{"paper_id":"b6350d0c-176d-48cd-b2ed-29f783dab9a0","body_text":"Emel Kiyak Caglayan ¹, A, D, Mustafa Kara ¹, B, Sema Etiz 2, B, F, Pinar Kumru 3, C, D, \nNurettin Aka 2, F, Gultekin Kose 2 \nThe Effects of Progesterone Selection  \non Psychological Symptoms  \nin Hormone Replacement Therapy\n1 Department of Obstetrics and Gynecology, Bozok University Faculty of Medicine, Yozgat, Turkey \n2 Department of Obstetrics and Gynecology, Haydarpasa Numune Research and Training Hospital, Istanbul,  \n Turkey \n3 Department of Obstetrics and Gynecology, Zeynep Kamil Research and Training Hospital, Istanbul, Turkey\nA – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation; \nD – writing the article; E – critical revision of the article; F – final approval of article; G – other\nAbstract \nObjectives. The aim of this study is to evaluate the effects of hormone replacement therapy using dienogest and \nmedroxyprogesterone acetate on psychological symptoms in perimenopausal and postmenopausal women.\nMaterial and Methods. A total of 73 patients who sought treatment at the menopause units of the authors’ gyne-\ncology and obstetrics clinics between of November 2003 and October 2004 complaining of vasomotor symptoms \nwere included in the study prospectively. The cases were divided into two groups: Group I (37 patients) was given \n2 mg estradiol valerate and 2 mg dienogest, and Group II (36 patients) was given 2 mg estradiol valerate and 10 mg \nmedroxyprogesterone acetate. The groups’ results in months 0 and 6 were compared through the evaluation of \nvasomotor and psychological symptom levels. \nResults. No significant difference was found between the groups when the initial levels of vasomotor and psy-\nchological symptom subtypes were compared (p = 0.16). It was observed that all the psychological symptoms \ndecreased in the 6th month in the group using dienogest in comparison with the initial situation, and that psycho-\nlogical symptoms increased in the group using medroxyprogesterone acetate in the evaluation performed in the \n6th month compared with the initial levels. It was also found out that there was a statistically significant difference \nbetween the two groups when compared in terms of these symptoms (p < 0.0001).\nConclusions. While the use of dienogest normalizes the general psychological situation and sleep, it was observed \nthat the use of medroxyprogesterone acetate (MPA) worsens the general psychological situation (Adv Clin Exp \nMed 2014, 23, 1, 63–67). \nKey words: menopause, dienogest, medroxyprogesterone acetate, psychological symptoms.\nAdv Clin Exp Med 2014, 23, 1, 63–67 \nISSN 1899–5276\nOR IGINA L PAPER S\n© Copyright by Wroclaw Medical University\nMenopause is generally defined as the ending \nof menstruation. Psychological, social and cultural \nfactors should be evaluated together in menopaus-\nal period. Although menopause is accepted as an \nendocrinopathy, its symptoms play an important \nrole in a woman’s life. It is controversial wheth-\ner this period is clinically a psychological disorder \nor a period that causes psychological symptoms to \nemerge more [1]. While some patients go through \nthis period with mild complaints, the others can \nhave a series of symptoms of physiological changes \nsuch as feeling hot, vasomotor symptoms, changes \nin mood, sleep disorders and somatic complaints. \nThe effects on cognitive functions can reduce the \nquality of life and social relationships. The aim of \npost-menopausal hormone therapy is to improve \nthe quality of the patient’s life and prevent the \nnegative changes affecting the patient’s life. Acute \nmenopausal symptoms are an effect of a decrease \nin estrogen levels [2, 3]. \nThe influence of hormone replacement ther-\napy (HRT) was assessed in a recent study that in-\nvestigated the symptoms arising in the meno-\npausal period of women treated with some of the \n\nE.K. Caglayan et al.64\ncurrent HRT preparations [4]. HRT improved \nnegative menopausal symptoms by affecting the \ncentral nervous system (CNS). However, some \nof the HRT preparations used for treatment are \nthought to worsen the woman’s current psycho-\nlogical situation. Among the explanations pro-\nposed for the fact that psychological symptoms \ndeteriorate with HRT are a premorbid personality \nstructure reacting to different progesterone types, \nor the structural sensitivity of women with indivi-\ndual predispositions [5]. \nThe aim of the current study is to investigate \nthe effects of 2 different HRT preparations used in \nmenopause, particularly their effects on patients’ \nvasomotor symptoms and current psychological \nsituations, and their psychological interactions af-\nter 6 months of treatment. \nMaterial and Methods\nThis was a prospective randomized controlled \nstudy. Seventy-three women who sought treatment \nat the menopause units of the authors’ gynecolo-\ngy and obstetrics clinics between November 2003 \nand October 2004 were included in the study. The \nstudy was reviewed and approved by local ethical \ncommittee. Informed consent was obtained from \nall the participants. They were randomly divided \ninto 2 groups: the first group constituted 37 pa-\ntients, and the second one was made up of 36 pa-\ntients. No patient was excluded from the study for \nany reason. The general characteristics of the pa-\ntients noted in the follow-up included in the study \nwere: the date of the last menstrual period, educa-\ntional and occupational situations, marital status, \nnumber of children, daily smoking and body mass \nindex (BMI). The participants in Group I were giv-\nen 2 mg estradiol valerate and 2 mg dienogest once \na day, while the participants in Group II were giv-\nen 2 mg estradiol valerate and 10 mg medroxypro-\ngesterone acetate per day. \nThe Symptom Checklist-90-R (SCL-90-R) and \nKupperman index were given to the subjects upon \ntheir initial hospital admission and after 6 months, \nand the results obtained from the patients were \nevaluated by psychologists in single-blind study \nstyle [6–8]. The level of stress and the response \nof these symptoms to the treatment were assessed \nat the beginning of the treatment and in the 6th \nmonth. While the findings obtained in the study \nwere being evaluated, Statistical Package for Social \nSciences for Windows (SPSS) software (version \n11.0) was used for the statistical analysis. Frequen-\ncy counting, average and standard deviation, which \nare descriptive statistical methods, were used. The \nKolmogorov-Smirnov test and graphical represen-\ntation were utilized for the normality distribution \nof the data. To compare the quantitative data, the \nMann-Whitney U test was performed; and to com-\npare the qualitative data, the chi-square test was \ncarried out. The results were in the 95% confidence \ninterval, the level of significance was p < 0.05 and \nthe highest level of significance was p < 0.01.\nResults\nThere was no statistically significant difference \nbetween the 2 groups according to the Kupper-\nman index (p = 0.16). Temporal changes in both \nGroup I and Group II were significantly higher in \nthe 6th month than at the start of the treatment \n(p < 0.0001) (Table 1). The difference between the \ninitial somatization scores in the 2 groups was not \nstatistically significant (p = 0.25). Group I’s symp-\ntoms were significantly improved in Month 6th as \ncompared to the 1st month (p < 0.0001). In Group \nII, the symptoms were worse in the 6th month \nthan in the 1st month and this difference was also \nstatistically significant (p < 0.0001).\nWhile in Group I social anxiety scores were \nfound to be significantly lower in the 6th month \nthan 1st month, in Group II the symptoms were \nstronger in the 6th month than at the beginning \n(p < 0.0001). \nDepression scores in the 6th month were \nfound to be significantly higher in Group II than in  \nGroup I (p < 0.0001). Anxiety scores in the 6th \nmonth were found to be significantly higher in \nGroup II than Group I (p < 0.0001). At the be-\nginning, the scores for anger and hostility were \nnot significantly different between the 2 groups \n(p = 0.57). However, 6 months later, those scores \nTable 1. Kupperman index distribution in the groups\nKupperman Index Group I (x ± Sx) Group II (x ± Sx) Total p value\nBeginning 25.4 ± 5.7 23.2 ± 7.02 24.3 ± 6.5 0.16\n6th Month 7.8 ± 4.6 8.6 ± 4.5 8.2 ± 4.5 0.38\nTemporal Change (p) 0.00001 0.00001 0.00001\nX ± Sx – average ± standard deviation.\n\nProgesterone Selection in Hormone Replacement Therapy 65\nwere significantly lower in Group I than Group II \n(p < 0.0001). \nAt the onset of the treatment, phobic anxiety \nscores were not significantly different between the \ntwo groups (p = 0.53), but at the end of the 6th \nmonth, they were found to be higher in Group II \nthan in Group I. This difference was statistically \nsignificant (p < 0.0001). \nParanoid ideation was assessed and there was \nno statistically significant difference between the \ntwo groups at the beginning (p = 0. 99) When the \nscores were reassessed after 6 months, the mea-\nsurement was significantly lower in Group I than \nin Group II (p < 0.0001) At the beginning, the \nscores for psychoticism did not significantly dif-\nfer between the 2 groups (p = 0.54). Months later, \nthese scores were found to be significantly higher in \nGroup II than in Group I (p < 0.0001) (Table 2). \nDiscussion\nA considerable degree of recovery was noted \nin the group using dienogest. In all the subgroups \nof psychological parameters – including soma-\ntization, obsessive-compulsive disorder, phobic \nanxiety, depression, anger and hostility, para-\nnoid ideation and psychoticism – the differenc-\nes were found to be statistically significant when \ncomparing the initial month and the 6th month. \nAmong the psychological subgroups whose symp-\ntoms improved to a more notable degree, soma-\ntization came first, while obsessive-compulsive \ndisorder and social anxiety ranked number two. \nComparing all the parameters in the 6th month \nbetween the Group I and Group II, the improve-\nment of Group I, using dienogest, was found to \nbe higher than in Group II, using MPA. This psy-\nchological improvement provided by dienogest \nTable 2. The results of the analysis of the psychiatric symptom and complaint screening test (SCL-90-R) for 9 different \nsymptoms and an additional scale at the start and in the 6th month \nScoring time Group I (x ± Sx)  Group II (x ± Sx) p value/temporal change\nSomatization Month 0 2.3 ± 0.5 2.1 ± 0.6 0.25\nMonth 6 1.01 ± 0.3 3.2 ± 0.3 < 0.0001\nObsessive-\ncompulsive scale\nMonth 0 2.1 ± 0.5 2.2 ± 0.6 0.39\nMonth 6 0.9 ± 0.4 3.7 ± 0.3 < 0.0001\nSocial anxiety Month 0 2.4 ± 0.5 2.2 ± 0.6 0.17\nMonth 6 0.9 ± 0.4 3.6 ± 0.3 < 0.0001\nDepression Month 0 2.3 ± 0.7 2.1 ± 0.8 0.36–41\nMonth 6 0.5 ± 0.4 3.6 ± 0.4 < 0.0001\nAnxiety Month 0 2.4 ± 0.6 2.2 ± 0.6 0.20\nMonth 6 0.9 ± 0.5 3.6 ± 0.3 < 0.0001\nAnger/Hostility Month 0 2.5 ± 0.5 2.3 ± 0.7 0.57\nMonth 6 0.8 ± 0.5 3.5 ± 0.3 < 0.0001\nPhobic anxiety Month 0 2.1 ± 0.6 2.2 ± 0.6 0.53\nMonth 6 0.9 ± 0.5 3.6 ± 0.3 < 0.0001\nParanoid ideation Month 0 2.2 ± 0.4 2.1 ± 0.3 0.99\nMonth 6 0.6 ± 0.5 3.4 ± 0.3 < 0.0001\nPsychoticism Month 0 2.04 ± 0.4 2.06 ± 0.4 0.54\nMonth 6 0.4 ± 0.4 3.5 ± 0.3 < 0.0001\nAdditional Scale Month 0 2.3 ± 0.7 2.3 ± 0.6 0.9\nMonth 6 0.8 ± 0.4 3.6 ± 0.3 < 0.0001\nX ± Sx – average ± standard deviation.  \n*p value of the temporal change of the evaluation for all 9 symptoms and additional scale at initial and in the 6th month was \ndetermined as < 0.0001 among the groups. \n\nE.K. Caglayan et al.66\nis statistically significant (p < 0.0001). With re-\ngard to the group using MPA, it was determined \nthat the participants’ psychological situation be-\ncame worse in the 6th month in comparison with \nthe initial status, and this decline was statistical-\nly significant (p  < 0.0001). Although the curative \neffects of MPA on vasomotor symptoms is the \nsame as the effects of dienogest, the authors note \nthat MPA affects the patient’s mood, sleep, de-\npression and other psychological subparameters \nnegatively. \nSimilar results were found in Schneider’s \nneurophysiological study: that dienogest pro-\nvided complete recovery in vasomotor and neu-\nrovegetative symptoms, and great improvement \nin postmenopausal women with cognitive func-\ntions and sleep disorders. The authors concluded \nthat the use of dienogest in continuous combined \nhormone replacement treatment was specifically \nindicated for postmenopausal women with dis-\norders of alertness and mood [8, 9]. Graser et \nal. compared 2 mg estradiol valerate and differ-\nent dose combinations of dienogest (0.5, 1, 2, 3 \nand 4  mg). They stated that all of the dienogest \ndoses provided significant recovery in vasomo-\ntor and psychoneurotic symptoms  [10]. Oettel et \nal. stated that 2  mg estradiol and 2  mg dienogest \naffected postmenopausal symptoms related to in-\nsomnia, sleep patterns and the patient’s general \nwell-being [11]. \nSaletu et al. carried out an evaluation of the \nalertness of patients with postmenopausal syn-\ndrome suffering from insomnia, using EEG map-\nping in a double-blind placebo-controlled study. \nThey compared a continuous 2 mg estradiol valer-\nate + 2 mg dienogest treatment with single estro-\ngen therapy, and determined that 2 mg of estradiol \nvalerate improved alertness slightly. The addition \nof dienogest did not minimize the effect of estro-\ngen, but rather increased it. This made the com-\nbination superior to both a placebo and to estra-\ndiol [12]. Saletu et al. also evaluated the quality of \nsleeping and awakening in 55 patients with insom-\nnia in a double-blind, trifurcate and placebo-con-\ntrolled study. They stated that estrogen/proges-\nterone combinations with dienogest significantly \nimproved subjective sleep quality and sleep-related \ndisorders, and marginally improved the objective \nquality of sleep and awakening [13].\nA multi-center double-blind study compared \nthe use of estradiol valerate 2 mg + dienogest 2 mg, \nestradiol valerate 2 mg + dienogest 3 mg and es-\ntradiol valerate 2 mg + norethisteroneacetate  \n(NETA) 1 mg daily throughout a year in 581 post-\nmenopausal women. Their climacteric symptoms \nhad been evaluated and Kupperman index scores \nwere found to be 78.5%, 74.5% and 75% respec-\ntively [14–16]. Although a number of studies have \nreported physical side effects (constipation, bloat-\ning and breast pain) and psychological side effects \n(depression, fatigue, irritability) resulting from \nmedroxyprogesterone acetate use, these were not \nobserved in prospective randomized studies [17].\nIn a prospective study by Kirkham et al. it was \nobserved that there was no significant difference \nin terms of depression and psychological symp-\ntoms in patients using medroxyprogesterone ace-\ntate treatment and those using a placebo [17]. In \nanother in vitro study, it was demonstrated that \nmedroxyprogesterone acetate and metabolites in-\nfluenced memory, learning and other cognitive \nfunctions unfavorably through the GABA-ergic \nsystem, and could cause neuronal toxicity, this ef-\nfect was not clearly revealed in in vivo clinical and \npreclinical studies [18].\nIn spite of the fact different ideas about the ef-\nfect of medroxyprogesterone acetate on psycholog-\nical symptoms can be found in the literature, the \nauthors of the current article observed that in the \ngroup taking MPA (Group II) all the psychological \nsymptoms worsened in the 6th month compared \nto the start of the treatment. When patients were \ncategorized according to their worst psychologi-\ncal symptoms, anger and hostility were more com-\nmon, followed by eating and sleeping disorders.\nIn brief, the present study showed that the use \nof dienogest provided significant improvement in \nall the psychological symptoms investigated, while \nthe use of medroxyprogesterone acetate worsened \npsychiatric symptoms. However, because of a lack \nof consensus on this topic in the literature, large \nprospective randomized studies are required in or-\nder to research the effect of medroxyprogesterone \nacetate on psychological symptoms.\nReferences\n [1] Zeyneloglu HB: Ergeneli MTreatment of menopausal symptoms. J Drug Treat 1995, 8, 230–232.\n [2] Haines JC, Xinq SM, Park KH, Holinka CF, Ausmanas KM: Prevalence of menopausal symptoms in different \nethnic groups of Asian women and responsiveness to therapy with three doses of conjugated estrogens/medroxy-\nprogesterone acetate: The Pan-Asia menopause (PAM) study. Maturitas 2005, 52, 264–276.\n [3] Nelson HD: Menopause. Lancet 2008, 371, 760–770.\n [4] Limouzin-Lamonthe MA, Mairon N, Joyce CR, Le Gal M: Quality of life after the menapause: Influence of hor-\nmonal replacement therapy. Am J Obstet Gynecol 1994, 170, 618–624. \n\nProgesterone Selection in Hormone Replacement Therapy 67\n [5] Cohen LS, Soares CN, Poitras JR, Prouty J, Alexander AB, and Shifren JL: Short-term use of estradiol for depres-\nsion in perimenopausal and postmenoupausal women: A preliminary report. Am J Psyhiatry 2003, 160, 1519–1522.\n [6] Dag I: Validity and reliability of symptom checklist for university students (SCL-90-R). Turk Psikiyatri Derg 1991, \n2, 5–12.\n [7] Aydemir O, Koroglu E: Symptom checklist (SCL–90-R), clinical scales used in psychiatry. Eds.: Aydemir O, \nKoroglu E, Istanbul 2000, 33–41.\n [8] Schneider HP, Rosemeier HP, Schnitker J, Gerbsch S, Turck R: Application and factor analysis of the menopause \nrating scale (MRS) in a post- marketing surveillance study of Climen. Maturitas 2000, 37, 113–124.\n [9] Schneider HP: The role of antiandrogens in hormone replacement therapy. Climacteric 2000, 3, 21–27.\n[10] Graser TA, Müler A, Mellinger U, Mück AO, Lippert TH, Oettel M: Continuous-combined treatment of the \nmenopause with combinations of estradiol valerate and diogenest – a dose ranging study. Maturitas 2000, 35, \n253–261.\n[11] Qettel M, Graser T, Hoffmann H: The preclinical and clinical profile of diogenest A short overview. Drugs of \nToday 1999, 35, 3–12.\n[12] Saletu B, Anderer P, Gruber D, Metka M, Huber J: Hormone replacement therapy and vigilance: double-blind, \nplacebo-controlled EEG-mapping studies with an estrogen-progestogen combination (Climodien, Lafamme) ver-\nsus estrogen alone in menopausal syndrome patients. Maturitas 2002, 43,165–181.\n[13] Saletu B: Insomnia related to postmenopausal syndrome: Sleep laboratory studies on differences between patients \nand normal controls, and influence of an estrogen-progestogen combination with dienogest versus estrogen alone \nand placebo. Drugs of Today 2001, 37, 39–62.\n[14] Von Schoultz B: Clinical efficacy and safety of combined estradiol valerate and dienogest: a new no-bleed treat-\nment. Climacteric 2003, 6, 24–32.\n[15] Graser TA, Hoffmann H, Zimmermann, Oettel M: New Oral Preparation for continuous combined hormone \nreplacement therapy in postmenopausal women. Drugs of Today 2001, 37, 17–27.\n[16] Wellington K, Perry CM: Estradiol valerate/dienogest. Drugs 2002, 62, 491–504.\n[17] Kirkham C, Hahn PM, Van Vugt DA, Carmichael JA, Reid RL: A randomized, double-blind, placebo-controlled, \ncross-over trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy. Obstet \nGynecol 1991, 78, 93–97. \n[18] Braden BB, Talboom JS, Crain ID, Simard AR, Lukas RJ, Prokai L: Medroxyprogesterone acetate impairs \nmemory and alters the GABA’ergic system in aged surgically menopausal rats. Neurobiol Learn Mem 2010, 93, \n444–453. \nAddress for correspondence:\nEmel Kiyak Caglayan\nBozok University Faculty of Medicine\nAdnan Menderes Bulvarı No. 190\n66200 Yozgat\nTurkey\nTel: + 90 354 212 70 01\nE-mail: emelkiyak@hotmail.com\nConflict of interest: None declared\nReceived: 14.12.2012\nRevised: 6.05.2013\nAccepted: 20.02.2014","source_license":"CC0","license_restricted":false}