KISEP Review Article J Korean Neuropsychiatr Assoc Vol 42, No 1 생식정신의학 : 폐경주변기및폐경기 전진숙 Reproductive Psychiatry:Perimenopause and Menopause Jin-Sook Cheon, MD Department of Neuropsychiatry, Kosin University, School of Medicine, Busan, Korea The most troublesome symptoms of perimenopause and menopause are hot flushes, insomnia, depression, sexual dysfunction and cognitive decline. The suggested mechanism is the hormonal changes of estrogen, progesterone and androgen as well as neuromodulating effect of estrogen, which enhances activity of 5-HT and norepinephrine, inhibiting monoamine oxidase and dopamine. Though testosterone deficiency is not analogous to female menopause, male climacteric has become a clinical issue in current psychiatry. KEY WORDS:Menopause Hot flushes Depression Estrogen Neuromodulation Male climacteric. 서 - - - 론 - 폐경기증상 46
Menarche Perimenopause Menopause Premenopause Postmenopause Ages 4257 Depressed, anxious, disturbed sleep, decreased concentration Fully assess/especially note 1. Somatic symptoms, menstrual pattern 2. Past psychiatric history, including reprodution-related history 3. Current psychosocial issues 4. TSH 0 10 20 30 40 50 60 70 80 Age years Fig. 1. Reproductive life cycle. 2) FSH & LH IU/L 100 090 080 070 060 050 200 040 160 030 120 020 180 010 140 010 140 Mean circulating hormone levels Estradiol Estrone Pg/mL Estradiol Estrone Fig. 2. The perimenopausal transition. 4) FSH 44 46 48 50 52 54 56 58 Age years Menopause LH No Yes FSH E2 1. Consider psychiatric d/o 2. Consider repeat FSH, E2 in 3 months 3. Consider standard psychiatric treatment Yes Yes Symptoms remit No further psychiatric treatment needed Vasomotor symptoms 1. Perimenopause does not rule out psychiatric comorbidity 2. Educate re menopause, HRT 3. Refer to gyencologist 4. Offer psychotherapy group, individual HRT Begin psychiatric treatment Symptoms remit No FSH E2 Yes Yes No NoNo 1. Consider psychiatric d/o 2. Consider standard psychiatric treatment No Yes No further psychiatric treatment needed Fig. 3. Psychiatric evaluation of the middle-aged depressed womanspecial considerations. 15) TSHthyroid-stimulating hormone, FSHfollicle-stimulating hormone, d/odisorder, E2estradiol, HRThormone replacement therapy. - - - - 47
기전 Cholesterol HO CH3 C=O CH3 C=O HO CH2OH H O=C C=O O O HO Pregnenolone Progesterone 11-Deoxycorticosterone Corticosterone 18-Hydroxycorticosterone Aldosterone CH3 CH3 C=O C=O OH OH HO CH2OH C=O OH O HO 17-Hydroxypregnenolone 17-Hydroxyprogesterone 11-Deoxycortisol Cortisol OH HO O O O O Dehydroepiandrosterone Androstenedione Testosterone O OH Estrone Estradiol HO O H Dihydrotestosterone OH Fig. 4. Synthetic pathways for steroid hormones. 25) Circled numbers identify synthetic enzymes 1 cytochrome P450 CYP 11A cholesterol desmolase, 23-hydroxysteroid dehydrogenase, 3CYP21 21- hydroxylase, 4CYP11B2 11hydroxylase, 18-hydroxylase, 18- oxidase, 5CYP17 17-hydroxylase, 17, 20-lyase, 617hydroxysteroid dehydrogenase or oxidoreductase, 7aromatase, 85-reductase, 9 CYP11B1 11-hydroxylase. 48
- - GABA VIP, NE, EP Aspartate FSH Estrogens Fig. 5. Ovarian axis. 26) Intrinsic circadian rhythm Hypothalamus CRH + Anterior pituitary ACTHLPH/-end + Adrenal cortex cortisol Stress Stress sensory stimuli Hypothalamus GnRH Pituitary Ovary Dopamine, serotonin, CRH, OT LH Progesterone Ovary estrogen/ progesterone Fig. 6. Overview of hypothalamic-pituitary-adrenal HPA axis function. 27) ACTHadrenocorticopropic hormone, -LPH/end-lipotropin and -endorphin, CRHcorticotropin-releasing hormone. - - 치료 - 49
- - - - 남성갱년기 Table 1. Alternative treatments for hot flushes 45) Clonidine, Bromocriptine, Naloxone, Bellergal, Veralipride, Methyldopa, Venlafaxine, Vitamin E, Megestrol acetate, Medroxyprogesterone acetate Tibolonea steroid related to 19-nortestosterone Natural therapiesginseng, Agnus castus, Red sage, Black cohosh, Beth root, Phytoestrogens legumes, soybeans Dehydroepiandrosterone DHEA 50
- - - - 결 T E2 LH GnRH Leydig cell + Testicle T Sperm Fig. 7. Hypothalamic-pituitary-testicular axis. 54) GnRHgonadotropin-releaing hormone, LHluteinizing hormone, FSHfolliclestimulating hormone, Ttestosterone, DHTdihydrotestosterone, ABPandrogen-binding protein, E2estradiol, +positive influence, negative influence. 론 Hypothalamus Pituitary + + + ABP Seminiferous tubule FSH Inhibin T DHT E2 Sertoli cell 51
중심단어 REFERENCES 1) 전진숙. 여성우울증의신경생물학. 노인정신의학 1999;3:129-139. 2) Joffe H. Mood disorders in the perimenopause: the estrogen connection. Advances in Women s Mental health: A Decade of Progress, Annual Meeting of American Psychiatric Association;2000 May 14; Chicago, U.S.A.: American Psychiatric Association;2000. 3) Hurd WW. Menopause. In: Berek JS, Adashi EY, Hillard PA, editors. Novak s Gynecology. 12th ed. Baltimore: Williams & Wilkins;1996. p.981-1011. 4) Speroff L, Glass RH, Kase NG. Menopause and the perimenopausal transition. In: Clinical Gynecologic Endocrinology and Infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins;1999a. p.642-724. 5) Seiden AM. Overview: research on the psychology of women. I. gender differences and sexual and reproductive life. Am J Psychiatry 1976; 133:995-1007. 6) Steiner M, Yonkers K. Mood disorders associated with the menopause. In: Depression in Women. London: Martin Dunitz;1998. p.48-59. 7) Oldenhave A, Jaszmann LJB, Haspels AA, Everaerd WThAM. Impact of climacteric on well-being: a survey based on 5213 women 39 to 60 years old. Am J Obstet Gynecol 1993b;168:772-778. 8) Oldenhave A, Jaszmann LJB, Everaerd WThAM, Haspels AA. Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age. Am J Obstet Gynecol 1993a;168:765-771. 9) Winokur G. Depression in the menopause. Am J Psychiatry 1973; 130:92-93. 10) Notman M. Midlife concerns of women: implications of the menopause. Am J Psychiatry 1979;136:1270-1274. 11) Brown RP, Sweeney J, Loutsch E, Kocsis J, Frances A. Involutional melancholia revisited. Am J Psychiatry 1984;141:24-28. 12) Gitlin MJ, Pasnau RO. Psychiatric syndromes linked to reproductive function in women: a review of current knowledge. Am J Psychiatry 1989;146:1413-1422. 13) Schmidt PJ, Rubinow DR. Menopause-related affective disorders: a justification for further study. Am J Psychiatry 1991;148:844-852. 14) Becker D, Lomranz J, Pines A, Shmotkin D, Nitza E, BennAmitay G, Mester R. Psychological distress around menopause. Psychosomatics 2001;42:252-257. 15) Burt VK, Hendrick VC. Perimenopause and menopause. In: Concise Guide to Women s Mental Health. Washington DC: American Psychiatric Press;1997. p.103-115. 16) Yaffe K, Krueger K, Sarkar S, Grady D, Barrett-Connor E, Cox DA, Nickelsen T. Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 2001;344:1207-1213. 17) Jacobs DM, Tang M-X, Stern Y, Sano M, Marder K, Bell KL, Schofield P, Dooneief G, Gurland B, Mayeux R. Cognitive function in nondemented older women who took estrogen after menopause. Neurology 1998;50:368-373. 18) Maki PM, Zonderman AB, Resnick SM. Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy. Am J Psychiatry 2001;158:227-233. 19) Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279:688-695. 20) Waring SC, Rocca WA, Petersen RC, O Brien PC, Tangalos EG, Kokmen E. Postmenopausal estrogen replacement therapy and risk of AD: a population-based study. Neurology 1999;52:965-970. 21) Geerlings MI, Ruitenberg A, Witteman JC, van Swieten JC, Hofman A, van Duijn CM, Breteler MMB, Launer LJ. Reproductive period and risk of dementia in postmenopausal women. JAMA 2001;285: 1475-1481. 22) LeBlanc ES, Janowsky J, Chan BKS, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 2001;285:1489-1499. 52 23) Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, McCleary CA, Klein RA, Hake AM, Farlow MR. Estrogen from Alzheimer s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000;54:295-301. 24) DeBattista C, Smith DL, Schatzberg AF. Modulation of monoamine neurotransmitters by estrogen: clnical implications. In: Leibenluft E, editor. Review of Psychiatry. vol 18. Gender Differences in Mood and Anxiety Disorders, From Bench to Bedside. Washington DC: American Psychiatric Press;1999. p.137-160. 25) Rubinow DR, Schmidt PJ. Androgens, brain, and behavior. Am J Psychiatry 1996;153:974-984. 26) Rubinow DR. Effects of gonadal steroids on brain & behavior. Advances in Women s Mental Health: A Decade of Progress, Annual Meeting of American Psychiatric Association;2000 May 14; Chicago, U.S.A.: American Psychiatric Association;2000. 27) Young E, Korszun A. Women, stress, and depression: sex differences in hypothalamic-pituitary-adrenal axis regulation. In: Leibenluft E, editor. Review of Psychiatry. vol 18. Gender Differences in Mood and Anxiety Disorders, From Bench to Bedside. Washington DC: American Psychiatric Press;1999. p.31-52. 28) 김진홍. 알츠하이머질환과에스트로젠. 대한폐경회지 2000;6: 3-11. 29) Shaywitz SE, Shaywitz BA, Pugh KR, Fulbright RK, Skudlarski P, Mencl WE, Constable RT, Naftolin F, Palter SF, Marchione KE, Katz L, Shankweiler DP, Fletcher JM, Lacadie C, Keltz M, Gore JC. Effects of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999;281:1197-1202. 30) Joffe H, Cohen LS. Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge? Biol Psychiatry 1998;44:798-811. 31) Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: implications for affective regulation. Biol Psychiatry 1998;44:839-850. 32) Di Paolo T, Poyet P, Labrie F. Effect of prolactin and estradiol on rat striatal dopamine receptors. Life Sci 1982;31:2921-2929. 33) Bassi F, Mannelli M, De Feo ML, Magini A, Jasonni VM. The adrenal secretion in postmenopausal women. In: Fioretti P, Flamigni C, Jasonni VM, Melis GB, editors. Postmenopausal Hormonal Therapy: Benefits and Risks. New York:Raven Press;1987. p.21-27. 34) Piletz JE, Halbreich U. Imidazoline and α 2 A-adrenoceptor binding sites in postmenopausal women before and after estrogen replacement therapy. Biol Psychiatry 2000;48:932-939. 35) Fioretti p, Paoletti AM, Gambacciani M, Mais V, Cagnacci A, Grimaldi E, Manetti P, Strigini F, Antinori D, Melis GB. Neuroendocrine effects of opioids in postmenopausal women. In: Fioretti P, Flamigni C, Jasonni VM, Melis GB, editors. Postmenopausal Hormonal Therapy: Benefits and Risks. New York: Raven Press;1987. p.1-8. 36) Smith MJ, Keel JC, Greenberg BD, Adams LF, Schmidt PJ, Rubinow DA, Wassermann EM. Menstrual cycle effects on cortical excitability. Neurology 1999;53:2069-2072. 37) Costa MM, Reus VI, Wolkowitz OM, Manfredi F, Lieberman M. Estrogen replacement therapy and cognitive decline in memory-impaired post-menopausal women. Biol Psychiatry 1999;46:182-188. 38) Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid [beta]-peptide toxicity in hippocampal neurons. J Neurochem 1996;66:1836-1844. 39) Seeman MV. Psychopathology in women and men: focus on female hormones. Am J Psychiatry 1997;154:1641-1647. 40) 지병철, 김형석. 호르몬대체요법후유방실질의음영증가. 대한산부인과학회지 2001;44:867-871. 41) Rodriquez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001;285:1460-1465. 42) Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-491. 43) Chouinard G, Steinberg S, Steiner W. Estrogen-progesterone combination: another mood stabilizer? Am J Psychiatry 1987;144:826. 44) Greenberg DB. Book Reviews: A Clinician s Guide to Menopause. Psychosomatics 1998;39:76-77. 45) Speroff L, Glass RH, Kase NG. Postmenopausal hormone therapy.
In: Clinical Gynecologic Endocrinology and Infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins;1999b. p.642-724. 46) Melis GB, Cagnacci A, Gambacciani M, Grimaldi E, Strigini F, Zichella L, Tesseri E, Bonamici E, Fiorretti P. Dopaminergic system and postmenopausal hot flushes: effects of domperidone treatment and dopamine infusion. In: Fioretti P, Flamigni C, Jasonni VM, Melis GB, editors. Postmenopausal Hormonal Therapy: Benefits and Risks. New York: Raven Press;1987. p.55-65. 47) Wheatley D. Trial of an adrenergic beta-blocker in the menopause. Psychosomatics 1984;25:208-211. 48) de Novaes Soares C, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-553. 49) 김수웅. 노인남성에서남성호르몬대체요법. 대한남성의학회지 2001;19:5-16. 50) Sternbach H. Age-associated testosterone decline in men: clinical issues for psychiatry. Am J Psychiatry 1998;155:1310-1318. 51) Wolf OT, Preut R, Hellhammer DH, Kudielka BM, Schümeyer TH, Kirschbaum C. Testosterone and cognition in elderly men: a single testosterone injection blocks the practice effect in verbal fluency, but has no effect on spatial or verbal memory. Biol Psychiatry 2000;47: 650-654. 52) Smith MJ, Schmidt PJ, Rubinow DR. Cognitive effects of testosterone supplementation. Am J Psychiatry 2000;157:307-308. 53) 정경우. PADAM: practical approach. 대한남성과학회지 2001;19: 1-4. 54) Braunstein GD. The testes. In: Greenspan FS, Forsham PH, editors. Basic & Clinical Endocrinology. Los Altos: Lange;1986. p.351-384. 55) Yates WR. Testosterone in psychiatry: risks and benefits. Arch Gen Psychiatry 2000;57:155-156. 56) Shaneyfelt T, Husein R, Bubley G, Mantzoros CS. Hormone predictors of prostate cancer: a meta-analysis. J Clin Oncol 2000;18:847-853. 53