Female Hormone Restoration
Hormone Replacement Therapy – Background
The rationale for HRT is that replacing hormones lost with age may help prevent manifestations of declining hormone levels. Although this basic premise that historically spurred the advent of conventional HRT was theoretically correct, we now know that optimal hormone restoration is much more nuanced and complex.
All steroid hormones are derived from cholesterol in a metabolic cascade. The first hormone in the cascade is pregnenolone, which can subsequently be converted into all other steroid hormones including DHEA, progesterone, testosterone, and various forms of estrogen (Hu 2010). These hormones are interrelated, yet each performs unique physiological functions. Biologically sound hormone therapy should aim to harmonize the physiological response to the milieu of hormonal signaling that is constantly taking place throughout the body.
One problem with classical HRT is that conjugated equine estrogens (CEE) stimulate a more pronounced estrogenic signal in some parts of the body compared with the endogenous estrogens produced by a woman’s body, potentially leading to adverse consequences (L'Hermite 2017). CEE, which is obtained from the urine of pregnant mares (horses) (Bhavnani 2003), is usually given in combination with a synthetic progestin, a chemical that stimulates progestogen signaling. However, CEE and chemical progestins cannot replicate the complex network of signaling stimulated by the diverse array of hormones and their metabolites under natural conditions in a woman’s body.
Another problem with conventional HRT is that CEE preparations contain other hormones, such as androgens and progestins, that differ from those naturally produced by humans (Notelovitz 2006). Also, because CEE has different forms and proportions of estrogens than those that occur in the body, its use may lead to different and disproportionate amounts of hormone metabolites than would be produced through metabolism of endogenous hormones (Bhavnani 1998). One manifestation of this divergent hormonal metabolism arising from oral equine estrogens is increased blood clotting risk, a well-known side effect of CEE (L'Hermite 2017).
In healthy reproductive-aged women, progesterone and estrogen are in a state of dynamic balance during the menstrual cycle. Progesterone has unique and essential functions in ovulation, implantation, pregnancy, and breast development and function (Ismail 2003; Al-Asmakh 2007), as well as in the brain (Mani 2012).
Progesterone can play a major role in relieving menopausal symptoms. Several studies have reported that women experienced similar or greater reductions in menopausal symptoms and improvements in quality of life, as well as fewer estrogen therapy-related side effects, with progesterone compared with medroxyprogesterone acetate, a synthetic progestin (Hargrove 1989; Montplaisir 2001; Ryan 2001; Lindenfeld 2002). In one study, symptom scores were 30% lower for sleep problems, more than 50% lower for anxiety, 60% lower for depression, 40% lower for cognitive difficulties, and 30% better for sexual function in progesterone users compared with users of a synthetic progestin. In addition, 80% of women using bioidentical progesterone reported overall satisfaction with their hormone therapy (Fitzpatrick 2000).
Progesterone has been shown to be safer than synthetic progestins for cardiovascular health. Certain synthetic progestins, but not progesterone, have been found to worsen the negative effect of oral estrogen therapy on risk of blood clots (Binkowska 2014; Scarabin 2014). The combination of conjugated equine estrogen and the synthetic progestin medroxyprogesterone acetate was found in a large case-control study to more than double the risk of venous thrombosis (Vinogradova 2019). Progesterone has demonstrated cardiovascular safety in postmenopausal women when used alone (Prior 2015). In one study, progesterone enhanced estrogen’s positive effect on blood flow to the heart muscle: when added to estrogen therapy, progesterone substantially improved coronary blood flow during treadmill exercise in women with a history of heart attack or coronary artery disease, but a synthetic progestin had no effect (Rosano 2000).
Progesterone plays a role in regulating cognitive function, social behavior, and mood, and has demonstrated neuroprotective and anti-inflammatory properties in the nervous system (Giatti 2016; Arbo 2016). Since some progesterone metabolites have anti-anxiety effects, it is thought that progesterone depletion may contribute to the increased incidence of anxiety and mood disorders seen in early menopause (Toriizuka 2000).
There are a number of naturally occurring forms of estrogen. The main estrogens in humans are estrone, estradiol, and estriol (Taioli 2010; Samavat 2015). Estrogens are produced by the ovaries during the reproductive years and in smaller amounts by the adrenal glands and other tissues throughout life. Non-ovarian sources of estrogens become more important after menopause (Rettberg 2014; Simpson 2003).
Estradiol is the most potent form in non-pregnant, reproductive-aged females and primarily aids in the cyclic release of eggs from the ovaries (ovulation) (Barbieri 2014; Chai 2014). Estradiol has beneficial effects on the heart, bone, brain, and colon (Cui 2013). Fluctuations and overall decline in estradiol levels contribute to common peri- and postmenopausal symptoms, such as hot flashes, mood swings, and vaginal atrophy (Freedman 2014; Finch 2014), and estradiol depletion after menopause impacts tissues throughout the body, contributing to a range of disease risks and frailty (Dalal 2015; Nedergaard 2013). Estrone is the dominant estrogen in postmenopausal women; it is produced by fat tissue (Wharton 2012). Estriol is a comparatively weak estrogen; because it is secreted by the placenta, estriol is the main estrogen during pregnancy (Liang 2013; Ali 2017).
The three main types of estrogen can be converted into many metabolites. Estrone, for example, may convert into the following metabolites among others (Ziegler 2015):
Some evidence suggests metabolism of estrogen into 2-hydroxylated forms may protect against breast cancer in postmenopausal women (Ziegler 2015; Moore 2016). However, more research is needed before firm conclusions can be drawn about the role of ratios among the various estrogen metabolites in breast cancer risk.
Estriol. Estriol has weaker estrogenic effects than other forms of estrogen. Studies have shown that estriol effectively treats menopausal hot flashes, night sweats, and insomnia. In addition, some studies have shown that estriol combats menopausal bone loss (Ali 2017). When taken together with estradiol, estriol opposes some of estradiol’s stronger estrogenic effects (Holtorf 2009). Applied vaginally, estriol is an excellent treatment for urinary and vaginal symptoms of menopause (L'Hermite 2017).
Estriol has been studied in the context of a range of chronic diseases. Researchers in Japan have conducted numerous trials showing that estriol may improve blood pressure, vascular function, and blood lipids (Takahashi 2000; Hayashi 2000; Kano 2002; Itoi 2000; Yamanaka 2005).
Emerging research suggests estriol has a potential role in the treatment of the autoimmune disease multiple sclerosis as well as other neurodegenerative conditions, in part through modulating immune function. This theory stems from the observation that remission and relapse of multiple sclerosis during and shortly after pregnancy is correlated with the secretion of estriol by the placenta (Ali 2017).
Estriol is not yet available in FDA-approved commercial formulations, but can be obtained through compounding pharmacies.
Beyond Estrogen and Progesterone: The Complete Hormonal Picture
In addition to estrogen and progesterone, it is important to consider the roles of the hormones pregnenolone, DHEA, and testosterone. Ideal bioidentical HRT involves comprehensive evaluation of all declining hormone levels.
DHEA. DHEA is a steroidal hormone secreted by the adrenal gland, gonads, and brain (Maninger 2009). Both men and women experience an age-related decline in DHEA (Labrie 2010). Peak levels are typically reached when women are in their 30s, after which they begin to lose approximately 2% per year (Fouany 2013). Decreased levels of DHEA and DHEA-sulfate (DHEA-s, a circulating form of DHEA) after menopause can impact cognition, mood, and sexuality (Pluchino 2015), and are thought to contribute to cancer, insulin resistance, decreased immune defenses, and psychiatric illness (Genazzani 2010).
DHEA has been shown to influence mood and neurological function (Dong 2012), immune function (Bauer 2013), energy and feelings of well-being (Rutkowski 2014), vascular health (Weiss 2012), insulin resistance and inflammatory marker levels (Weiss 2011), and the maintenance of muscle and bone mass (Kenny 2010; Weiss 2009). Furthermore, DHEA has been found to enhance sexual function and the use of intravaginal DHEA in particular has demonstrated efficacy as a treatment for postmenopausal vulvovaginal atrophy (Pluchino 2015; Archer 2015).
Testosterone. Like DHEA, testosterone levels in women gradually decrease with age (Schneider 2003). Loss of testosterone affects libido, bone and muscle mass, vasomotor symptoms, cardiovascular health, mood, and well-being (Bain 2007; Simon 2001; Watt 2003; Cameron 2004).
Testosterone therapy in women has been shown to improve quality of life, mood, concentration, bone health, markers of cardiovascular risk, cognitive function, and vulvovaginal atrophy (Braunstein 2002; Davis 2015). In addition, testosterone, both alone and in conjunction with estrogen therapy, has been shown to be effective in treating low libido and increasing sexual satisfaction in women (Bolour 2005; Achilli 2017; Cappelletti 2016; Al-Azzawi 2010). Because DHEA can be converted into testosterone, it may be possible to obtain some of the benefits of testosterone using DHEA (Cameron 2004; Labrie 2017).
Pregnenolone. As is the case with some other hormones, a significant reduction of pregnenolone begins when women reach their early 30s (Havlikova 2002). As the initial hormone in the overall steroid hormone cascade, pregnenolone is derived from cholesterol mainly in the adrenals, gonads, brain, and other tissues. In addition to acting as a precursor for other hormones, pregnenolone appears to have direct effects on regulation of neurological function (Vallee 2016; Zheng 2009). Pregnenolone may be especially important for age-related sleep and cognitive changes (Mayo 2003), and deficiencies have been associated with diminished brain function and dementia (Mellon 2007).
Hormones and Cancer Risk
Although many factors affect breast cancer risk, it is well established that high estrogen levels and increased estrogen exposure over a lifetime, especially due to an early onset of puberty, are associated with an increased risk of breast cancer (Dall 2017). Establishing a proper balance of hormones and incorporating foods and supplements that support healthy hormone metabolism may help mitigate estrogen’s breast cancer-promoting properties.
Current evidence suggests that, while CEE appear not to increase breast cancer risk, the synthetic progestin used in conventional HRT (primarily medroxyprogesterone acetate) is associated with increased risk (L'Hermite 2017). In the Women’s Health Initiative, CEE alone did not increase breast cancer risk, while CEE plus medroxyprogesterone acetate was associated with increased risk (Chlebowski 2010; Zhao 2014; Shah 2006).
The use of bioidentical progesterone in combination with estrogen has not been found to increase breast cancer risk (Fournier 2008). In fact, in vitro research suggests progesterone may actually reduce estrogen-triggered cell proliferation (Mohammed 2015). Although more research is needed to clearly establish the risks and safety of progesterone therapy with regard to breast cancer, evidence to date suggests it is safer than synthetic progestins, particularly medroxyprogesterone acetate (Asi 2016; Prior 2015).
In addition, studies suggest testosterone has anti-proliferative effects on breast tissue, countering the cancer-promoting effect of estrogen (Glaser 2015). In one study, women with breast cancer were found to have lower salivary testosterone levels than cancer-free women (Dimitrakakis 2010). In another study, postmenopausal HRT that included estrogen, progestin, and testosterone was associated with a substantially lower occurrence of breast cancer than that predicted using historical data on HRT without testosterone (Dimitrakakis 2004).