Exploring New Applications for Rhodiola rosea : Can We Improve the Quality of Life of Patients with Short-Term Hypothyroidism Induced by Hormone Withdrawal?

Abstract

Patients treated for differentiated thyroid cancer (DTC) are subjected to periodic surveillance that includes serum thyroglobulin measurements followed by radioiodine administrations for diagnostic and therapeutic purposes if necessary. Both procedures require adequately elevated blood levels of thyroid-stimulating hormone (TSH), which can be achieved by two approaches: parenteral administration of recombinant human TSH (rhTSH) or stopping thyroid hormone replacement until optimal levels of endogenous TSH are achieved. Although rhTSH administration does not require hormone withdrawal, it is not inexpensive and carries the risk of secondary effects. The latter option is simpler but induces a profound state of hypothyroidism, which results in physical and mental complaints that may interfere severely with the patient's activities of daily living. Rhodiola rosea is a popular plant in traditional medical systems in Eastern Europe and Asia with a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, and eliminating fatigue, all features of clinical hypothyroidism. Investigators have also suggested additional benefits such as cardioprotection or even tumor growth inhibition. Here, we propose R. rosea as a viable alternative treatment for the symptoms of short-term hypothyroidism in patients with DTC who require hormone withdrawal.

Introduction

T hyroid cancer is the most common malignancy of the endocrine system and accounts for about 1% of all malignancies and 0.2% of cancer-related deaths.¹ Current management guidelines recommend total or near total thyroidectomy for the initial treatment, which is usually followed by radioactive ablation of any remnant tissue (or potential microscopic residual tumor) using radioiodine (I-131). During follow-up, abnormal levels of thyroglobulin will be investigated by imaging techniques, including whole-body scintigraphy after oral administration of radioiodine. Administration of radioiodine can be performed for both diagnostic and therapeutic purposes. These procedures are typically repeated periodically with the intent of achieving complete remission.² Serum thyroglobulin measurements and radioiodine oral administrations will require adequately high levels of thyroid-stimulating hormone (TSH), which can be achieved by thyroid hormone replacement withdrawal or by administering recombinant human TSH (rhTSH). Serum levels of TSH greater than 30 mU/L can be achieved in about 90% of the patients by stopping levothyroxine (LT4) replacement therapy for at least 3 weeks. Alternatively, LT4 can be switched to triiodothyronine for 2 weeks and then withdrawn for 2 weeks. The rationale behind these two schemes is to avoid long-term hypothyroidism while achieving adequate levels of TSH in serum.^3,4

The unequivocal consequence of these approaches is the induction of short-term hypothyroidism, which affects the quality of life of the patients and carries important health problems. Larisch et al.⁵ reported a sevenfold increase in critical mood deterioration induced by hypothyroidism in a sample of 254 subjects. In another study, the health-related quality of life (HRQL) of a group of inpatients with differentiated thyroid carcinoma (DTC) who had LT4 withdrawn for 4 weeks was compared with that of a group of DTC outpatients who were taking LT4; the results showed that both groups had impaired HRQL compared with the general population, with higher prevalence of anxiety in the inpatient population.⁶ Furthermore, this withdrawal period can carry societal economic consequences in terms of work hours missed.⁷

Recently it has been revealed that these patients may develop impairment of the cardiovascular function (electrocardiogram abnormalities, worsened diastolic dysfunction, reduced ejection fraction during effort, and increased prevalence of hypertension), lipid profile changes leading to an atherogenic state, and neuropsychological problems such as depressive mood and slowing of psychomotor functions.⁸

The use of rhTSH overcomes the issue of LT4 withdrawal (and subsequent short-term hypothyroidism) and has been becoming the modality of choice. Although the intensity of the stimulation and the bioavailability of radioiodine seem to be lower, both local and distant disease can be adequately detected.⁹ Parenteral administration of rhTSH, however, requires careful consideration of the safety aspects. Common side effects include headache, nausea, asthenia, dizziness, paresthesia, pain, fever, chills, and flu symptoms. Pain, pruritus, and maculopapular rash have been reported at the injection site. Development of antibodies may affect its efficacy.¹⁰ Patients with central nervous system metastases may develop neurological symptoms, which can be attributed to local edema and/or focal hemorrhage at the metastatic sites. In addition, sudden, rapid, and painful enlargement of locally recurring DTC has been reported within 12–48 hours of administration. This enlargement was accompanied by dyspnea and stridor and responded rapidly to glucocorticoid therapy.¹¹

The ideal approach would be one that minimizes risks and side effects while achieving optimal levels of TSH, hence providing reassurance on the reliability of the laboratory/imaging data obtained.

Hypothesis

Rhodiola rosea extracts (RREs) have been used extensively in Asian traditional folk medicine to stimulate the nervous system, to decrease depression, to enhance work performance, and to treat fatigue and symptoms of asthenia subsequent to intense physical and/or psychological stress.^12,13 Because most of these symptoms are in fact part of the clinical spectrum of hypothyroidism, RRE is proposed to aid in patient preparation during the hormone withdrawal period.

The main active ingredients isolated in RRE are p-tyrosol, organic acids (such as gallic, caffeic, and chlorogenic acids), flavonoids (catechins and proanthocyanidins), and other stimulating compounds (salidrose, rhodioniside, rhodiolin, rosin, rosavin, rosarin, and rosiridin).¹⁴ Further investigations have also revealed that the alcoholic extract could inhibit acetylcholinesterase.¹⁵ Some of these phenylethane derivatives, such as salidroside, are present in all species of the Rhodiola genus and outside this genus, but phenylpropane derivatives, such as the rosavins (rosavin, rosine, and rosarin), are specific components of R. rosea.¹⁶ Rosavine, salidroside, and other phenolic compounds are thought to be critical in the actions of this adaptogen, while organic acid and flavonoids have been demonstrated to contribute to the antioxidant activities of the extract.¹⁷

Evaluation of the Hypothesis

R. rosea is recognized for its adaptogenic properties. An adaptogen is almost nontoxic to the recipient, acts by increasing the resistance of the organism to a broad spectrum of adverse biological, chemical, and physical factors, and tends to be a regulator having a normalizing effect on the organism. The concept is mainly used for herbals.¹⁸ We now would consider short-term hypothyroidism as the stressor and then RRE as the adaptogen that could help the organism in responding.

Empirical data on the quality of life and neuropsychological aspects

R. rosea has been extensively studied in different models of depression, fatigue, and performance in animal models and has been summarized elsewhere.^12,13 However, because results in humans supersede animal data only a summary of clinical studies is provided.

A randomized, double-blind, placebo-controlled trial was performed in a total of 89 patients diagnosed with mild to moderate depression according to the DSM-IV criteria. Patients were randomly assigned to one of three groups: placebo (n = 29), RRE 340 mg/day (n = 31), and RRE 680 mg/day (n = 29) for up to 6 weeks. The investigators found clinically significant improvements (P < .001) in overall depression (Beck Depression Inventory and Hamilton Rating Scale for Depression [HAMD]) and, more specifically, in insomnia, emotional instability, and somatization (HAMD score subgroups) in the treated groups.¹⁹

In a double-blind, placebo-controlled crossover trial in 56 healthy physicians, the fatigue index during night shifts (which involved associative thinking, short-term memory, and concentration among other perceptive and cognitive functions) improved significantly with the addition of 340 mg of RRE.²⁰ Similar results were replicated later in another placebo-controlled trial in 161 cadets, where the treatment groups (standardized RRE at two dose levels) had significant improvement in their antifatigue index compared with placebo (P < .0001), which translated into lower number of errors in their tests. The investigators noted no differences between a 370-mg Rhodiola dry extract dose and a 50% increase in the dose in terms of efficacy.²¹

Improvements in stress-related fatigue were also found in a total of 60 individuals in a phase III trial using RRE as the test substance (576 mg/day) and placebo as the control. Although both groups had significant improvements in the burnout scale (Pine's), mental health scale (Health Survey Short-Form 36 [SF-36]), and depression rating scale (Montgomery-Åsberg Depression Rating Scale [MADRS]) at the end of the trial, a clinical and statistically significant improvement was noted in the RRE group over the placebo group in the burnout (Pine's) and attention (Conners' Computerized Continuous Performance Test II [CCPT II]) scales.²² Finally, a pilot study performed at the University of California Los Angeles in 10 patients with generalized anxiety disorder who received 340 mg of RRE showed significant reductions in the Hamilton Anxiety Rating Scale after 10 weeks of administration.²³

Although preliminary and heterogeneous, the available data suggest the potential of RRE in alleviating conditions such as fatigue, anxiety, and depressive mood.

Empirical data on the cardiovascular aspects

As stated previously, short-term hypothyroidism can also increase the risk for cardiovascular disease.⁸ Data regarding the effects of RRE on the cardiovascular system are more difficult to evaluate. To the best of our knowledge there are no clinical trials available in this area, and extrapolations need to be made from animal models. Some of these studies date back to the early 1990s, and a full-text report in English is usually not available, as they were originally published in Russian, making this assessment more cumbersome.

Using Wistar rats, Afanas'ev et al.²⁴ found that RRE prevented the decrease in contractility immediately after cooling (4 hours, −10°C) and contributed to a stable contractility, while having no impact on the diastolic dysfunction. Anti-arrhythmic effects of RRE have been found later in the epinephrine-induced rat model, in which a mechanistic effect mediated by the activation of the opioid system (through κ-receptors) was proposed after high doses of naloxone reverted the resistance of the heart to epinephrine.²⁵

Alterations of the oxidative metabolism of the myocardium during short-term hypothyroidism have been reported using tracer positron emission and magnetic resonance scans.²⁶ Salidrose (one of the active components of RRE) has been found to significantly enhance glucose uptake and decrease cardiomyocyte injury following ischemia/reperfusion using cell cultures.²⁷

As stated above, the evidences in this area are weak, and results found in nonclinical models should be assessed in humans. Nevertheless, there are early indicators of RRE having a positive impact on heart function under stress conditions.

Additional potential benefits: the molecular links

Supplementation with RRE may have potentially additional benefits beyond improving neuropsychological symptoms induced by thyroid hormone withdrawal. Oxidative stress has been linked to many important conditions, including cardiovascular and neurodegenerative diseases, and oxidation status has been investigated during hypothyroidism. Studies in rats indicate that total antioxidant status is decreased in the brain and that levels of paraoxonase/arylesterase activity in plasma are impaired, indicating an increased oxidative stress when thyroid hormones are missing.^28,29 This finding has been replicated also in humans. The status of the oxidant–antioxidant system (malonylaldehyde, paraoxonase activity, nitric oxide, and superoxide dismutase serum levels) was correlated with the thyroid function status in 33 patients with hypothyroidism before and after treatment. Patients were compared with normal controls (n = 26). The investigators found increased levels of reactive oxygen species in hypothyroidism with some normalization of the antioxidant markers after 6 months of treatment.³⁰ This increase in oxidative stress was also confirmed later in another sample of 20 patients with overt hypothyroidism.³¹

In vitro experiments using human erythrocytes have shown that RRE can protect these cells from oxidative injuries in a dose-dependent manner.^32,33 Interestingly, De Sanctis et al.³² have proposed that RRE confers protection by acting inside the cells.³² A more detailed antioxidant effect has been characterized in neuronal cells. Salidrose obtained from RRE was able to protect SH-SY5Y cells from the H₂O₂-induced viability loss and apoptosis by induction of several antioxidant enzymes, down-regulation of apoptotic genes (Bax), and up-regulation of anti-apoptotic genes Bcl-2 and Bcl-X, thus supporting an intracellular effect.³⁴ Similar results have been replicated using human keratinocytes exposed to different oxidant insults such as Fe(III)/ascorbate, Fe(II)/H₂O₂, and tert-butylhydroperoxide. A modulation effect of the production of intracellular reactive oxygen species and on the activity of antioxidant enzymes was found in RRE-cultured NCTC 2544 cells, accompanied by an increase in a a time- and dose-dependent manner in the activity of the trans-plasma membrane oxidoreductase.³⁵

The body of knowledge about the antioxidant activity of RRE is still thin. Results of cellular-based experiments are encouraging and provide useful insights into possible mechanisms. Studies in humans would be warranted.

Finally, there is a more intriguing question to be explored, and that is whether RRE exerts any beneficial effects in controlling tumor growth or not. Indeed, antitumor effects have been described for RRE in animal models,^36,37 but up to this point no human studies with (thyroid) cancer are available. Therefore we can only explore any molecular links available through cell experiments.

Recently, many molecular markers expressed in thyroid cancer, including heat shock protein 70 (Hsp70), have been identified.³⁸ This “chaperone” protein has been closely linked to endocytosis, vesicular trafficking, and exocytosis. Experiments with thyroid cancer cells have shown that decreased expression of Hsp70 in the membrane of tumor cells led to a reduced sensitivity to lysis mediated by natural killer cells.³⁹ Thyroid tumor growth also requires blood support, which is mediated by angiogenesis. Vascular endothelial growth factor (VEGF) has been shown to be the most important endothelial mitogen, and TSH has been shown to increase VEGF (mRNA and protein) in a dose-dependent manner in follicular and Hurtle-cell cancer cellular lines in vitro.⁴⁰

Several groups have found that RRE can modulate important cell functions at the molecular level, and some of the factors involved are in fact common to tumor biology. Panossian et al.⁴¹ indicated in a recent review that resistance to stress conditions induced by RRE is mediated by the modulation of many chaperone molecules, with Hsp70 being one of them. Rhodiola has also been found to decrease plaque formation in an atherosclerotic plaque model in the rat. This decrease in proliferation was mediated by inhibition of VEGF.⁴² If these models were applicable to thyroid cancer, RRE would then help in stopping tumor growth, but the level of evidence at this point is quite low, and further work is clearly necessary. In our laboratory, we have demonstrated the inhibitory effect of RhodioLife™ (Polinat S.L., Las Palmas, Spain), a proprietary extract of R. rosea, on the growth of an embryonary rhabdomyosarcoma cell line through the activation of the apoptogenic, antiproliferative, anti-angiogenic, and antimetastatic molecular pathways.⁴³

Risk-Benefit Analysis

Up to this point the common links between short-term hypothyroidism in DTC patients and RRE effects have been described. The evidence in support of improving quality of life aspects is stronger than in other areas. These are all efficacy aspects (benefits), but the question of safety remains unsolved. During the course of clinical trials adverse events have been few or not reported at all, and no serious adverse events have been reported.^19,23,44 Many Rhodiola preparations are sold throughout the world without the need for prescription, and although adverse events spontaneously generated in the general population are likely to be underreported for nontraditional medicines, any serious side effects (or any early indicators of) would have surfaced by now most likely.

It is also important to avoid any interference in the diagnostic process and blocking the thyroid with unsuspected sources of iodine is certainly a consideration because it may happen with some food supplements (i.e., multivitamins). This should not be the case with RRE as it is not an alga, but a shrub. Certainly confirmation that iodine is not present in any significant amount in a particular preparation would be needed. At the molecular level, there is currently no evidence that modulation of both Hsp70 and VEGF may interfere with the expression of the sodium iodine symporter-related genes, mainly thyroid transcription factors 1 and 2, and Pax-8,⁴⁵ to the best of our knowledge. The possibility of drug interactions should also be considered, and again scientific data are scarce. Panossian et al.⁴⁶ did not find any pharmacokinetic interactions in rats medicated with warfarin and theophylline. No other data are available.

Even at this level of evidence, it appears that RRE could be administered to patients who suffer withdrawal-induced, short-term hypothyroidism as long as there is close monitoring because benefits may outweigh risks.

Further Steps and Conclusions

It is clear that although the possible clinical benefits that supplementation with Rhodiola may bring to these patients are unknown, data look promising. The next logical step would be a clinical study under controlled conditions. A randomized controlled trial comparing two arms (test vs. placebo) would indeed help in answering the question. Because the intention is to improve HRQL, the primary efficacy values should be validated clinical scales to that regard that would allow reliable, meaningful comparisons such as the SF-36, the Hospital Anxiety and Depression Scale (HADS), the Profile of Mood States (POMS), and the Hypothyroid Physical Complaints Scale as tested previously.⁶ Because different doses have been tested clinically (mainly 340 and 680 mg) the study may include a third arm with the upper dose level. The study may also allow for the collection of other secondary variables that would shed light on the additional potential benefits such as cardiovascular health and, obviously, the outcome of the whole body radioiodine scans. It is of paramount importance that safety data are actively looked for and collected for an accurate assessment. Alternatively, a crossover design would be preferred to diminish intra-individual variability, although theoretically it could take a longer time to conduct because the washout period would be 6–12 months depending on the surveillance scheme (Fig. 1). As described in Figure 1, patients would undergo two trial periods. In period 1 they would receive either RRE or placebo. Once radioiodine and/or treatment are done, they would come back for period 2, receiving the opposite substance. The logistics seem to be far more complex than a parallel arm design and would require careful consideration. Also, follow-up losses would be even more crucial.

FIG. 1.

Schematic example of clinical trial designs with two possible designs for clinical trials. Rhodiola supplementation would start when hormone replacement is stopped and would be withdrawn once desired levels of thyroid-stimulating hormone are obtained after hormone replacement therapy is reinstated. Option A depicts a parallel group design, which allows simple dose level assessment. Option B depicts a crossover design, which minimizes intra-individual variability but likely increases the time to complete and makes additional dose level assessment cumbersome. RRE, R. rosea extract.

In conclusion, we propose that in order to improve the quality of life of those patients who undergo a state of hypothyroidism to have follow-up tests for DTC, supplementation with RRE represents an attractive prospect.

Footnotes

Acknowledgment

We are indebted to Mrs. Marina Kuznetsova for her most valuable contributions in translating work originally published in Russian.

Author Disclosure Statement

J.M.Z., M.J.R., and J.G. work for Polinat S.L., which manufactures a proprietary R. rosea extract (RhodioLife™). H.A.N. declares no conflict of interest.

References

Mazzaferri

. An overview of the management of papillary and follicular thyroid carcinoma. Thyroid, 1999; 9:421–427.

Pacini

, Castagna

, Brilli

, Jost

. Differentiated thyroid cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol, 2008; 19,Suppl 2:ii99–ii101.

Pacini

, Schlumberger

, Dralle

, Elisei

, Smit

, Wiersinga

. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol, 2006; 154:787–803.

American Thyroid Association Guidelines Taskforce: Management guidelines for patient with thyroid nodules and differentiated thyroid cancer. Thyroid, 2006; 16:109–141.

Larisch

, Kley

, Nikolaus

, Sitte

, Franz

, Hautzel

, Tress

, Müller

. Depression and anxiety in different thyroid function states. Horm Metab Res, 2004; 36:650–653.

Tagay

, Herpertz

, Langkafel

, Erim

, Freudenberg

, Schöpper

, Bockisch

, Senf

, Görges

. Health-related quality of life, anxiety and depression in thyroid cancer patients under short-term hypothyroidism and TSH-suppressive levothyroxine treatment. Eur J Endocrinol, 2005; 153:755–763.

Nijhuis

, vanWeperen

, de Klerk

JMH

. Costs associated with the withdrawal of thyroid hormone suppression therapy during the follow-up treatment of well-differentiated thyroid cancer. Tijdschr Nucl Geneeskd, 1999; 21:98–100.

Dunatas

, Biondi

. Short-term hypothyroidism after levothyroxine-withdrawal in patients with differentiated thyroid cancer: clinical and quality of life consequences. Eur J Endocrinol, 2007; 156:13–19.

Schulumberger

, Ricard

, Pacini

. Clinical use of recombinant human TSH in thyroid cancer patients. Eur J Endocrinol, 2000; 143:557–563.

10.

Committee on Human Medicinal Products: Thyrogen: European Public Assessment Report. Published online, May 13, 2009. www.ema.europa.eu/humandocs/Humans/EPAR/thyrogen/thyrogen.htm. 2009 September 22.

11.

Genzyme Corp. Thyrogen Package Insert. Genzyme Corp.: Cambridge, MA, 2008.

12.

Kelly

. Rhodiola rosea: a possible plant adaptogen. Altern Med Rev, 2001; 6:293–302.

13.

Brown RP

, Ramazanov

. Rhodiola rosea. A phytomedicinal overview. Herbal Gram, 2002; 56:40–52.

14.

, Li

, Dou

, Chang

, Bai

, Satou

, Li

, Sun

, Kang

, Nikaido

, Koike

. Rhodiolosides A–E, monoterpene glycosides from Rhodiola rosea. Chem Pharm Bull (Tokyo), 2006; 54:1229–1233.

15.

Wang

, Zhou

, Gao

, Wang

, Yao

. Acetylcholinesterase inhibitory-active components of Rhodiola rosea L. Food Chem, 2007; 105:24–27.

16.

Kurkin

, Zapesochnaya

. [Chemical composition and pharmacological properties of Rhodiola rosea] Khim Pharm Z (Moscow), 1986; 20:1231–1244.

17.

Furmanowa

M, S.-R.E.

, Rogala

, Hartwich

. Rhodiola rosea in vitro culture—phytochemical analysis and antioxidant action. Acta Soc Bot Pol, 1998; 67:69–73.

18.

Herbal Medicinal Products Committee: Reflection Paper on the Adaptogenic Concept. Document Reference EMEA/HMPC/102655/2007. Herbal Medicinal Products Committee: London, 2007. www.ema.europa.eu/pdfs/human/hmpc/eleutherococci_radix/10265507enfin.pdf. 2009 September 22.

19.

Darbinyan

, Aslanyan

, Amroyan

, Gabrielyan

, Malmström

, Panossian

. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry, 2007; 61:343–348Erratum in: Nord J Psychiatry 2007;61:503.

20.

Darbinyan

, Kteyan

, Panossian

, Gabrielian

, Wikman

, Wagner

. Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine, 2000; 5:365–371.

21.

Shevtsov

, Zholus

, Shervarly

, Vol'skij

, Korovin

, Khristich

, Roslyakova

, Wikman

. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine, 2003; 10:95–105.

22.

Olsson

, von Schéele

, Panossian

. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract SHR-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med, 2009; 75:105–112.

23.

Bystritsky

, Kerwin

, Feusner

. A pilot study of Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD) J Altern Complement Med, 2008; 14:175–180.

24.

Afanas'ev

, Alekseeva

, Bardamova

, Maslova

. Lishmanov IuB: [Cardiac contractile function following acute cooling of the body and the adaptogenic correction of its disorders] Biull Eksp Biol Med, 1993; 116:480–483.

25.

Maĭmeskulova

, Maslov

, Lishmanov

IuB

, Krasnov

. [The participation of the mu-, delta- and kappa-opioid receptors in the realization of the anti-arrhythmia effect of Rhodiola rosea] Eksp Klin Farmakol, 1997; 60:38–39.

26.

Bengel

, Nekolla

, Ibrahim

, Weniger

, Ziegler

, Schwaiger

. Effect of thyroid hormones on cardiac function, geometry and oxidative metabolism assessed noninvasively by positron emission tomograpy and magnetic resonance imaging. J Clin Endocrinol Metab, 2000; 85:1822–1827.

27.

, Zhou

, Jin

, Bi

, Yang

, Yi

, Liu

. Cardioprotection of salidroside from ischemia/reperfusion injury by increasing N-acetylglucosamine linkage to cellular proteins. Eur J Pharmacol, 2009; 613:93–99.

28.

Sarandöl

, Taş

, Dirican

, Serdar

. Oxidative stress and serum paraoxonase activity in experimental hypothyroidism: effect of vitamin E supplementation. Cell Biochem Funct, 2005; 23:1–8.

29.

Carageorgiou

, Pantos

, Zarros

, Mourouzis

, Varonos

, Cokkinos

, Tsakiris

. Changes in antioxidant status, protein concentration, acetylcholinesterase, (Na⁺,K⁺)-, and Mg²⁺-ATPase activities in the brain of hyper- and hypothyroid adult rats. Metab Brain Dis, 2005; 20:129–139.

30.

Baskol

, Atmaca

, Tanriverdi

, Baskol

, Kocer

, Bayram

. Oxidative stress and enzymatic antioxidant status in patients with hypothyroidism before and after treatment. Exp Clin Endocrinol Diabetes, 2007; 115:522–526.

31.

Erdamar

, Demirci

, Yaman

, Erbil

, Yakar

, Sancak

, Elbeg

, Biberoğlu

, Yetkin

. The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clin Chem Lab Med, 2008; 46:1004–1010.

32.

De Sanctis

, De Bellis

, Scesa

, Mancini

, Cucchiarini

, Dachà

. In vitro protective effect of Rhodiola rosea extract against hypochlorous acid-induced oxidative damage in human erythrocytes. Biofactors, 2004; 20:147–159.

33.

Battistelli

, De Sanctis

, De Bellis

, Cucchiarini

, Dachà

, Gobbi

. Rhodiola rosea as antioxidant in red blood cells: ultrastructural and hemolytic behaviour. Eur J Histochem, 2005; 49:243–254.

34.

Zhang

, Yu

, Sun

, Lin

, Chen

, Tan

, Cao

, Wang

. Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur J Pharmacol, 2007; 564:18–25.

35.

Calcabrini

, De Bellis

, Mancini

, Cucchiarini

, Potenza

, De Sanctis

, Patrone

, Scesa

, Dachà

. Rhodiola rosea ability to enrich cellular antioxidant defences of cultured human keratinocytes. Arch Dermatol Res, 2010; 302:191–200.

36.

Udintsev

, Shakhov

. The role of humoral factors of regenerating liver in the development of experimental tumors and the effect of Rhodiola rosea extract on this process. Neoplasma, 1991; 38:323–331.

37.

Udintsev

, Schakhov

. Decrease of cyclophosphamide haematotoxicity by Rhodiola rosea root extract in mice with Ehrlich and Lewis transplantable tumors. Eur J Cancer, 1991; 27:1182.

38.

Brown

, Helmke

, Hunsucker

, Netea-Maier

, Chiang

, Heinz

, Shroyer

, Duncan

, Haugen

. Quantitative and qualitative differences in protein expression between papillary thyroid carcinoma and normal thyroid tissue. Mol Carcinog, 2006; 45:613–626.

39.

Gehrmann

, Schönberger

, Zilch

, Rossbacher

, Thonigs

, Eilles

, Multhoff

. Retinoid- and sodium-butyrate–induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology. Cell Stress Chaperones, 2005; 10:136–146.

40.

Hoffman

, Hofbauer

, Scharrenbach

, Wunderlich

, Hassan

, Lingelbach

, Zielke

. Thyrotropin (TSH)-induced production of vascular endothelial growth factor in thyroid cancer cells in vitro: evaluation of TSH signal transduction and of angiogenesis-stimulating growth factors. J Clin Endocrinol Metab, 2004; 89:6139–6145.

41.

Panossian

, Wikman

. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol, 2009; 4:189–219.

42.

Shen

, Fan

, Shi

. [Effects of Rhodiola on expression of vascular endothelial cell growth factor and angiogenesis in aortic atherosclerotic plaque of rabbits] Zhongguo Zhong Xi Yi Jie He Za Zhi, 2008; 28:1022–1025.

43.

Zubeldia

, Perez

, Spadaccio

, Diaz Hernandez

, Jimenez Del Rio

, Genovese

. A Rhodiola rosea extract induces apoptosis, modulates essential genes for tumor reversion in human rhabdomyosarcoma cells. Poster presentation at Malta Polyphenols, 2009. www.malta-polyphenols.com. 2009 September 22.

44.

Fintelmann

, Gruenwald

. Efficacy and tolerability of a Rhodiola rosea extract in adults with physical and cognitive deficiencies. Adv Ther, 2007; 24:929–939.

45.

De la Vieja

, Dohan

, Levy

, Carrasco

. Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathphysiology. Physiol Rev, 2000; 80:1083–1105.

46.

Panossian

, Hovhannisyan

, Abrahamyan

, Gabrielyan

, Wikman

. Pharmacokinetic and pharmacodynamic study of interaction of Rhodiola rosea SHR-5 extract with warfarin and theophylline in rats. Phytother Res, 2009; 23:351–357.