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Pause menopause with Rhodiola rosea, a natural selective estrogen receptor modulator.

ABSTRACT

Background: Menopausal women are challenged by the adverse effects of estrogen loss on energy, mood, cognitive function, and memory. These stresses are compounded by increased risks for cardiovascular disease, osteoporosis, and cancer. Known to have neuroprotective, cardio-protective, anti-oxidative and anti-carcinogenic effects, Rhodiola rosea extracts have also been shown to improve energy, mood, cognitive function and memory.

Purpose: We propose that R. rosea be investigated for use as a potential selective estrogen receptor modulator (SERM) in the prevention and treatment of menopause-related fatigue, stress, depression, cognitive decline, memory impairment, cardiovascular disease, osteoporosis and cancer.

Method: This paper briefly reviews the relationship between estrogen decline and menopause-related health risks, the molecular mechanisms underlying estrogenic effects on health, and the evidence indicating beneficial effects of R. rosea extracts on these mechanisms and health risks. Mechanisms include nongenomic and genomic effects, for example: activation of intra-cellular signal transduction pathways by binding to estrogen receptors, ER[alpha]-mediated activation of endothelial nitric oxide synthase with increased nitric oxide release; and anti-inflammatory effects, counteracting TNF[alpha] by inhibiting nuclear factor-Kappa-B (N[F-.sub.kB)] and protection of osteoblasts from hydrogen peroxide. A clinical case illustrating treatment of a menopausal woman with R. rosea is presented. Risks, benefits, gaps in knowledge, and future directions are discussed.

Conclusion: Numerous lines of evidence indicate that R. rosea should be investigated as a potential selective estrogen receptor modulator (SERM) to prevent, delay or mitigate menopause-related cognitive, psychological, cardiovascular and osteoporotic conditions.

Keywords:

Menopause

Selective estrogen receptor modulator

Rhodiola rosea

Cognitive function

Cardiovascular

Introduction and background

Menopause-related illnesses constitute a major public health concern. In countries where women's life expectancy exceeds 80 years, the average age of menopause (defined as the absence of menstrual cycle for 12 months) is 51. An inter-continental review estimated that women spend one third of their lives in menopause regardless of ethnicity or socio-economic factors (Makara-Studzinska, Krys-Noszczyk, Jakiel, 2014). Menopause is often accompanied by declining energy, mood, cognitive function, and memory. In addition, menopausal women are at increased risks for cardiovascular diseases, dementia, osteoporosis, and cancer. It has been estimated that about half of women over the age of 50 will experience menopause-related symptoms that will cause somewhat or fairly difficult problems at work; about 5% will have severe difficulties (Kopenhager and Guidozzi, 2015).

Hormone Replacement Therapy (HRT), once thought to be the panacea for menopause, has fallen out of favor since findings from the Women's Health Initiative (WHI) indicated that: estrogen plus progestin does not provide cardioprotection and might increase the risk of coronary heart disease; estrogen plus progestin did not prevent mild cognitive impairment and increased the risk for dementia in postmenopausal women aged 65 and older (Manson et al., 2003; Shumaker et al., 2003). Although estrogen plus progestin increased bone mineral density (BMD) and decreased the risk of fractures, these benefits were not considered to outweigh the other possible increased health risks for breast cancer and venous thrombosis (Cauley et al., 2003). More recent interpretations of the WHI data on HRT distinguish between early menopause, as a time of less risk and greater benefit, versus later menopause (after 10 years), as a time of greater risk and less benefit (Chlebowski and Anderson, 2015; Roehm, 2015). Furthermore, the WHI Study found that in women 65 years of age and older and 15 or more years past the onset of menopause, HRT with conjugated equine estrogens (Premarin) did not improve cognitive function and slightly increased the risk of dementia (Luine, 2008). Studies of 17[beta]-estradiol given during or shortly after the onset of menopause showed improvements in verbal memory, working memory, and visuospatial function with a comparatively lower risk of dementia (Frick, 2010).

Since the introduction of Premarin 75 years ago, no new treatments have been approved as HRT for menopause-related cognitive or cardiovascular symptoms. Selective estrogen receptor modulators (SERMS) are estrogen receptor ligands that exert estrogen agonistic or antagonistic activity in a tissue-specific manner. Starting in the 1990's, the development of SERMS has been directed towards preventing osteoporosis (agonists in bone) and reducing cancer risks (antagonists in breast tissue). Examples of SERMS include, tamoxifen for treatment of estrogen receptor (ER) positive breast cancer, raloxifene for postmenopausal osteoporosis, and bazedoxifene (BZA) to prevent osteoporosis while blocking estrogenic stimulation in breast and uterus. BZA combined with conjugated estrogens, is a new tissue-selective estrogen complex (TSEC) (Xu et al., 2015). Side effects of SERMS include fatigue, hot flushes, leg cramps, vaginal discharge, and mood swings. These prescription SERMS also increase the risk of arterial and venous thrombosis, pulmonary embolism and retinal vein thrombosis. Many women are reluctant to try synthetic SERMS, while others discontinue use after a few years. The quest continues for an ideal selective estrogen receptor modulator (SERM), the Holy Grail of menopausal medicine. The ideal SERM would exert agonistic effects on estrogen receptors (ERs) in bone, vascular and brain tissues, while simultaneously causing anti-estrogenic or no estrogenic effects in healthy breast, endometrial or ovarian tissue.

In deciding whether to initiate HRT, patients and physicians must weigh the risks, benefits, personal and family history, and other individual complicating factors. Many women choose to endure the discomforts of menopause rather than expose themselves to the risks associated with HRT. Women are placing greater importance on maintaining their physical and cognitive health, in part due to cultural changes in their expectations regarding their abilities to continue working, caring for family members, and functioning at higher levels later in life. These aspirations are reflected in the adage, "Seventy is the new fifty." Women are changing their lifestyles, exercising more, improving their diets, and hoping that healthy choices will mitigate the changes and the risks associated with menopause, even in the absence of definitive studies.

The search for effective alternatives to HRT is gaining momentum. Adaptogenic herbs contain numerous constituents that can act on estrogen receptors, intra-cellular signaling, genomic regulation, and inter-cellular transmission involved in supporting the brain functions that become impaired with estrogen decline and aging (Panossian et al., 2013, 2014; Panossian and Wikman, 2010). Certain physiological mechanisms whereby estrogen decline leads to common health problems experienced by menopausal women can be modulated by adaptogenic herbs, particularly Rhodiola rosea. Therefore, a review of the impact of R. rosea, estrogens, and estradiol, on neuroprotection, stress resistance, anxiety, depression, cardiovascular protection, osteoprotection, and cancer is in order. Data from in vitro, in vivo and clinical trials as well as case examples contribute to the growing evidence that supports the proposal that R. rosea be investigated as a potential SERM for the treatment of menopause-related symptoms.

Rhodiola rosea and salidrosides

Animal and human studies of Rhodiola rosea indicate that it can improve many of the neuropsychological symptoms experienced by menopausal women, including fatigue, anxiety, depression, cognitive dysfunction, memory decline, reduced executive functions, and stress intolerance (Bystritsky et al., 2008; Darbinyan et al., 2007; Gerbarg et al., 2015; Panossian, 2013; Panossian and Wagner, 2011; Shevtsov et al., 2003). Salidroside [2-(4-hydroxyphenyl)ethyl-[beta]-D-glucopyranoside], a phenylpropanoid glycoside, is one of the bioactive constituents in R. rosea root extracts. Evidence indicates that R. rosea and salidroside may protect endothelial and cardiac function, reduce the risk of cancer, and cause fewer adverse effects compared with synthetic SERMS (Brown et al., 2009; Ciumasu-Rimbu et al., 2012; Xing et al., 2015; Zhang et al., 2012). In vitro and in vivo studies of R. rosea extracts are extensive. Although the methodologies of some older studies of R. rosea extract have been criticized, the risk benefit ratio is considered to be favorable (European Medicine Agency, 2012).

Neuroprotection

Effects of estrogen on cognitive functions

Estrogen loss can exacerbate the effects of aging on cognitive functions, particularly learning, memory and executive functions. Estradiol enters the cell nucleus where it may bind to estrogen receptor alpha (ER[alpha]) or estrogen receptor beta (ER[beta]). The bound complexes function as nuclear transcription factors which bind to estrogen response elements, stimulating gene transcription and consequent increased production of cellular proteins that can enhance cognitive functions by increasing neural transmission, spinogenesis and synaptogenesis, for example, in the prefrontal cortex and hippocampus (Hara et al., 2015). These actions enhance memory formation, consolidation, storage and retrieval. Estradiol can initiate intracellular signal transduction pathways via ERs. In addition to genomic effects, through activation of ER[alpha] and ER[beta], rapid nongenomic effects are mediated through membrane-bound ER[alpha], ER[beta], and membrane glucocorticoid protein coupled estrogen receptor 1 (GPER1) (Hara et al., 2015). These estrogen receptors are found in synapses in the hippocampus and prefrontal cortex. Estrogens synthesized locally in the brain can rapidly modulate cognitive and other neuronal functions (Luine, 2014).

Cholinergic and serotonergic systems function as biological mediators of hormonal effects on the brain (Comasco et al., 2014). Animal and human trials show that chronic administration of estradiol upregulates neuronal systems (including cholinergic, monoaminergic, gamma aminobutyric acid [GABA]-ergic, and glutaminergic) which enhance cognition, memory and emotion regulation (Levine, 2011).

Menopausal changes in reproductive hormone levels have been linked to an increased incidence of Alzheimer's Disease (AD) in women (Blair et al., 2015). The concept of a "critical window" between the onset of menopause and 10 years post-menopause has been used to explain why HRT may have beneficial effects such as reduced AD risk if given during early menopause, but no benefit and possibly adverse effects when given during later menopause (after 10 years) (Daniel et al., 2015). Studies of this "critical window" have produced mixed results. Oxidative stress and inflammatory cytokines contribute to progression of neuronal dysfunction associated with menopause.

Effects of rhodiola rosea and salidrosides on cognitive functions

Numerous in vitro and animal studies demonstrate neuroprotection by salidrosides. Clinical studies of R. rosea have shown improvement in cognitive functions and physical performance, especially under stress (reviewed by Brown et al., 2009; Panossian and Wagner 2011; Panossian and Gerbarg, in press). Most of these studies were in young healthy students, military cadets, and cosmonauts. A combination of R. rosea, vitamins and minerals (Vigocana[R]) was given to 120 adults including 38 women between the ages of 50 and 89 years who had physical problems, cognitive and memory decline, impaired concentration, and reduced stress tolerance (Fintelmann and Gruenwald, 2007). Statistically significant improvements were found in physical and cognitive functions over 12 weeks in the whole group. Treatment was well-tolerated with no adverse effects.

Psychological stress, anxiety, depression, and fatigue

Clinical trials of R. rosea with moderate to good methodology indicate beneficial effects on mental performance, anxiety and depression (Hung et al., 2011). In animal studies, salidrosides showed anti-stress effects and protection of hypothalamic-pituitary-adrenal (HPA) function (Wang et al., 2009) [abstract only], A 4-week open-label trial of 20 mg twice daily R. rosea extract WS[R] 1375 administered to 101 subjects aged (40-60 years) significantly improved life-stress symptoms based on Perceived Stress Questionnaire, Sheehan Disability Index, Clinical Global Impression, and Multidimensional Fatigue Inventory 20 (Edwards et al., 2012). Adverse events (44 mild and 10 moderate) were predominantly consistent with patients' underlying conditions. In a 4-week randomized, double-blind, placebo-controlled trial, 60 adults with stress-related "fatigue syndrome" [International Classification of Diseases (ICD) F43.8A (WHO, 1992)], "burnout" and mildly impaired cognitive function were given 228 mg twice daily R. rosea SHR-5 (4% rosavins, 1% salidrosides). Significantly greater improvements were reported with R. rosea, in comparison to placebo, for fatigue (Pine's Burnout Scale), mood (Montgomery-Asberg Depression Rating Scale), several indices of attention (Conners' Computerized Continuous Performance Test II), and saliva cortisol response to awakening (Olsson et al., 2009).

A small open-label study of 10 adults (aged 18-55) with generalized anxiety disorder given 340 mg per day of R. rosea (Rhodax) showed significant improvements in anxiety and depression ratings (Bystritsky et al., 2008). In a 6-week double-blind randomized, placebo-controlled study of 91 patients (aged 18-70) with mild to moderate depression significant improvements (p < 0.001) occurred in depression, insomnia, emotional instability, somatization, and self-esteem (Darbinyan et al., 2007). Numerous studies have shown that R. rosea reduces mental fatigue (Shevtsov et al., 2003; Spasov et al., 2000a, 2000b; Olsson et al., 2009).

Cardiovascular protection

Estrogen decline and vascular aging

During menopause, vascular aging accelerates with endothelial dysfunction and large artery stiffening, a major risk factor for cardiovascular and cerebrovascular disease. Reduction in endothelial-dependent vasodilation (EDV) is a major predictor of cardiovascular events. Several mechanisms contribute to the reduction of EDV (Moreau and Hildreth, 2014):

(1) Reduced availability of the vasodilator nitric oxide (NO).

(2) Reduced estrogen receptor alpha (ER[alpha]) expression and reduced ER[alpha]/endothelial nitric oxide synthase (eNOS) signaling.

(3) NO release is triggered by ER[alpha]-mediated activation of endothelial nitric oxide synthase (eNOS) and increased eNOS transcription.

(4) Increased oxidative stress is another critical factor in endothelial dysfunction. The loss of antioxidant effects of estrogen and the concomitant increase in other causes of oxidative stress contribute to oxidative damage to the vascular endothelium.

(5) It has been proposed that under pathophysiological states, including aging, eNOS can become uncoupled, producing reactive oxygen species (ROS) instead of NO. Reduced tetrahydrobiopterin ([BH.sub.4]), a necessary cofactor for eNOS function, has been associated with impaired EDV. In a randomized controlled trial (RCT), postmenopausal women given oral [BH.sub.4] increased EDV by 35% (Yang et al., 2009).

(6) Tumor necrosis factor-alpha (TNF[alpha]:) upregulates inflammatory markers (eg. C-reactive protein) and vasoconstrictors (eg. angiotensin). TNF[alpha] also increases neutrophils and promotes the adhesion of leucocytes to endothelial surfaces.

Large artery stiffening also accelerates during menopause due to (Moreau and Hildreth, 2014):

(1) Structural changes such as increased collagen, reduced elastin, and intimalmedial thickening.

(2) Changes in smooth muscle contractility, related to decreased NO availability.

(3) Oxidative stress.

(4) Vascular inflammation and other inflammatory diseases.

In rat studies, estrogen has shown anti-inflammatory effects, counteracting TNF[alpha] by inhibiting nuclear factor-Kappa-B (NF-[KAPPA]B), enhancing NO release, and reducing ROS-stimulated proinflammatory cytokine expression (Arenas et al., 2005).

Rhodiola rosea and salidroside: evidence of cardiovascular protection

R. rosea derived salidroside acts through many of the same mechanisms as estrogen. In animal studies, salidroside protected endothelium from hydrogen peroxide ([H.sub.2][O.sub.2]) cytotoxicity, upregulated mitochondrial biogenesis factors, inhibited N[F.sub.K]B, and prevented [H.sub.2][O.sub.2]-induced overactivation of oxidative stress-related downstream signaling pathways (Xing et al., 2014). In in vitro and in vivo studies, salidrosides protected endothelial functions from disruption by reactive oxygen species, preserved nitric oxide (NO) bioavailability, protected mitochondria, and prevented cardiac ischemia/reperfusion injury (Zhao et al., 2015; Xing et al., 2015; Wu et al., 2009).

In a study of six-week old apoE(-/-) male mice following 8 weeks of a high fat diet, salidroside administration significantly improved endothelial function, reduced the area of atherosclerosis, and decreased inflammation in aortic sinus lesions (Xing et al., 2015). These effects were associated with activation of adenosyl monophosphate-activated protein kinase (AMPK), which activates the downstream phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) pathway that activates eNOS. Improved endothelial function was attributed to promotion of NO production associated with mitochondrial depolarization and activation of the AMPK/PI3K/Akt/eNOS signaling pathway. R. rosea root extracts contain many anti-oxidants in addition to salidroside that could help protect endothelial function and prevent cardiovascular and cerebrovascular disease. R. rosea extracts also showed a high degree of inhibitory activity on angiotensin I-converting enzyme (ACE) in rabbit lungs (Kwon et al., 2006). ACE causes vascular constriction by converting angiotensin-I to angiotensin-II. As an ACE-inhibitor R. rosea may help to counteract the pathophysiological mechanisms that impair vasodilation. Thus, through the mechanisms described above, R. rosea could be used to compensate for estrogen deficiency during menopause by helping to preserve EDV and arterial wall flexibility.

A systematic review of 13 randomized Chinese controlled trials of the safety and efficacy of related species, Rhodiola sacra and Rhodiola kirilowii formulations, as solo treatments or combined with routine western medicines for treatment of ischemic heart disease found statistically significant differences indicating greater symptomatic (p < 0.01) and electrocardiographic (ECG) improvement (p < 0.01) in patients given Rhodiola formulations (Yu et al., 2014). Poor methodology and heterogeneity of the studies was cited as indicating the need for larger controlled trials. Trials of Rhodiola rosea in animal models of cardiac and cerebrovascular ischemia show significant protective effects; clinical trials in patients with cardiac disease are needed.

Osteoporosis prevention

A study of 197,848 postmenopausal women found that after one year new fractures were reported for the spine, hip, forearm and wrist in 2414 (approximately 8%) (Barrett-Connor et al., 2005). Fracture risk was strongly influenced by bone mineral density (BMD). Early onset of menopause, diabetes, nutritional deficiencies, and other comorbid conditions increase the risk of fractures. Among women less than 65 years of age, the 10 year predicted risk of major osteoporotic fracture was reported to be [greater than or equal to] 9.3% (Crandall et al., 2014). The effectiveness of antiresorptive agents, such as biphosphonates and denosumab, can be limited due to intolerance, adverse events, and non-adherence. Alternative treatments with fewer side effects are needed.

Postmenopausal osteoporosis bone formation declines while bone resorption accelerates, leading to loss of bone density. Resorption is increased and formation is decreased by ROS. Decline in BMD has been associated with increased oxidative stress.

R. rosea derived salidroside was tested in preosteoblastic mouse cells and in vivo in OVX mice to study protective effects and mechanisms relevant to loss of bone density (Zhang et al., 2013). Hydrogen peroxide ([H.sub.2][O.sub.2]) induces oxidative stress and plays an important role in estrogen deficiency osteoporosis. Salidroside protected osteoblastic MC3T3-E1 cells from H202-induced suppression of differentiation, mineralization and expression of osteogenic genes (Zhang et al., 2013). Pretreatment with salidroside also inhibited production of ROS by [H.sub.2][O.sub.2]. In OVX mice salidroside reduced serum oxidative stress markers and prevented bone loss and deterioration of trabecular microstructure. These results support the potential use of salidroside for prevention and treatment of menopause-related osteoporosis. Numerous other antioxidants present in R. rosea extracts could provide additional protection against bone loss.

Anticarcinogenic and chemoprotective

Patricia Eagon tested the effects of R. rosea extracts on ER-positive Michigan Cancer Foundation (MCF-7) breast adenocarcinoma cells. She tested high (0.065 ng/ml) and low (0.065 mcg/ml) concentrations of R. rosea extract (3% rosavins, 1% salidrosides; National Biosciences Corp., Hartford, CT) with and without estradiol (Eagon et al., 2004). Cell proliferation was determined by cell counts at 24, 48, and 72 h. The growth of cells treated with high-dose R. rosea plus estradiol was equal to the growth of cells treated with estrogen alone. Cells treated with low-dose R. rosea plus estrogen showed a slight stimulation of growth. Proliferation of cells treated with high-dose R. rosea alone was equal to the untreated control cells.

Salidrosides inhibited proliferation and induced cell cycle arrest and apoptosis in human breast cancer MDA-MB-231 (estrogen receptor negative) and MCF-7 (estrogen receptor-positive) cells in vitro (Hu, et al., 2010). Another study in which salidrosides inhibited the growth of human MCF-7 cells in vitro and in vivo found that salidroside significantly inhibited intracellular reactive oxygen species (ROS) formation and mitogen-activated protein kinase (MAPK) pathway activation (Zhao et al., 2015). This was thought to contribute to the inhibition of tumor growth of breast cancer and the reduction of oxidative stress. The mechanisms of action of R. rosea extracts, particularly salidroside, overlap with mechanisms attributed to estrogen. R. rosea extract also induced apoptosis of human leukemic HL-60 cancer cells (Majewska et al., 2006). Numerous studies of human tumors transplanted into rodents have shown that R. rosea increased the effectiveness of chemotherapies and protected stem cells in the bone marrow and liver from toxic effects of chemotherapy (reviewed by Brown et al., 2009; Brown et al., 2004).

Differences in the results of studies in breast cancer cell lines may be attributable to differences in preparations and concentrations of extract constituents.

An herbal formula, AdMax (Nulab inc., Cledarwater, FL) containing R. rosea, Leuzea carthamoides, Eleutherococcus senticosus and Schizandra chinensis was given for four weeks to 28 women following treatment with cisplatin and cyclophosphamide for stage III-IV epithelial ovarian cancer (Kormosh et al., 2006). Those who took AdMax had increases in four T cell subclasses, IgG, and IgM when compared with those who did not, suggesting that this herbal combination could increase immune defenses in immunosuppressed patients following cancer chemotherapy.

Hormonal effects of Rhodiola rosea

R. rosea has been used for centuries in the Republic of Georgia and Siberia to enhance fertility among the people living at high altitudes in the Caucasus Mountains. In an open study of 40 women with primary and secondary amenorrhea R. rosea extract 100 mg twice daily restored normal menstrual cycles in 25 subjects and 11 of them became pregnant (Gerasimova, 1970). In these 25 women, uterine length increased to normal size. Gerasimova (1970) also reported that the intra-peritoneal injection of R. rosea extract in ovariectomized (OVX) rats resulted in a significant increase in uterine size.

Studies of ER-enriched cellular extracts indicated that R. rosea extracts interacted with ERs in a moderate fashion, as determined by an assay detecting displacement of radio-labeled estradiol from the ER protein. However, when R. rosea was tested in vivo by oral administration to OVX rats, no evidence of estrogenicity was noted by the standard criteria of uterine growth and reduction of serum leutinizing hormone levels (Eagon et al., 2004). Patricia Eagon (2004) tested a standardized extract of R. rosea (3% rosavins, 1% salidrosides) in OVX rats. She found evidence of strong estrogen receptor binding without estrogen receptor activation in vitro. Furthermore, OVX rats fed therapeutic doses of R. rosea by mouth showed no increase in circulating estradiol levels, no reduction of serum leutinizing hormone levels, and no increase in uterine size.

The discrepancy between the lack of estrogenicity in the Eagon study versus Gerasimova's observations may be due to differences in the source of the herb (wild grown vs cultivated), extraction procedures, and routes of administration (oral versus intraperitoneal injection) (Brown et al., 2004). Following oral ingestion, the plant constituents undergo digestion and conversion to secondary metabolites with different effects than those of the undigested extract (Gerbarg and Brown, 2013).

An in vitro study of the effects of R. rosea constituents on estrogen receptors ER[alpha] and ER[beta] identified strongly docking flavonoids, gossypetin, herbacetin, and rhodiolin. The lignan (+)-lariciresinol also strongly docked to both ER[alpha] and ER[beta] (Powers and Setzer 2015). Further studies are needed to elucidate the complex effects of R. rosea constituents on the activities of ERs.

Clinical case illustration

Although R. rosea has not been studied for cognitive enhancement specifically in menopausal and postmenopausal women, the authors find that it is particularly helpful in improving their memory, mental clarity, cognitive speed, energy, and mood, as Case #1 illustrates. In addition, it can improve libido and sexual function in some cases. Studies are needed to validate these clinical observations in women.

Case #1

Ms. N., a 55 year old married mother of two was the chief financial officer of a multi-million dollar company. Her menopause began at age 44 with irregular menses. Hot flushes worsened over the next 5 years, tapered in her early 50s and remitted by age 54. When mild memory problems began around age 50, she compensated by keeping careful checklists. Known among her friends as the supreme multitasker, Ms. N. was proud of her abilities to juggle work and home life. However, when the health of her octogenarian parents declined, burdening her with their emergency medical needs, she began experiencing insomnia, anxiety, fatigue and mild depression. Adding to her concerns were increasing problems remembering details, losing her train of thought when interrupted, and difficulty completing tasks at work. Worried about her parents, her job, and whether she was losing control, she sought psychiatric help. Ms. N.'s primary care doctor had already tried her on antidepressants, including sertraline, fluoxetine, and paroxetine. These improved the depression by about 30%, but they caused weight gain, sexual dysfunction, and feeling, "strange, not myself." Zolpidem exacerbated her forgetfulness. Xanax and clonazepam dampened her anxiety, but caused "mental fogginess." Seeking a nonpharmacological alternative, Ms. N. consulted an Integrative Psychiatrist who prescribed R. rosea at a starting dose of 150 mg twice a day. In the first week she noticed an increase in energy. By the third week she felt less depressed and anxious. A new feeling of wanting to get up and do things occurred in the morning. After increasing the R. rosea in two steps to 300 mg twice daily for six weeks, Ms. N. reported improvement in her speed of recall, "mental sharpness," mental focus, and ability to plow through work effectively. There were no changes in weight, no adverse effects, and her libido increased. She has remained on the same daily dose of R. rosea for ten years and plans to continue as long as possible.

Cognitive enhancing SERMs: strategies for estradiol replacement treatments

Victoria Luine reviewed the effects of estradiol on the development and enhancement of cognitive functions and memory through membrane interactions and inter-cellular signaling pathways as well as genomic mechanisms. She described several strategies for developing cognitive-enhancing SERMS (Luine, 2014).

* ER[beta] is present primarily in brain, but minimal in uterine and breast tissues. In animal models several ER[beta] specific SERMs enhanced memory. A phytoestrogen formula, Phyto-[beta]-SERM (genistein, daidzein, and equol) improved spatial memory and slowed progression of amyloid pathology in a female mouse model of Alzheimer's disease (Zhao et al., 2015).

* Another strategy targets neuronal molecules and cellular mechanisms downstream from hormone receptors that are involved in memory-enhancing effects of estradiol. By interacting with cellular signaling molecules rather than the ERs, these would provide beneficial effects on cognitive and memory function similar to those of estrogen.

* A third approach would aim to increase local estradiol (within the brain) through modulation of estrogen production and release.

The development of R. rosea (other adaptogenic) extracts to counteract adverse effects of estradiol decline in menopausal women would follow the first two strategies. First, the components of R. rosea that interact with estrogen receptors and the nature of these interactions in different tissues need to be clarified. Secondly, by interacting with cellular signaling molecules rather than the ERs, R. rosea affects a myriad of potential targets, genes, molecules and cellular mechanism downstream from hormone receptors that are involved in cognitive function, mood regulation, energy, cardiovascular function, and bone structuring.

Safety, contraindications, adverse reactions

Rhodiola rosea is generally well tolerated, even in elderly populations (Fintelmann and Gruenwald, 2007). The most common side effects are due to its stimulative properties, which are beneficial for patients who complain of fatigue, poor concentration, loss of motivation, or cognitive slowing. However, in patients with anxiety, sensitivity to stimulants or cardiac arrhythmias, administration of activating agents, such as R. rosea may exacerbate anxiety or insomnia, or occasionally increase heart rate or frequency of irregular rhythms. Patients should be advised to avoid combining R. rosea with large amounts of caffeine because the stimulative effects are additive and can lead to tachycardia. As with antidepressants, there is a potential risk for triggering or exacerbating hypomanic or manic symptoms in patients with Bipolar Disorder, particularly if manic symptoms are not fully controlled by prescription medications.

For most patients, the dose of R. rosea extract should not exceed 800 mg per day (3%rosavins, 1%salidrosides). At higher doses some individuals manifest increased bruising due to an anti-platelet effect. The concurrent use of anticoagulants requires monitoring and possibly dose adjustments. To our knowledge, to date, no cases of bleeding attributable to R. rosea have been reported.

Although in vitro studies have shown that R. rosea affects CYP450 enzyme systems, in vivo and human studies have not corroborated many of these effects. This is to be expected because, unlike the direct application of herbal extract to in vitro enzymes, orally ingested extracts undergo digestion and metabolism which convert them to secondary metabolites (as mentioned above). Further human studies of R. rosea given with CYP450 test medications would help identify any potentially significant herb-drug interactions (Panossian et al., 2009; Helium et al, 2010).

Conclusions

Menopause is associated with increased risks for cardiovascular disease, osteoporosis, and cancer. Many women experience declining energy, mood, cognitive function and memory during menopause. Rhodiola rosea extracts have been shown to enhance mood, cognitive function, and memory. Moreover, these extracts possess anti-stress, neuroprotective, cardiovascular-protective, and anti-carcinogenic properties, which are particularly valuable to counteract some of the common health risks seen in women as they age. R. rosea is low in side effects compared to synthetic selective estrogen receptor modulators (SERMS). Predinical and clinical studies suggest that R. rosea extracts provide a combination of effects that could counteract the adverse consequences of estrogen decline by improving neurological, endothelial, and cardiovascular functions. As a natural SERM, R. rosea could alleviate menopause-related symptoms while conferring additional neuro-protective, cardio-protective, anti-stress, anti-fatigue, osteoprotective, and other health benefits. Unlike HRT, preliminary evidence indicates that orally ingested R. rosea extracts are unlikely to cause estrogenic effects or increased the risk of cancer in hormone sensitive tissues. R. rosea extracts and salidroside do not significantly stimulate, but rather inhibit growth of human breast cancer in vitro and in vivo in some studies. Human studies are needed to verify the safety of R. rosea in postmenopausal women who are at increased risk or who are being treated for breast cancer. Further research on the use of R. rosea alone and in combination with other adaptogens during menopause would enable development of this promising alternative SERM.

ARTICLE INFO

Article history:

Received 28 October 2015

Revised 16 November 2015

Accepted 17 November 2015

Conflict of interest

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome.

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Patricia L. Gerbarg (a), *, Richard P. Brown (b), (1)

(a) New York Medical College, 86 Sherry Lane, Kingston, NY 12401, United States

(b) Columbia University College of Medicine, NY, 86 Sherry Lane, Kingston, NY 12401, United States

Abbreviations: ACE, angiotensin-1 converting enzyme; AD, Alzheimer's Disease; BMD, bone mineral density; AMT, adenosine monophosphate; ATP, adenosine triphosphate; eNOS, endothelial nitric oxide synthase; GABA, gamma-aminobutyric acid; NF-[kappa]B, nuclear factor-Kappa-B; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ER, estrogen receptor; EDV, endothelial-dependent vasodilation; MAPK, mitogen-activated protein kinase; OVX, ovariectomized; ROS, reactive oxygen species; SERM, selective estrogen receptor modulator; TNF[alpha], Tumor necrosis factor-alpha.

* Corresponding author. Tel.: +1 845 331 8881; fax: +1845 331 3562.

E-mail address: PGerbarg@aol.com (P.L Gerbarg).

(1) Tel: +1 212 737 0821 86.

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