Female Hormone Restoration

Until 2002 mainstream physicians routinely prescribed conventional hormone replacement therapy (HRT) in order to alleviate menopausal symptoms, such as hot flashes, mood swings, decreased sexual desire, vaginal dryness, and difficulty sleeping, as well as to prevent heart disease and osteoporosis. In 2002, however, the results of a landmark study, the Women’s Health Initiative (WHI), identified grave dangers associated with conventional hormone replacement therapy in women. More than 160,000 women participated in this study. Conventional HRT side effects included a 26% increased risk of breast cancer, a 29% increased risk of heart attack, a 41% increase in risk for strokes, and a doubling in risk for blood clots relative to the untreated group. Moreover, women receiving conjugated equine (horse-derived) estrogen experienced a six-fold increased risk for uterine cancer. Only a small sub-group of women, those under 60 years of age who had undergone a hysterectomy (surgical removal of the uterus), experienced a reduction in breast cancer risk when using estrogen without medroxyprogesterone acetate (MPA), a synthetic progestogen (Rossouw et al 2002; Grady et al 2002; Hulley et al 2002; Azoulay 2004; Moskowitz 2006; Ragaz 2010).

Given these substantial risks of conventional HRT, many women began to seek alternatives. Up to 70% of women taking HRT stopped, and overall, women’s trust in the mainstream medical establishment declined significantly (Roumie 2004; Schonberg 2005). Data from the study also resulted in many physicians discouraging the use of conventional HRT for the prevention of osteoporosis and cardiovascular disease in aging women (Sharma 2003, Azoulay 2004).

Though many mainstream physicians were shocked by the results of the WHI study, Life Extension was not surprised. The hormones utilized in the WHI study consisted of oral equine (horse) estrogen and a synthetic progestogen, both of which differ in chemical structure from the hormones a woman’s body produces naturally. Life Extension has discouraged the use of conventional HRT for many years and has instead recognized the value of bioidentical HRT, which uses hormones that are exactly the same as those naturally produced in women. Bioidentical HRT is associated with far fewer side effects than conventional HRT and there is intriguing evidence that it may reduce the risk of certain cancers (Holtorf 2009).

Moreover, supplementation with scientifically studied vitamins and natural plant extracts can help promote healthy metabolism of female hormones and complement the actions of bioidentical HRT.

Understanding Conventional HRT

The rational for conventional HRT is that women’s hormone levels decline with age. Replacement, therefore, should reverse troubling menopausal consequences, which include increased risk of heart attack and cancer (Wren 2009; Lenfant 2010; Lee 2010). While the original understanding of menopause and the logic of HRT were theoretically correct, modern science is showing that the true story of HRT is much more complex (Sitruk-Ware 2007). Early views did not do justice to the finely tuned hormonal system that operates throughout a woman's life.

It is impossible to consider estrogen and progesterone in isolation from other hormones. All steroid hormones are created from cholesterol in a hormonal cascade. The first in the cascade is pregnenolone, which is subsequently converted into other hormones, including dehydroepiandrosterone (DHEA), progesterone, testosterone, and the various forms of estrogen. These hormones are interrelated, yet each performs unique physiological functions. Biologically sound hormone replacement should focus on a woman's total hormone balance, and not only on estrogen and progesterone.

The importance of balance cannot be overstated. Mainstream physicians are just now beginning to recognize estrogen dominance (Turgeon 2006), a term used to characterize the relative imbalance between excess estrogen and insufficient progesterone. Estrogen dominance helps explain many of the conditions that confront modern Western women, such as fibrocystic breast disease (Kubista 1990), and cancer (Bentrem 2003; Bradlow 1995; Papaconstantinou 2000). Estrogen dominance can occur in any woman, but perimenopausal women, who typically experience a more rapid decline in progesterone relative to estrogen, are especially at risk (Fauser and Van Heusden 1997).

Conventional HRT makes use of non-bioidentical hormones that differ chemically from those naturally produced by a woman’s body. Furthermore, the relative levels of the female hormones administered in conventional HRT are also different (Turgeon 2006; Chlebowski 2010).

For instance, conjugated equine estrogen (CEE), as the name implies, is obtained from the urine of pregnant mares (horses) (Bhavnani 2003). CEE is usually given in combination with progestin, a chemical compound modified for the purpose of appearing structurally similar to natural, bioidentical progesterone, but which, in fact, is not the same. These structural differences between conjugated equine estrogens and chemical progestins, and the hormones that women’s bodies produce naturally explain many of the adverse affects associated with conventional HRT.

Another major problem with conventional HRT is the ratio of estrogens. Specifically, an approximate ratio of estrogens in Premarin® is about 75% estrone, up to 15% equilin (a potent horse estrogen), estradiol, and at least two other equine estrogens. These are substantially different from the ratios observed naturally in a woman’s body (Wright 1999).

Is Cancer Risk a Reason to Deprive Aging Women of Natural Hormones?

Concern about cancer is an important reason why more aging women do not restore their hormones to youthful levels. Hormones like estrogen and testosterone affect cell growth and proliferation. Does that mean aging women should simply accept the sex hormone deficiencies they face as a part of "normal" aging?

To fully understand the carcinogenic effects of aging, we have reprinted a chart showing women's breast cancer risk by age (Simone 2005). If estrogen caused breast cancer, then we would expect to see very high rates of breast cancer in young women of childbearing age, with a dramatic decrease in breast cancer after menopause. This is not observed. Clearly aging is the primary cause of breast cancer.

The reason cancer risk increases with aging is that the genes that help regulate healthy cell growth can mutate. In fact, mutations in cells’ regulatory genes are an underlying cause of cancer (Haber 2000). The concern is that breast cells with mutated regulatory genes may be more vulnerable to estrogen’s growth stimulating effects.

Information on nutrients that complement bioidentical HRT and may combat these age-related genetic mutations is provided in this protocol in the section entitled “Anticancer Nutrients to Complement Bioidentical HRT.”

Estrogen Explained

To fully appreciate the complexity of HRT, it is important to understand the various forms of estrogen and their effects in the body. More than 15 forms of estrogen naturally created in a woman’s body have been identified (Taioli, 2010). These include estrone, estradiol, and estriol.

Each of these estrogens has particular functions. Estradiol (E2), the predominant form in reproductive-age non-pregnant females, primarily aids in the cyclic release of eggs from the ovaries for potential fertilization and preparation of the uterus for pregnancy. Estradiol also has beneficial effects on heart, bone, brain and colon. Reduction in the level of estradiol causes common menopausal symptoms such as hot flashes and night sweats. Estrone (E1), produced in the ovaries but also generated in fat cells, is another relatively potent form of estrogen, and is the dominant estrogen in postmenopausal women. Estriol (E3) is secreted in large quantities during pregnancy by the placenta; however, it is a comparatively weak estrogen, and the form of estrogen least associated with hormone-related cancers. In Europe and Japan, estriol is frequently used for HRT (Head 1998; Kano 2002, Moskowitz 2006, Holtor 2009).

The three estrogens convert into many metabolites. Estrone, for example, may convert into three different forms:

• 2-hydroxyestrone
• 4-hydroxyestrone
• 16-alpha-hydroxyestrone

Scientists have identified 2-hydroxyestrone as a “good,” or chemoprotective estrogen, while 16-alpha-hydroxyestrone and 4-hydroxyestrone have been associated with the development of cancer (Bradlow 1996; Muti 2000). The relationship between 2-hydroxyestrone and 16-alpha-hydroxyestrone is sometimes expressed as the 2:16 ratio (Taioli 2010).

By increasing the ratio of 2-hydroxyestrone to 16-alpha-hydroxyestrone, it may be possible to reduce the risk of estrogen-related cancers (Bradlow 1986; Taioli 2010).

3,3’-Diindolylmethane (DIM) and indole-3-carbinole (I3C), found in appreciable concentrations in cruciferous vegetables, favorably affect estrogen metabolism and help to optimize the 2:16 ratio. A placebo-controlled, double-blind study of women at increased risk for breast cancer found that four weeks of supplementation with I3C promoted favorable changes in the urinary estrogen metabolite ratio of 2-hydroxy-estrone to 16-alpha-hydroxyestrone (Wong 1997; Dalessandri 2004).

Estrogen Receptors and a Closer Look at Estriol

As mentioned previously, estriol (E3) is the form of estrogen least associated with cancer. Estriol’s protective effects become apparent when examining the differing actions that each of the three primary estrogens exerts upon the estrogen receptors. On breast cells there are two distinct classical estrogen receptors that bind estrogens, estrogen receptoralpha and estrogen receptorbeta. In addition, there is one non-classical estrogen receptor, GPR30 (Paruthiyll 2004; Paech 1997; Katzenellenbogen 2000; Nilsson 200; Wang 2010). The binding of estrogen hormones to estrogen receptor alpha promotes breast cell proliferation, which can exacerbate the spread of existing breast cancer. Conversely, the binding and activation of estrogen receptor betaattenuates breast cell proliferation and may slow the development of a cancerous tumor (Helguero 2005; Bardin 2004; Isaksson 2002; Weatherman 2001).

Estrone and estradiol preferentially bind to and activate estrogen receptor alpha, thereby explaining the proliferative effects of these two hormones (Zhu 2006; Rich 2002). Estriol, on the other hand, binds to and activates estrogen receptor beta (Zhu 2006; Rich 2002). This critical fact helps to explain estriol’s “anti-estrogenic” activity, which led a noted researcher in hormone replacement therapy to state, “This unique property of estriol, in contrast to the selective ER [estrogen receptor] alpha binding by other estrogens, imparts to estriol a potential for breast cancer prevention, while other estrogens [estrone and estradiol], would be expected to promote breast cancer… Because of its differing effects on ER alpha and ER beta, we would expect that estriol would be less likely to induce proliferative [potential cancerous growth] changes in breast tissue and to be associated with a reduced risk of breast cancer” (Holtorf 2009).

Moreover, groundbreaking research has revealed that the non-classical estrogen receptor, GPR30, mediates proliferation of breast cancer cells independently of the two classical estrogen receptors. Estradiol strongly binds to and activates GPR30, driving proliferation. Estriol, on the other hand, acts as an antagonist of GPR30, though it has a much lower affinity for GPR30 than does estradiol (Wang 2010; Lappano 2010). Many carcinogenic toxins, including bisphenol A (BPA) and polychlorinated biphenyl’s (PCB’s), promote the growth of breast cancer cells by functioning as agonists of GPR30 (Wang 2010).

Significantly, the traditional breast cancer drug tamoxifen, which blocks the activity of the classical estrogen receptors, fails to suppress the cancer-promoting effects of GPR30. It is by this mechanism that some estrogen receptor positive breast cancers become drug-resistant. In fact, tamoxifen has been shown to stimulate the growth of drug-resistant breast cancer cells via activation of GPR30 (Ignatov 2010).

Estriol, through its estrogen receptor modulatory capacity, combats the proliferative effects of estrone and estradiol (Melamen 1997; Wang 2010). These scientific findings highlight the importance of emphasizing estriol in any bioidentical hormone replacement program intended to restore youthful hormone balance and guard against breast cancer development.

Progesterone's Balancing Act

Estrogen is only part of the hormonal picture. Progesterone is equally important. In a healthy young woman, progesterone serves as a counterweight to estrogen. While estrogen builds up during the first half of a menstrual cycle, progesterone levels do not start rising until the middle of the cycle. Progesterone's job is to prepare the uterus for implantation with a healthy fertilized egg and to support the early pregnancy. If no implantation occurs, progesterone levels drop and another cycle begins.

Studies have shown that progesterone has anti-proliferative effects on at least two different types of breast cancer cells, as well as leukemia cells (Formby 1998; Hayden 2009; Hilton 2010). Breast cancer is 5.4 times more common in pre-menopausal women with low progesterone than in pre-menopausal women who have favorable progesterone levels (Cowan 1981). Data suggest that while natural, bioidentical progesterone does not increase breast cancer risk, synthetic progestins used in conventional HRT do raise the risk. (Campagnoli 2005).

Natural progesterone has also demonstrated neuroprotective properties. For example, one study called for more attention to progesterone as a “potent neurotrophic agent that may play an important role in reducing or preventing motor, cognitive, and sensory impairments [in both men and women].” (Stein 2005)

Progesterone deficiency has also been linked to migraine (Colson et al 2005).

Bioidentical Hormone Replacement Therapy

Bioidentical hormone formulations in doses tailored to individual patients can be obtained from a compounding pharmacy after a physician’s prescription has been submitted. The use of bioidentical estrogens has been utilized extensively in Europe and Japan for several years (Kano et al 2002).

Estriol has shown beneficial effects in women at risk for cardiovascular disease.

Japanese scientists found that a group of menopausal women treated with estriol for 12 months had a significant decrease in both systolic and diastolic blood pressure (Takahashi 2000). Another placebo-controlled study demonstrated that estriol replacement for 30 weeks improved flow-mediated dilation, a measure of arterial relaxation (Hayashi 2000). Estriol accomplishes these effects by strongly activating nitric oxide signaling systems and stabilizing atherosclerotic plaques (Kano 2002).

Estriol may further reduce cardiovascular risk through its beneficial effects on lipid profiles. One Japanese study found that estriol prevented a postmenopausal rise in total cholesterol, and did not induce the elevated triglyceride levels, a side effect frequently seen after treatment with conventional estrogen therapy (Itoi 2000). Estriol, in combination with a statin drug, can reduce carotid artery intima-media thickness, a measure of atherosclerosis, in postmenopausal women with elevated blood lipids (Yamanaka 2005).

Estriol also increases bone mineral density, a vital parameter in post-menopausal women at risk for osteoporosis. In one study, women treated with estriol exhibited an increase in bone mineral density and improved climacteric symptoms with no increased risk of endometrial hyperplasia (Minaguchi 1996). In a second study, researchers treated postmenopausal and elderly women with estriol and 1,000 mg/day of calcium lactate versus 1,000 mg/day of calcium lactate alone. Bone mineral density significantly increased in women who received estriol, while those who did not take estriol experienced a decrease in bone mineral density (Nishibe 1996). In a summary statement, the researchers wrote, “the acceleration of bone turnover usually observed after menopause was prevented by treatment with E3 [estriol].” (Nozaki 1996)

Estriol also supports sexual and urinary health. For example, one study showed that estriol-treated women reported a 68% reduction in symptoms of incontinence, a significant result compared with just 16% of women in the placebo group (Dessole 2004). Women with recurrent urinary tract infections experienced a 91% reduction in infections following treatment with an intravaginal estriol cream, compared with placebo recipients (Raz 1993). Another study demonstrated that locally administered estriol therapy significantly increased the number of blood vessels surrounding the urethra, thereby improving its ability to keep urine in the bladder until urination is desired (Kobata 2008). The addition of estriol to standard therapy for prevention of urinary tract infections reduced the number of recurrences 11-fold, and the days of antibiotic therapy more than 12-fold in another study (Davidov 2009).

Stress incontinence refers to intermittent loss of urine with pelvic floor stress from laughing, coughing, etc. Pelvic floor muscle exercises are effective in reducing stress incontinence, and studies suggest that estriol adds substantially to the beneficial effect (Ishiko 2001).

Estriol can offer relief for women suffering from atrophic vaginitis, the symptoms of which include vaginal dryness, vaginal burning, and painful intercourse. After 4 weeks of treatment with an intravaginal estriol cream, researchers noted,“atrophy of vaginal epithelium and chronic vaginitis stopped or significantly decreased… The subjective complaints relating to the estrogen deficiency (vaginal burning and dryness, itching, dyspareunia [painful sex] and urinary dysfunctions) ceased. Side-effects and complications during the treatment were not found.” (Koloszar 1995) More objective improvements to vaginal dryness and acidity have been demonstrated in recent studies (Chollet 2009).

Topical estriol creams applied to the face and neck can also reduce many of the symptoms of aging skin, such as dryness and wrinkling. Animal studies demonstrate that estriol cream promotes collagen production and enhances the elasticity of treated skin (Ozyazgan 2005).

Studies have also shown estriol to be effective in the treatment of menopausal symptoms. In one investigation of women given varying doses of estriol for six months, vasomotor symptoms of menopause, such as hot flashes, decreased. The improvements were found to be dose-dependent. There were no detrimental effects on uterine or breast tissue (Tzingounis 1978). Other studies have shown similar results, with up to 71% of patients reporting elimination of hot flashes and sweating, and 21% reporting substantial reduction (Lauritzen 1987).

Progesterone complements and balances the impact of estrogen in aging women. Combined with estrogen, progesterone substantially improved the amount of time women with a history of heart attack or coronary artery disease could work out on a treadmill before reducing blood flow to the heart. Use of non-bioidentical progesterone produced no effect (Rosano 2000). Another mechanism by which progesterone enhances cardiovascular health is its ability to maintain or even increase HDL levels in women receiving estrogen replacement therapy (Bernstein and Pohost 2010; Ottosson 1985; Jensen 1987).

Progesterone has a major role in relieving menopausal symptoms as well. Four head-to-head studies comparing progesterone to non-bioidentical progestin reported that women experienced greater satisfaction, improved quality of life, and fewer side effects when they were switched from non-bioidentical progestin to progesterone (Hargrove 1989; Montplaisir 2001; Ryan 2001; Lindenfeld 2002). In a landmark study at the Mayo Clinic, the beneficial effects of progesterone compared to nonbioidentical progestin included a 30% reduction in sleep problems, a 50% reduction in anxiety, a 60% reduction in depression, a 25% reduction in menstrual bleeding, a 40% reduction in cognitive difficulties, and a 30% improvement in sexual function. 80% of women in the study reported overall satisfaction with the bioidentical progesterone formulation (Fitzpatrick 2000).

Beyond Estrogen and Progesterone: The Complete Hormonal Picture

In addition to estrogen and progesterone, it is also important to monitor levels of the hormones pregnenolone, DHEA, and testosterone. Ideal bioidentical HRT goes beyond the mere suppression of symptoms caused by declining ovarian hormone levels. The real goal of Life Extension's approach to female hormone restoration is to restore hormones to youthful levels. Such an approach has wide-ranging benefits throughout the body and significantly enhances physical and psychological well-being.

DHEA is a natural steroidal hormone secreted by the adrenal gland, the gonads, and the brain (Maninger 2009). Although women usually have less DHEA than men, both sexes lose DHEA over time, suggesting that its decline is age-related (Labrie 2010). Peak levels are typically reached when women are in their third decade of life, after which they begin to lose approximately 2% per year. Decreased levels of DHEA are associated with cancer, diabetes, lupus, and psychiatric illness (Genazzani and Pluchino 2010). Low levels of DHEA are also associated with higher levels of insomnia, pain, and disability (Morrison et al 2000).

DHEA has been shown to improve mood, neurological functions, immune functions, energy, feelings of well-being, and the maintenance of muscle and bone mass (Kenny 2010; Weiss 2009). A combination of DHEA and pregnenolone has been shown to improve memory (Ritsner 2010). DHEA may also improve insulin sensitivity and lower triglyceride levels (Genazzani 2010; Casson 1995).

Life Extension suggests that maturing women strive to keep their DHEA-sulfate (DHEA-s) levels in a range of 250 – 380 µg/dL in order to promote optimal health and vitality.

Testosterone levels in women also gradually decrease with age (Schneider 2003). Loss of testosterone affects libido, bone and muscle mass, vasomotor symptoms, cardiovascular health, mood, and well-being (Simon 2001; Watt 2003). Testosterone therapy, in conjunction with estrogen therapy, has been shown to improve quality of life, vigor, mood, ability to concentrate, bone mineralization, libido, and sexual satisfaction (Al-Azzawi 2010; Simon 2001; Braunstein 2002; Cameron 2004). This combination therapy also helps reduce hot flashes, sleep disturbances, night sweats, and vaginal dryness (Guillermo 2010). Because DHEA converts into testosterone, it is possible to raise testosterone levels with DHEA (Cameron 2004; Schneider 2003).

Studies also suggest that testosterone, in the context of hormone restoration, may prevent or reduce estrogenic cancer risk in the treatment of women with ovarian failure (Dimitrakakis 2003; Zhou 2000). In addition, testosterone is effective in the treatment of decreased libido in women (Guillermo 2010).

Life Extension encourages females to maintain a total testosterone level of 35-45 ng/dL and a free testosterone level of 1 – 2.2 pg/mL.

Pregnenolone levels also decline with age. As the initial hormone in the overall steroid hormone cascade, pregnenolone is derived from cholesterol. As is the case with other hormones, a significant reduction begins when women reach their early thirties (Havlikova 2002). Pregnenolone deficiencies have been associated with diminished brain function and dementia (Mellon 2007).

Aging women should attain a pregnenolone blood level of 130 -180 ng/dL for optimal performance.

It is very important that women have their hormone levels checked before beginning bioidentical hormone restoration therapy. To ensure safe and adequate levels, testing should occur one month after commencing HRT, and then again after two more months. Those women who wish to enhance their sexual desire and have already tried DHEA and pregnenolone therapy, should talk to their physician about options that may include small amounts of testosterone. Women should always consult a physician before beginning HRT, especially if they have had a hormone-responsive cancer (e.g., breast or endometrial) or are at high risk (e.g., have a first-degree relative with breast cancer).

Moving Forward with Bioidentical HRT

Given the wealth of data demonstrating the superiority of bioidentical HRT, a noted researcher in hormone replacement therapy proclaimed, “Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their… animal-derived [non-bioidentical] counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT.” (Holtorf 2009)

Compounded prescription bioidentical estrogen formulas include Bi-Est and Tri-Est. Bi-Est consists of estradiol and estriol, while Tri-Est contains estradiol, estrone, and estriol (Taylor 2001). Bi-Est typically consists of 80% estriol and 20% estradiol. Tri-Est usually contains 80% estriol, 10% estradiol, and 10% estrone. In some situations these proportions do not meet the needs of every woman. For example, the proportions observed naturally in reproductive age women were 90% estriol, 7% estradiol, and 3% estrone (Wright 1999). In these cases a prescription is tailored to the needs of the patient by an experienced physician, and is based upon the results of hormone tests and assessment of symptoms.

A comprehensive hormone restoration program should also include progesterone, DHEA, pregnenolone, and perhaps testosterone.

There are two differing philosophies regarding the dosing of hormones. The first encourages using the lowest possible dose that will ameliorate the symptoms. This is a very conservative approach that may appeal to some women and their treating physicians. This approach is also unlikely to cause a menopausal woman to generate bleeding associated with a menstrual cycle. It is, however, unlikely to bring hormones back to the levels Life Extension would consider optimal.

The second approach involves significantly higher hormone dosages. The idea here is that a woman needs to “trick” her brain into thinking she is still of reproductive age. According to this strategy, the goal is to achieve levels that mimic the hormonal fluctuations of a menstruating young woman, thereby restoring the menstrual cycle.

Physicians experienced in bioidentical hormone replacement can help women find an optimal dosing strategy based on the results of hormone testing and clinical evaluation. Most women find they respond desirably to bioidentical hormone replacement therapy when the dosing strategy combines aspects of both of the aforementioned approaches.