雌激素在男性的生理功能---2010

Review Article R Ma at fo anc D Er Fro and Pu lu fec re no M ap Re in re ha tra wh m Ho ca an in au pr be Co se ca K AN ica tre ca pla ca th Ab 002 TH © 2 ik Wibowo, Paul Schellhammer and Richard J. Wassersug*,† m the Department of Anatomy & Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada (EW, RJW) Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia (PS) rpose: Patients with prostate cancer on androgen deprivation therapy with teinizing hormone-releasing hormone agonists experience deleterious side ef- ts, including sexual dysfunction, hot flashes and osteoporosis. Estrogen may lieve or reduce some of these side effects. We explore the role of estrogen in rmal male function, emphasizing sexual interest and performance. aterials and Methods: We reviewed the literature on androgen deprivation ther- y, estrogen and sexual function in males using PubMed® and other sources. sults: Estrogen receptors are present in tissues involved in sexual behavior cluding several brain centers and pelvic floor muscles. Exogenous estrogens can store some sexual interest to greater than castrate level in castrated animals. This s also been reported for certain androgen deprived patients (eg voluntarily cas- ted men, male-to-female transsexuals) who take exogenous estrogens and others o are on high dose antiandrogens which increase endogenous estradiol levels. Estrogen also helps prevent hot flashes and bone mineral loss, which com- only occur with luteinizing hormone-releasing hormone agonist treatment. wever, estrogen may cause gynecomastia and increases the risk of breast ncer. Thus, patients with prostate cancer should be informed about the pros d cons of estrogen therapy before starting androgen deprivation therapy. Based on these data estrogen is likely to have maximal benefits in men if itiated simultaneously with androgen deprivation therapy. Because estrogen toregulates its own receptors, a constant dose of estrogen will not likely oduce a constant serum concentration, suggesting that its effectiveness could optimized if administered cyclically. nclusions: Prospective studies on the ability of parenteral estrogen to pre- rve sexual interest at greater than castrate level in patients with prostate ncer are warranted. ey Words: estradiol, neurobiology, perineum, libido, androgen antagonists DROGEN deprivation therapy as chem- l or surgical castration is used to at metastatic PCa as well as lo- lly advanced disease. ADT reduces sma androgen levels and retards ncer growth. LHRH agonists are e dominant method of castration. out a third of approximately 2 million PCa survivors in the United States are receiving this treatment at any given time.1 Side effects of surgical castration or LHRH agonist administration in- clude loss of libido, impaired sexual function, decreased erectile rigidity and reduced penile length.2 With im- Abbreviations and Acronyms ADT� androgen deprivation therapy DES� diethylstilbestrol E� estrogen E2� estradiol ER� estrogen receptor LHRH� luteinizing hormone- releasing hormone MtF� male-to-female PCa� prostate cancer SDN-POA� sexually dimorphic nucleus of the preoptic area SNB� spinal nucleus of the bulbocavernosus Submitted for publication October 20, 2009. Supported by the Canadian Cancer Society, the “Motorcycle Ride for Dad” (through the Dal- housie Medical Research Foundation), Nova Sco- tia Health Research Foundation, Canadian Insti- tutes of Health Research and a trainee award from the Beatrice Hunter Cancer Research Insti- tute with funds provided by the Canadian Cancer Society, Nova Scotia Division (EW). Supplementary material for this article can be obtained at http://www.anatomy.dal.ca/wassersug/ Expanded_bibliography_for_Wibowo_et_al.html. * Correspondence: Department of Anatomy & Neurobiology, Sir Charles Tupper Medical Building, 5850 College St., Dalhousie University, Halifax, Nova Scotia, B3H 1X5, CANADA (telephone: 902- 494-2244; e-mail: richard.wassersug@dal.ca). † Current address: Australian Research Centre in Sex, Health & Society, La Trobe University, 1st Floor, 215 Franklin St., Melbourne, Victoria 3000, Australia. 2-5347/11/1851-0017/0 Vol. 185, 17-23, January 2011 E JOURNAL OF UROLOGY® Printed in U.S.A. 011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2010.08.094 www.jurology.com 17 ole of Estrogen in Normal r Patients With Prostate C eprivation Therapy le Function: Clinical Implic er on Androgen ions pr be im m de th be qu at th ag go sid an ha an ES Of ER ER or bu cle eff ha be sh ge ior In m in ra in BE Co E ior gu in wi ta siv of in a d te bu we lat ra ex tio se Pe Th on lib ac m m of stu blo te am th co wh m an qu on ES NE Se of Th an tiv re in SD th in in um PO in da th al se fem th bo th in ac ESTROGEN IN PATIENTS ON ANDROGEN DEPRIVATION THERAPY18 oved detection methods in recent years, men are ing diagnosed with PCa at younger ages. Sexual pairment tends to be more pronounced in younger en.1 Such adverse effects often lead to anxiety and pression, greatly reducing the quality of life of ese patients.1 In addition, spousal distress has en associated with patient distress, such that the ality of life of the sexual partner tends to be neg- ively affected by the side effects experienced by e patient.3 Estrogen can be used as an alternative to LHRH onists to shut down the hypothalamic-pituitary- nadal axis while avoiding some of the negative e effects of LHRH agonists such as hot flashes d osteoporosis.4 We explore other roles that E may ve in males, focusing primarily on sexual interest d function. TROGEN RECEPTORS the 4 estrogen receptors, ER�, ER�, GPR30 and -X, only ER� and ER� are well characterized.5 � and ER� have been found in male reproductive gans, including the erectile tissues, neurovascular ndles, sensory corpuscles, urethra, seminal vesi- s and prostate,6 suggesting that E may have some ect on male reproductive organs. In males neurons that control reproductive be- vior, such as in the medial preoptic area and the d of the stria terminalis, are positive for ERs and ow high aromatase activity.5 This finding sug- sts that testosterone effects on male sexual behav- are partly due to conversion of testosterone to E2. fact, E2 implanted in the medial preoptic area is ore effective than testosterone for inducing mount- g and intromission behavior in castrated male ts, increasing the likelihood that E2 positively fluences male sexual behavior.7 HAVIORAL STUDIES IN ANIMALS pulatory Behavior improves some components of male sexual behav- in castrated hamsters, horses, rabbits, deer, inea pigs, quail and even lizards.8–11 These find- gs suggest that E can promote sexual interest in a de variety of animals and, thus, may help main- in libido in humans as well. Sexual behavior has been studied most exten- ely in rats. In 1937 Ball observed that a high dose E (estrin) injected into castrated adult male rats creased their sexual activity.12 Davidson observed ose dependent increase of sexual activity in short- rm (1 week) castrated male rats treated with E2 t the sexual activities decreased when these rats re reinjected with E2 and retested 5 weeks te olf tio er.12 These findings suggest that castrated male ts exhibit increased sexual interest when given ogenous E and that the timing of E supplementa- n after castration may affect the extent to which xual function is maintained or restored. nile Reflexes e impaired sexual function of patients with PCa ADT can be variably attributed to the loss of ido, lower frequency of sexual activity, inability to hieve firm erections and/or reduced ability to aintain erections. Evidence that E has a role in aintaining ex copula erection (tactile stimulation the penis in restrained animals) arises from a dy using the antiandrogen flutamide, which cks the androgen receptors resulting in increased stosterone being aromatized to E2. When flut- ide was administered to long-term castrate rats, ere was a significant increase in the number of ex pula erections, although to a lesser degree than en testosterone was administered.13 E2 can also aintain erections in copula (ie during copulation) d E2 treated rats have similar intromission fre- ency compared to those treated with testoster- e.13 TROGEN IN THE UROBIOLOGY OF MALES xually Dimorphic Nucleus Preoptic Area and Medial Amygdala e SDN-POA controls sexual behavior in mammals d the homologous region in humans is highly ac- e during putative pheromonal stimulation.14 This gion is thought to develop under E influence dur- g a critical perinatal period. The morphology of N-POA can still change during adult life despite e hypothesis that its development only occurs dur- g a narrow period in perinatal life.15 In a study of tact rats high phytoestrogen diets altered the vol- e of SDN-POA.15 How E may affect the SDN- A in adult androgen deprived men has not been vestigated. The posterodorsal nucleus of the medial amyg- la is a sexually dimorphic structure in the brain at controls sexual arousal. In a study by Cooke et E2 administered to castrated male rats facilitated xual arousal induced by pheromonal cues from ale rats.16 The authors found that E2 increased e volume and soma size in the medial amygdala, th of which decreased after castration. In humans e amygdala is also involved in emotional process- g in response to olfactory stimuli and shows high tivity after ejaculation.17,18 Whether E adminis- red to androgen deprived men promotes arousal by actory stimuli is an area worth further investiga- n. Sp In for tra is ba th te du m nu E2 SN E2 ac a re ST In E2 en low te th no an fre er low en de m on sc th lec ut th se ha po af de ca su su Cl ua af m re pa st til st es tiv on of se fin at wi a qu to ob pr fa a l ist de to ua tro ca in ex no Ra gr wh se all va pe co va te tra Es Th E2 pa m m m te “[M ta ca ESTROGEN IN PATIENTS ON ANDROGEN DEPRIVATION THERAPY 19 inal Nucleus of Bulbocavernosus mammals the bulbocavernosus muscle is crucial maintaining erection and produces rhythmic con- ctions during ejaculation. In rodents this muscle innervated by a group of motoneurons in the lum- r spinal cord called the SNB, which also supplies e levator ani muscle and the external anal sphinc- r.19 Castration of adult male rodents results in re- ced weight of bulbocavernosus and levator ani uscles as well as dendritic atrophy, and smaller clear and soma size in the SNB motoneurons.19 cannot reverse the morphological changes to B motoneurons but despite the muscle atrophy, can maintain the excitability of bulbospongiosus tivity in castrated rats.19 Therefore, E2 may have role in maintaining erections or may be able to store some erectile function in castrated males. UDIES ON HUMAN SEXUAL FUNCTION sights From Androgen Deprived Populations is present in males as a result of the action of the zyme aromatase on testosterone, although at a er level than in females. Since castration lowers stosterone levels, it reduces E2 levels as well. In men with aromatase gene mutation who are us hypoestrogenic, libido and sexual activity are rmal, likely due to the presence of endogenous drogens. However, transdermal E2 increased the quency of sexual intercourse, masturbation and otic fantasies in these men, although at doses er than that used for ADT, suggesting that exog- ous E2 can improve sexual interest in aromatase ficient individuals.20 In addition, hypogonadal en who were treated with aromatizable testoster- e undecanoate had better mood, libido, erection ore and ejaculation score than those treated with e nonaromatizable androgen mesterolone.20 Col- tively these results suggest again that E2 contrib- es to sexual behavior in adult human males. In patients with PCa who receive E treatment ere is typically some proportion who do not lose all xual potency. By pooling data from Ellis and Gray- ck,21 and Choi et al22 we found that 13 of 18 (72%) tent patients who received DES remained potent ter treatment compared to 4 of 10 (40%) who un- rwent orchiectomy. The difference is not signifi- nt (Fisher’s exact test p � 0.1245), which is not rprising given the small sample size, but the data ggest better sexual performance with estrogen. early this research is worth revisiting. In addition, Ellis and Grayhack found more sex- lly active patients after E treatment (4) than ter orchiectomy (2).21 In a similar study Berg- an et al reported that 8 of 10 E treated patients mained sexually active with their partner com- an is te red to 3 of 10 orchiectomy patients.21 In that udy the majority of E treated patients lost erec- e and orgasmic function. However, the authors ated that a “[m]ajority of those treated with trogen . . . continued partner-related sexual ac- ity . . . [whereas this] . . . was the case for only e-third of the men after orchiectomy. Seven [out twelve] men treated with estrogen continued xual activity without reaching orgasm.” These dings confirm that some level of sexual interest greater than castrate levels may be preserved th estrogen treatment. Davidson et al tested the effect of E2 injection in castrated man.23 The subject had similar fre- ency of sexual intercourse while taking either tes- sterone or E2 alone. The highest frequency was served when E2 was given in combination with ogesterone. However, in this single case study E2 iled to increase spontaneous erection frequency to evel comparable to when testosterone was admin- ered. E has been studied in MtF transsexuals who un- rgo surgical castration and, thus, are comparable patients with PCa on ADT. Many MtF transsex- ls remain sexually active after castration and es- gen therapy.24 Indeed, Brett et al found signifi- ntly increased libido at greater than castrate level surveys of voluntarily castrated males receiving ogenous E.25 However, these studies suffer from t being randomized or longitudinal in design. ther they relied on a comparison between 2 oups of androgen deprived males who self-selected ether to receive E. Historically some men who were castrated to rve as court eunuchs and singers remained sexu- y active.26 Throughout history eunuchs have been riably asexual, bisexual, hyposexual and even hy- rsexual. This suggests that there is a cultural mponent in how men respond to androgen depri- tion. This may help explain some of the inconsis- nt results of E treatment on contemporary MtF nssexuals. trogen and Antiandrogens ere is additional although indirect evidence that helps maintain libido in humans from studies of tients using antiandrogens, such as bicaluta- ide.27 Patients with advanced PCa who elect treat- ent with high dose (ie 150 mg/day) bicalutamide onotherapy have significantly greater sexual in- rest than castrated males. According to Penson, ]en who elect this treatment can expect to main- in sexual activity for a longer period than if . . . strated.”27 The understanding is that with the drogen receptors blocked the excess testosterone converted to E2. The side effect profile is consis- nt with increased E2 as well, including higher in th W m m an Pe Th ur eja to m af m we ar pe tio ua E2 on im E2 AD th or Es tie ga for OT IN Ho Am LH Ho di ar in pa fla pa fla wi Fe th po tri Os LH 13 tu sk ba ap te in po m lar eld AD UN ON Ba ve pa fem of tre wh ni on on tiv fin E2 ea wi me NE Th m ha ra be pa to alo Th Sh dr PC ac va th th na ESTROGEN IN PATIENTS ON ANDROGEN DEPRIVATION THERAPY20 cidence of gynecomastia and fewer hot flashes an with orchiectomy or LHRH agonist castration. hen reviewing these data it is important to keep in ind that they compare sexual interest for castrated ales with or without supplemental antiandrogens d not for eugonadal males. lvic Floor Function e pelvic floor muscles are involved in maintaining inary continence, supporting pelvic viscera and culation. The main pelvic floor muscle, the leva- r ani, contracts rhythmically during orgasm in en and women. Changes in the pelvic floor muscles ter ADT have not been widely researched in hu- ans, but in animal studies castration reduces the ight of the pubococcygeous and the cross-sectional ea of its muscle fibers, whereas E helps maintain lvic floor morphological integrity for normal func- n.28 Atrophy in this musculature may impair sex- l function, particularly orgasms in both sexes. To date no study has demonstrated the effect of specifically on the orgasm of patients with PCa ADT. However, considering the fact that E2 can prove sexual function in postmenopausal women, may also restore the sexual function of men on T to some degree. Even if erection is impaired, e quality of life of men on ADT may be improved if gasmic function is fully or partially preserved. trogenic effects on pelvic floor structure in pa- nts with PCa on ADT need to be further investi- ted, considering how crucial those structures are genitourinary functions. HER BENEFITS OF ESTROGEN ANDROGEN DEPRIVED MEN t Flashes ong the top 3 common complaints of patients on RH agonists are hot flashes and night sweats.29 t flashes can be so severe that they lead to sleep sturbance, which may subsequently cause leth- gy and affect cognitive function. Sleep disturbance patients can also interfere with the sleep of their rtners, impacting the quality of life of the couple. E significantly reduces the incidence of hot shes in patients with PCa as it does in meno- usal women who also frequently experience hot shes.29 In fact E2 is prescribed to some patients th PCa on ADT to reduce the severity hot flashes. wer hot flashes may improve sleep quality in ese patients. Indeed, E improves sleep quality in stmenopausal women,30 which may be partly at- butable to reducing the incidence of hot flashes. teoporosis RH agonists reduce bone mineral density 4% to % annually, increasing the risk of bone frac- bo es en res.31 However, ERs are expressed in the male eletal system and are involved in bone mineral lance. Thus, castration induced bone resorption pears to be due to E depletion and not solely to low stosterone. In fact, just as hormonal replacement menopausal women can reduce the risk of osteo- rosis, E2 does the same for androgen deprived ales.32 This osteoprotective effect of E2 is particu- ly important for patients with PCa who are often erly and frail, as bone fractures associated with T negatively impact survival. RESOLVED EFFECT COGNITIVE FUNCTION sed on data from females, E seems to reduce rbal memory impairment associated with meno- use.33 However E is not cognitively protective in ales when given years after the commencement menopause.33 This suggests that the timing of E atment is crucial, with the most benefit shown en E supplementation is initiated at the begin- ng of menopause. The literature on cognitive impairment in patients ADT is inconsistent. A study of patients with PCa ADT showed that E2 can be cognitively protec- e,34 although other studies did not support that ding.35 Collectively we believe that for men on ADT, is more likely to be cognitively protective if given rlier rather than later.36 This is directly in accord th the critical period hypothesis of Sherwin for nopausal and postmenopausal women.33 GATIVE SIDE EFFECTS OF ESTROGEN e data reviewed support the thesis that normal ale health, particularly sexual interest, is en- nced by endogenous E2. Clinical trials are war- nted to determine if patients with PCa, who are ginning ADT, are in fact better off if treated with renteral E2 as a monotherapy or as a supplement a LHRH agonist rather than a LHRH agonist ne. romboembolism ortly after Huggins and Hodges reported that an- ogen suppression could slow the progression of a, the inexpensive oral estrogen DES became the cepted pharmacological agent for treating ad- nced PCa.37 However, DES carried a high risk of romboembolytic events, which eventually led to e development of the LHRH agonists as an alter- tive way of suppressing