nutrients Article The Oak–Wood Extract Robuvit® Improves Recovery and Oxidative Stress after Hysterectomy: A Randomized, Double-blind, Placebo-Controlled Pilot Study Vladimír Ferianec 1 , Matej Fülöp 2, Miriam Ježoviˇcová 2, Jana Radošinská 3,4 , Marta Husseinová 3, Michaela Feriancová 1, Dominika Radošinská 5, Miroslav Baranˇcík 4, Jana Muchová 2, Petra Högger 6 and Zde ˇnka Duraˇckovˇ á 2,7,* 1 Department of II. Gynecology and Obstetrics, Medical Faculty, Comenius University, 82606 Bratislava, Slovakia; [email protected] (V.F.); [email protected] (M.F.) 2 Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Medical Faculty, Comenius University, 81108 Bratislava, Slovakia; [email protected] (M.F.); [email protected] (M.J.); [email protected] (J.M.) 3 Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia; [email protected] (J.R.); [email protected] (M.H.) 4 Center of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; [email protected] 5 Faculty of Natural Sciences, Comenius University in Bratislava, 84215 Bratislava, Slovakia; [email protected] 6 Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, 97074 Würzburg, Germany; [email protected] 7 Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Sasinkova 2, 81108 Bratislava, Slovakia * Correspondence: [email protected] Received: 10 March 2020; Accepted: 25 March 2020; Published: 27 March 2020 Abstract: Hysterectomy has a variety of medical indications and improves pre-operative symptoms but might compromise the quality of life during recovery due to symptoms such as fatigue, headache, nausea, depression, or pain. The aim of the present study was to determine the effect of a standardized extract from French oak wood (Quercus robur) containing at least 40% polyphenols of the ellagitannins class, Robuvit®, on convalescence and oxidative stress of women after hysterectomy. Recovery status was monitored with the SF-36 questionnaire. The supplementation with Robuvit® (300 mg/day) during 4 weeks significantly improved general and mental health, while under placebo some items significantly deteriorated. Oxidative stress and enhancement of MMP–9 activity was significantly reduced by Robuvit® versus placebo. After 8 weeks of intervention, the patients’ condition improved independently of the intervention. Our results suggest that the use of Robuvit® as a natural supplement relieves post-operative symptoms of patients after hysterectomy and reduces oxidative stress. The study was registered with ID ISRCTN 11457040 (13/09/2019). Keywords: hysterectomy; Robuvit®; oak wood extract; post-operative recovery; oxidative stress; matrix metalloproteinases; complementary medicine 1. Introduction The surgical removal of the uterus, a hysterectomy, is one of the most common operative gynecological procedures. Nutrients 2020, 12, 913; doi:10.3390/nu12040913 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 913 2 of 13 Total hysterectomy refers to the removal of the whole uterus including the cervix, subtotal hysterectomy refers to the removal of the uterus without the cervix. The latter is preferred by some surgeons in order to decrease the negative effect on pelvic floor and sexual functions, however, this has not been confirmed [1]. surgeonsIndications in order for to hysterectomy decrease the include negative menorrhagia effect on pelvic as the floor most and frequent sexual indicationfunctions, however, in premenopausal this has womennot been due confirmed to myomas [1]. or adenomyosis, pelvic pain due to endometriosis/adenomyosis after unsuccessfulIndications conservative for hysterectomy treatment andinclude uterine menorrhagia prolapse. Malignancyas the most or postpartumfrequent indication hemorrhage in accountpremenopausal only for 10%women of all due hysterectomies to myomas or adenomyosis, [2]. pelvic pain due to endometriosis/adenomyosis afterIn unsuccessful general, hysterectomy conservative improves treatment psychological and uterine prolapse. and general Malignancy wellbeing or postpartum of the patients hemorrhage due to removalaccount of only the symptomsfor 10% of all that hysterectomies led to the surgery. [2]. However, patients’ quality of life during postoperative recoveryIn general, can be significantly hysterectomy impaired improves by psychological symptoms such and asgeneral fatigue, wellbeing headache, of nausea,the patients depression, due to pain,removal wound of the infection symptoms and bleedingthat led to [ 3the,4]. surgery. These symptoms However, maypatients’ have quality an important of life during social postoperative and economic impactrecovery [5]. can be significantly impaired by symptoms such as fatigue, headache, nausea, depression, pain,So wound far, only infection a few and studies bleeding have [3,4]. investigated These symptoms the may pathophysiology have an important of the social aforementioned and economic impact [5]. postoperative symptoms. Some studies determined an association between fatigue, depression, So far, only a few studies have investigated the pathophysiology of the aforementioned anxiety, nausea and headache with oxidative stress [6–9]. postoperative symptoms. Some studies determined an association between fatigue, depression, anxiety, During surgery, biological pathways leading to oxidative stress and the production of free radicals nausea and headache with oxidative stress [6–9]. are activated [10,11]. The extent of oxidative stress depends on many factors such as the type, extent During surgery, biological pathways leading to oxidative stress and the production of free radicals andare time activated of surgery, [10,11]. operation The extent technique, of oxidative type stress of anaesthesia depends on or many perioperative factors such analgesia as the [type,12–19 extent]. andDespite time of surgery, many studies operation on technique, aspects of type postoperative of anaesthesia recovery, or perioperative no consensus analgesia about [12–19]. a validated procedureDespite to accelerate many studies or assist on recoveryaspects of in postoperative this period exists recovery, [6]. no consensus about a validated ® procedureBased on to accelerate the reported or assist positive recovery effects in ofthis Robuvit period existson energy [6]. levels and mental health [7] and the outcomesBased on of the clinical reported studies positive related effects to the of improvementRobuvit® on energy of fatigue levels symptoms and mental [8 –health10], burnout [7] and [the11], recoveryoutcomes after of sport clinical [20 ,studies21] or fatigue related in to medical the improvement convalescence of [22fatigue], all in symptoms conjunction [8–10], with burnout the reduction [11], ofrecovery oxidative after stress, sport we [20,21] aimed or to investigatefatigue in themedical influence convalescence of Robuvit [22], on all the in recovery conjunction of women with afterthe hysterectomy.reduction of oxidative Robuvit® stress,(Horphag we aimed Research) to investigate (further the referred influence to of as Robuvit Robuvit) on is the the recovery proprietary of women water extractafter hysterectomy. from the wood Robuvit of French® (Horphag oak (Quercus Research) robur (further L.) and referred contains to atas least Robuvit) 40% polyphenolsis the proprietary such aswater ellagitannins. extract from Roburins the wood are of ellagitannin French oak ( dimersQuercus of robur which L.) fiveand structurescontains at haveleast 40% been polyphenols reported so far,such named as ellagitannins. A (Figure1), Roburins B, C, D andare ellagitannin E. Ellagitannin dimers monomers of which are five the structures stereoisomers have been vescalagin reported and so castalaginfar, named [23 A,24 (Figure]. In addition 1), B, C, to D roburins, and E. Ellagitannin Robuvit also monomers contains are gallic the acid stereoisomers and ellagic vescalagin acid [25,26 and]. castalagin [23,24]. In addition to roburins, Robuvit also contains gallic acid and ellagic acid [25,26]. FigureFigure 1. 1.Chemical Chemical structurestructure of roburin A. A. DueDue to to their their high high molecularmolecular weight, weight, ellagitannins ellagitannins are are not not absorbed absorbed in the in thegastrointestinal gastrointestinal tract, tract, but butare are metabolized metabolized by by gut gut bacteria bacteria yielding yielding urolithins urolithins [27]. [27 Urolithins]. Urolithins A, B A, and B and C have C have been been detected detected in inplasma plasma samples samples after after the the intake intake of ofRobuvit Robuvit (25). (25). In addition to the antioxidant properties of ellagitannins, anti‐carcinogenic [28,29], anti‐ inflammatory effects [30,31], antithrombotic [32] and antiplatelet properties [33] were described for 2 Nutrients 2020, 12, 913 3 of 13 In addition to the antioxidant properties of ellagitannins, anti-carcinogenic [28,29], anti-inflammatory effects [30,31], antithrombotic [32] and antiplatelet properties [33] were described for ellagic acid. In our previous study, an increased total antioxidant capacity and a higher activity of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase as well as decreased levels of advanced oxidation protein products and lipoperoxides were determined after Robuvit administration (300 mg/day)