxide, which in turn dilates the blood vessels of the heart and improves blood circulation. [363-366]
5. In the heart, estrogen receptors preserve cardiac function and protect against tissue damage caused by lack of oxygen (ischemia). [367-368]
6. Estrogen protects against heart disease by reducing oxidative stress, which is one of the major causes of heart failure. [369-372]
7. Estrogen has a profound antiapoptotic (prevents cells death) and pro-survival effect on heart muscle cells (cardiomyocytes). [373-374]
8. Estrogen protects against heart disease by reducing inflammatory markers. [375-376]
9. Estrogen promotes migration of stem cells into the injured heart muscle after ischemia, thereby improving endothelial and myocardial function. [377-379]
10. ERT decreases the risk of cardiovascular disease (CVD) and reduces mortality in postmenopausal women with heart disease. [380-381]
11. ERT use early after menopause significantly reduces risk of mortality, heart failure, or myocardial infarction. [382-386]
12. ERT use in postmenopausal women is associated with the cessation and potentially with the reversal of the progression of carotid artery atherosclerosis (plaque build-up) as assessed by ultrasonography. [387]
13. Estrogen exerts its antiatherogenic activity (fights plaque build-up) by improving cholesterol levels and preventing oxidation in the walls of the blood vessels of the heart.      [388-395]
14. In postmenopausal women with stable angina, atypical chest pain, or an abnormal exercise electrocardiogram (ECG), intravenous administration of estrogen significantly improves blood flow to the heart. [396-397]
15. In postmenopausal women, ERT significantly increases brachial arterial blood flow, which is an independent marker of blood circulation in the heart. [398-403]

Improves Cholesterol Profile

Cholesterol levels spike in men and women with advancing age. For women, however, this age-related change is striking at the menopausal transition stage. With falling estrogen levels, high-density lipoprotein (HDL) cholesterol, also known as the “good cholesterol”, starts to decline. On the other hand, the age-related decline in estrogen levels increases low-density lipoprotein (LDL) cholesterol, also known as the “bad cholesterol”. These changes in cholesterol levels are very detrimental to health because it drastically increases one’s risk of developing fatal medical conditions such as heart disease, stroke, cancer, diabetes, and hypertension. While diet and lifestyle modifications can be beneficial in improving cholesterol profile, there is strong evidence that ERT may also help normalize cholesterol levels:

1. In healthy postmenopausal women, oral estrogen supplementation increases HDL cholesterol levels by 15-18%. [404]
2. In healthy postmenopausal women who had surgical removal of the uterus, both oral and transdermal estradiol for 4 weeks increase HDL by 7.1%. [405-406]
3. In healthy premenopausal women, ERT increases HDL and decreases LDL levels without any adverse side effects. [407-418]
4. In postmenopausal women with elevated cholesterol levels, ERT produces significant and therapeutic reductions in LDL cholesterol. [419-421]
5. Oral estrogen administration for 6 months significantly increases HDL and decreases LDL in menopausal women, making it the most effective route. [422-423]

Improves Blood Sugar Levels

Estrogen helps optimize the action of insulin, the hormone that stabilizes blood sugar levels. Consequently, the age-related decline in estrogen may lead to insulin resistance, a condition in which the body doesn’t respond to the effects of insulin. Falling estrogen levels can also impair the function of insulin, resulting in sudden spikes in blood sugar levels. Studies show that by restoring estrogen to youthful levels, blood sugar levels can be normalized, thus, preventing chronic medical conditions such as diabetes:

1. In postmenopausal women with type 2 diabetes, ERT is associated with statistically significant increase in insulin sensitivity (a condition in which small amount of insulin is needed to keep blood sugar levels in the normal range). [424]
2. In diabetic women, ERT significantly lowers hemoglobin A1c, a three-month average measure of blood sugar level. [425-430]
3. In diabetic women, ERT is associated with better glycemic control. [431]
4. In postmenopausal women, low-dose combined ERT is associated with decreased risk of developing diabetes and better diabetic control. [432]
5. In non-diabetic women, the prescription of ERT improves mortality by stabilizing blood sugar levels. [433]
6. Postmenopausal estrogen use is associated with lower fasting glucose. [434]
7. In postmenopausal women with type 2 diabetes, ERT use is associated with better blood sugar control and improved insulin sensitivity. [435-440]

Improves Blood Pressure

During menopause, women lose hormone protection against a wide array of fatal medical conditions. Among them is high blood pressure or hypertension, which is highly prevalent in menopausal women. In addition to this, the age-related decline in estrogen levels puts them more at risk since estrogen engages several mechanisms that protect against hypertension. An overwhelming body of clinical trials supports the antihypertensive effect of estrogen:

1. Transdermal delivery of estrogen appears to have blood pressure-lowering effect in postmenopausal women and may be a safer alternative in hypertensive women. [441]
2. In postmenopausal women with arterial hypertension, one-year ERT improves circadian blood pressure pattern by inhibiting age-related rigidity of large arteries. [442]
3. In women with elevated resting blood pressure and positive family history of congestive heart failure (CHD), ERT inhibits exaggerated BP reactivity to stress. [443]
4. In postmenopausal women, transdermal ERT improves 24-hour blood pressure profile. [444]
5. In hypertensive postmenopausal women, ERT is associated with a lower diastolic blood pressure and decrease use of antihypertensive drugs. [445]
6. In menopausal women with mild to moderate hypertension, ERT use is associated with lower blood pressure. [446]
7. In postmenopausal women, ERT use is associated with lower pulse wave velocity (PWV), a measure of arterial stiffness. [447-450]
8. ERT improves blood pressure by counteracting arterial distensibility and increasing nitric oxide levels which both lead to widening of blood vessels. [451-456]

Decreases Risk of Stroke

Although middle-aged women have a lower incidence of stroke than men, their risk significantly increase by as much as 50% in the decade after menopause. [457] This may be due to the fact that estrogen deficiency during the postmenopausal period leads to obesity and increases in blood pressure, cholesterol and blood sugar levels – all of which are major risk factors of stroke. Interestingly, there is robust clinical evidence that ERT may actually protect against different types of stroke:

1. In postmenopausal women, ERT use is associated with a decrease in the incidence of stroke, suggesting that the treatment is safe and effective. [458]
2. In middle-aged and older women, researchers found that ERT decreases risk of total stroke during 10.5 years follow-up. [459]
3. In younger postmenopausal women, ERT is associated with lower prevalence of stroke. [460]
4. Studies indicate a reduced risk of stroke and its consequent mortality among estrogen users. [461]
5. In younger postmenopausal women with normal blood pressure (50-59 years), there is a reduced risk of stroke associated with ERT use, particularly when lower doses are prescribed soon after menopause. [462]
6. In women aged 50-79 years, transdermal ERT reduces stroke risk by 25%. [463]
7. In users of low-dose ERT, the treatment significantly reduces the risk of stroke without any adverse side effects. [464]
8. In postmenopausal women without personal history of cardiovascular disease or contraindication to hormone therapy, short-term ERT use is associated with lower risk of stroke and is considered safe. [465]
9. In postmenopausal women, ERT protects against stroke by increasing membrane fluidity of red blood cells and improving the rigidity of cell membranes via activation of nitric oxide. [466]
10. Experimental evidence suggests that estradiol can protect the brain from stroke and that surgical removal of the ovaries removes this neuroprotective effect. [467-468]
11. In animals, estradiol administration decreases infarct size (extent of tissue injury) in the brain. [469]
12. In male adult rats, higher blood estradiol protects against ischemic injury. [470]
13. In rats, administration of estrogen protects against stroke by reducing the levels of inflammatory substances. [471-490]

Boosts Immune Function

With aging, estrogen levels along with immune function start to decline predisposing a person to wide array of diseases. This is because sex hormones such as estrogen are known as the “master regulators” of the immune system. Therefore, restoring estrogen to youthful levels through ERT can significantly boost immune function and prevent fatal illnesses related with advancing age. An increasing number of scientific evidence supports the “immune-boosting” effect of estrogen:

1. In patients with early breast cancer, ERT does not increase either the risk of recurrence or of death. [491]
2. In patients with rheumatoid arthritis and systemic lupus erythematosus, ERT is associated with decreased risk of disease flare and improvement in disease activity. [492]
3. In perimenopausal women, ERT regulates immune function by increasing immune cells such as CD8+ cells. [493]
4. In postmenopausal women, ERT reverses immune alterations associated with normal aging. [494]
5. In postmenopausal women, ERT restores immune balance by enhancing antibody-mediated immunity. [495]
6. The use of ERT alone in female patients is associated with a significant reduction in lung cancer risk and related death. [496-499]
7. Estradiol reduces programmed cell death (apoptosis) of immature B cells of the immune system. [500]
8. Estrogen indirectly boosts the immune function by modulating the levels of growth hormone, prolactin, or thymosin. [501]
9. In postmenopausal women with arthritis, ERT significantly decreases disease activity and signs of inflammation. [502]
10. In postmenopausal women, ERT reverses the deleterious effects of aging on the immune system by increasing the number of B-cells and improving T-cell function. [503]
11. In postmenopausal women, ERT improves immune function by reducing elevated blood levels of the pro-inflammatory cytokines TNF-α, IFN-γ and IL-6. [504-507]

The Women’s Health Initiative (WHI): What Went Wrong?

By the mid-1990s, ERT had become one of the most widely prescribed medications for women in their menopausal period. Several observational studies have shown that women who were given ERT had lower risk of heart disease. However, in 2002, the results of the large Women’s Health Initiative (WHI) study have been both influential and controversial. This study involved 27,347 U.S. women ages 50-79 – 16,608 of them had a uterus and were given estrogen-plus-progestin while 10,739 had no uterus and were given estrogen alone. Unfortunately, the study concluded that ERT can increase one’s risk of developing breast cancer, heart disease, stroke, blood clots, and overall harm, which led to early stoppage of the clinical trial. [508] While the WHI study is considered as one of the largest clinical trials assessing the safety and efficacy of estrogen on women, several high quality studies do not agree with its results because of the following reasons:

1. The hazard ratio (HR) of the WHI study did not reach statistical significance. The authors of the WHI study reported a “significant” hazard ratio for coronary heart disease (CHD), breast cancer, blood clots, and stroke. However, other health experts who have carefully examined the WHI study suggest that the conclusions drawn were incorrect because their hazard ratio for each potential health hazard did not reach statistical significance and was based on unadjusted risk hazards. [509-510]
2. The WHI study does not even qualify as a randomized placebo-controlled study.

The reasons for this are the following: [511-515]

1. After randomization, the women were free to decide whether to continue their assigned treatment or whether to undergo diagnostic procedures.
2. Almost 50% of the women were aware of their treatment.
3. The participants received several warnings regarding increased risks of heart disease, stroke and blood clots during the study.
4. Post-hoc analyses suggest no increase in CHD in women starting estrogen treatment within 10 years of menopause. Post-hoc analyses are analyses that were not pre-planned and were conducted as additional analyses after completion of the experiment or clinical trial. Authors of the WHI study concluded that estrogen therapy had no beneficial effect on the risk of CHD and such treatment might increase CHD risk. On the contrary, post-hoc analyses found that there was no increase in CHD risk in women starting estrogen treatment within 10 years of menopause. [516]
5. The authors of the WHI study did not mention the other significant benefits of estrogen treatment among the participants. The authors only reported increased risk of breast cancer, heart attacks, stroke and blood clotting among women receiving estrogen therapy. They did not mention that the treatment “significantly” decreased the risk of colon cancer and hip fractures among the participants. [517]
6. There are some health factors that might have altered the outcome of the WHI study. The participants in the WHI study has an average BMI of 28 (overweight), one-third were hypertensive and one-half were smokers, suggesting that these factors might have significantly altered the outcome of the clinical trial. [518]   
7. The women in the WHI study were 12-15 years past the onset of menopause. This means that the participants were without their pre-menopausal estrogen levels long enough to bring about various changes in bodily functions. For instance, when estrogen is no longer secreted at menopause, this causes a decline in bone mineral density, thereby increasing a person’s risk of fractures and osteoporosis. In addition, estrogen is crucial for maintaining normal structure and function of the blood vascular system. Once a disease has already afflicted this system, ERT will not likely reverse its negative effects. [519] Therefore, ERT should be used as preventive, not corrective therapy; therefore, administration of estrogen should start during the menopausal transition and not 12-15 years past the onset of menopause.
8. The WHI study actually found beneficial effects of estrogen on heart disease, breast cancer and diabetes risk as well as improvements in menopausal symptoms, joint pain and physical functioning. The authors of the WHI study found the following beneficial effects of estrogen on various health hazards: [520]

• Diabetes risk decreased by 14-19%.
• For every 10,000 women taking estrogen-alone over a one-year period, there were 11 fewer diagnoses of CHD among women in their 50s and a 40% reduction in heart attack compared to placebo when examined over the whole 13-year time period.
• In the estrogen-alone trial, the participants had a reduced risk of breast cancer (21%) over the 13-year follow-up. The reduction in breast cancer risk even persisted after stopping the treatment.
• In women ages 50-54 years taking estrogen only, menopausal symptoms such as hot flashes and night sweats were decreased by 28%.
• Joint pain decreased during estrogen treatment.
• Over the 13-year follow-up, the rates of hip fractures were still lower in women who received estrogen.
• Physical functioning improved in the estrogen-alone group.
• There were reduced risks of overall illness and death in women taking estrogen-alone in their 50s.

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