ORIGINAL RESEARCH—ENDOCRINOLOGY

Clomiphene Citrate and Testosterone Gel Replacement Therapyfor Male Hypogonadism: Efficacy and Treatment Costjsm_1454 269..276

Frederick Taylor, MD, and Laurence Levine, MD

Rush University Medical Center—Department of Urology, Chicago, IL, USA

DOI: 10.1111/j.1743-6109.2009.01454.x

A B S T R A C T

Introduction. The efficacy of oral clomiphene citrate (CC) in the treatment of male hypogonadism and maleinfertility (MI) with low serum testosterone and normal gonadotropin levels has been reported.Aim. The aim of this article is to evaluate CC and testosterone gel replacement therapy (TGRT) with regard tobiochemical and clinical efficacy and cost.Main Outcome Measures. The main outcome measures were change in serum testosterone with CC and TGRTtherapy, and change in the androgen deficiency in aging male (ADAM) questionnaire scores with CC therapy.Methods. Men receiving CC or TGRT with either Androgel® 1% or Testim® 1% for hypogonadism (defined astestosterone < 300 ng/mL) or MI were included. Serum values were collected 1–2 months after treatment initiationand semi-annually thereafter. Retrospective data collection was performed via chart review. Subjective follow up ofpatients receiving CC was performed via telephone interview using the ADAM questionnaire.Results. A hundred and four men (65 CC and 39 TGRT) were identified who began CC (50 mg every other day)or TGRT (5 g). Average age (years) was 42(CC) vs. 57 (TGRT). Average follow up was 23 months (CC, range 8–40months) vs. 46 months (TGRT, range 6–149 months). Average posttreatment testosterone was 573 ng/dL in the CCgroup and 553 ng/dL in the TGRT group (P value < 0.001). The monthly cost of Testim® 1% (5 gm daily) is $270,Androgel® 1% (5 gm daily) is $265, and CC (50 mg every other day) is $83. Among CC patients, the averagepretreatment ADAM score was 4.9 vs. 2.1 at follow up (P < 0.05). Average pretreatment ADAM sexual functiondomain score was 0.76 vs. 0.23 at follow up (P < 0.05). There were no adverse events reported.Conclusion. CC represents a treatment option for men with hypogonadism, demonstrating biochemical and clinicalefficacy with few side effects and lower cost as compared with TGRT. Taylor F, and Levine L. Clomiphene citrateand testosterone gel replacement therapy for male hypogonadism: Efficacy and treatment cost. J Sex Med2010;7:269–276.

Key Words. Hypogonadism; Selective Estrogen Receptor Modulator; Testosterone; Testosterone DeficiencySyndrome; Male

Introduction

M ale hypogonadism results from a decline inserum testosterone levels and is associated

with a constellation of symptoms includingdecrease in libido, lack of energy, easy fatigability,decrease in strength, loss of vertical height,decrease in enjoyment of life, diminished mood,and decreased potency [1]. The decrease in serumtestosterone (T) may be due to primary testicular

failure or dysfunction of the hypothalamic–pituitary axis. Hypogonadotropic hypogonadismmay result from abuse of anabolic steroids, or maybe congenital in the form of Kallman syndrome.When secondary to anabolic steroid abuse,hypogonadotropic hypogonadism may be treatedby discontinuation of the steroid. In the case ofKallman syndrome, administration of exogenousT will effectively treat the symptoms of hypogo-nadism and cause virilization of adolescents. As

269

© 2009 International Society for Sexual Medicine J Sex Med 2010;7:269–276

exogenously administered T has been shown toinhibit spermatogenesis, gonadotropin therapymay be considered in those men who desirefertility.

The primary goal of therapy for men withhypogonadism is the elevation of serum T intothe normal range in order to effect symptomaticimprovement. The primary treatment offeredmost men with symptomatic hypogonadism con-tinues to be T replacement via one of the manydelivery methods, including transdermal, buccal,oral, and short- and long-acting intramuscularinjection. Although exogenous T delivery is effi-cacious in the elevation of serum T and theimprovement of symptoms, exogenous T deliveryresults in negative feedback of the hypothalamo–pituitary axis, which down-regulates the produc-tion of serum luteinizing hormone (LH) andfollicle stimulating hormone (FSH), resultingin decreased endogenous T production anddecreased spermatogenesis.

More recently, interest has grown in the use ofclomiphene citrate (CC) for the treatment of malehypogonadism and male infertility [2–4]. CC is aselective estrogen receptor modulator (SERM)that blocks the feedback inhibition of estradiol atthe level of the hypothalamus, thus increasingpituitary release of both LH and FSH [5]. LH andFSH then act on the testis via Leydig and Sertolicells, respectively, to increase serum T levels andspermatogenesis.

Several publications have demonstrated theefficacy of CC in treatment of both male hypogo-nadism and male infertility [2–4]. However, to ourknowledge, a comparative analysis of CC and tes-tosterone gel replacement therapy (TGRT) withregard to efficacy and cost has not been performed.In addition, although the biochemical response ofpatients with male hypogonadism to CC has beenreported, there is very little data regarding thesubjective outcomes of men treated with CC forhypogonadism.

The aim of our study was to evaluate the bio-chemical efficacy (i.e., appropriate elevation ofserum T levels) and cost of CC and TGRT in menwith hypogonadism and male infertility, and toreport on the subjective outcomes of our patientstaking CC for hypogonadism.

Patients and Methods

Men receiving either CC or TGRT with eitherAndrogel 1% (Solvay Pharmaceuticals, Marietta,GA, USA) or Tesim 1% (Auxilium Pharmaceuti-

cals, Malvern, PA, USA) Gel for hypogonadism(defined as serum total T < 300 ng/mL) or maleinfertility (MI) with low normal or below normalT and low or normal LH were included for thisretrospective analysis of our clinical data. Thedecision to treat with either TGRT or CC was leftto the discretion of the treating physician andpatient choice after discussing treatment options.Men with above normal LH levels, indicatingprimary testicular failure, were not offered CCtreatment. Patients with symptoms suspicious forhypogonadism underwent an am peripheral blooddraw at approximately 8 o’clock for serum T. Menwhose initial T was in the lowest 1/3 of our refer-ence range (<330 ng/dL) underwent a second 8amperipheral blood draw. The results of the second,confirmatory blood draw are used in this analysis.All patients had normal pretreatment serum pro-lactin levels.

Serum T, prostate-specific antigen (PSA), lipidprofile, hemoglobin, hematocrit, prolactin, LH,and FSH values were collected prior to treatmentinitiation. T, PSA, and hemoglobin levels wereobtained prospectively at 1–2 months after treat-ment initiation and semi-annually thereafter. Alipid profile, LH, and FSH levels were collectedat least 6 months after treatment initiation. Datawere collected in a prospective fashion to guideclinical patient management. Retrospective analy-sis of this clinical data was performed via chartreview; and subjective follow up was performedvia office and telephone interview using the vali-dated androgen deficiency in aging male (ADAM)questionnaire [6]. In this study, biochemical effi-cacy is defined as an elevation of serum T to themid-normal range (approximately 550 ng/dL;normal range 241 ng/dL–827 ng/dL, Immunoas-say, Quest Diagnostics, Wood Dale, IL, USA).Student t-test was used to determine statisticalsignificance. Statistical analysis was performedusing Microsoft Excel® with P values < 0.05 con-sidered statistically significant.

A hundred and four men taking either CC orTGRT with complete follow-up data were identi-fied. Of these, 65 were taking CC, with dosageinitiation at 50 mg orally every other day. Thedosage was titrated either down to 25 mg orallyevery other day or up to 100 mg every other day toeffect an elevation of serum T to the mid-normalrange. Thirty-nine men were taking TGRT at aninitial dose of 5 g 1% Androgel® or 5 g 1%Testim®; doses were similarly titrated to achieveT elevation. A hundred percent of TGRT patientsbegan therapy for hypogonadism; 65% of CC

270 Taylor and Levine

J Sex Med 2010;7:269–276

patients began therapy for hypogonadism. Thirty-five percent of CC patients began therapy formale infertility with the associated symptoms ofhypogonadism.

Results

An overview of the pretreatment values is presentedin Table 1. Pretreatment differences in age, T, LH,

and FSH were statistically significant. The differ-ences in LH and FSH reflect a larger number ofmen with primary hypogonadism in the TGRT-treated group as compared with the CC group;there were no men with primary hypogonadism inthe CC group. The average age at treatment initia-tion was 42 years (CC) vs. 57 years (TGRT).Average pretreatment serum T was 277 ng/dL(CC) vs. 221 ng/dL (TGRT). Average follow upamong the CC patients was 23 months (range 8–40months). Average follow up among the TGRTpatients was 46 months (range 6–149 months).

Average posttreatment T was 573 ng/dL in theCC group and 553 ng/dL in the TGRT group,reflecting an average increase in T of 296 ng/mLand 332 ng/mL, respectively. As demonstrated inFigures 1 and 2, the increase in serum T was sta-tistically significant for both treatment modalities.The Rush University Medical Center pharmacyprovided the extrapolated cost of a 30-day supplyof the study drugs. The monthly cost of each

Table 1 Pretreatment parameters

Parameter CC TGRTPvalue

Age (years) 42 (19–70) 57 (30–78) <0.05Serum T (ng/dL) 277 (16–381) 221 (27–363) <0.05Serum LH (IU/L) 3.57 (0.02–11.6) 7.52 (1.8–37.5) <0.05Serum FSH (IU/L) 3.25 (0.7–7.8) 7.53 (0.8–28.7) <0.05Hemoglobin (gm/dL) 15.0 (12.6–16.7) 14.9 (13.4–16.1) 0.48Cholesterol (mg/dL) 171 (91–248) 199 (150–287) 0.46PSA (ng/mL) 0.78 (0.3–1.5) 0.95 (0.1–2.8) 0.13

CC = clomiphene citrate; TGRT = testosterone gel replacement therapy;PSA = prostate-specific antigen; T = testosterone; LH = luteinizing hormone;FSH = follicle stimulating hormone.

Figure 1 Change in testosterone withclomiphene citrate.

Figure 2 Change in testosterone withandrogen replacement.

Figure 3 One-month treatment cost.

Efficacy and Treatment Cost 271

J Sex Med 2010;7:269–276

medication is $270 (Testim® 1% 5 gm daily), $265(Androgel® 1% 5 gm daily), and $83 (CC 50 mgorally every other day), with no pharmacy programdiscount (Figure 3).

Patients being treated with CC for hypogo-nadism (N = 42) were contacted via telephonefollow up to determine their subjective outcomeswith 22 patients responding. Pretreatment andposttreatment ADAM questionnaire answersare presented in Table 2. Among hypogonadalpatients treated with CC, the average pretreat-ment ADAM score was 4.9 vs. 2.1 at the time offollow up (P < 0.05; Figure 4), and the averageimprovement in ADAM score was 2.8 points(range 0–6). Ninety-one percent of patientsresponded to the ADAM questionnaire with animproved score over pretreatment. Average pre-treatment ADAM “sexual function” score (createdby combining the scores from questions 1 and 7,regarding a loss of libido and loss of erection hard-ness, respectively) was 0.76 vs. 0.23 at the time offollow up (P < 0.05; Figure 5).

With regard to side effect profile, there was onepatient in the Testim® group who discontinuedthe medication secondary to local skin irritation.There were no other patients who discontinuedtherapy due to side effects, and there were noreported adverse events with CC therapy. Therewere no significant changes in serum hematocrit,PSA, or lipid profile for either therapy (Table 3).

Discussion

The past decade has seen significant advancementsin the study and understanding of male hypogo-nadism and the natural hormonal changes of theaging male [7–9]. As the understanding of the bio-logic effects of aging have advanced, so too has anunderstanding of the symptomatic effects thatbring many men to seek treatment. Despite theseimportant advances, controversy persists regard-ing the biochemical definition of hypogonadism. Itis well understood that neither a low serum T, northe presence of symptoms consistent with hypogo-nadism alone makes the clinical diagnosis. Rather,it is the combination of symptoms and a low orborderline low T that defines the clinical condi-tion [10]. Our current understanding of malehypogonadism precludes the definition of a serumT “cut-off”, above which no man can be consid-ered hypogonadal and below which all men arehypogonadal. Without a well-defined biochemicalT value required to diagnose hypogonadism, cli-nicians are left to weigh each patient individually Ta

ble

2A

DA

Mqu

estio

nnai

rere

sults

pre-

and

post

-tre

atm

ent

with

clom

iphe

neci

trat

e

AD

AM

ques

tion

Tota

lAD

AM

scor

e

Do

you

have

ade

crea

sein

libid

o(s

exdr

ive)

?

Do

you

have

ala

ckof

ener

gy?

Do

you

have

ade

crea

sein

stre

ngth

and/

oren

dura

nce

Hav

eyo

ulo

sthe

ight

?

Hav

eyo

uno

ticed

ade

crea

sed

enjo

ymen

tof

life?

Are

you

sad

and/

orgr

umpy

?

Are

your

erec

tions

less

stro

ng?

Hav

eyo

uno

ticed

are

cent

dete

riora

tion

inyo

urab

ility

topl

aysp

orts

?

Are

you

falli

ngas

leep

afte

rdi

nner

?

Has

ther

ebe

enre

cent

dete

riora

tion

inyo

urw

ork

perf

orm

ance

?

Pre

trea

tmen

t4.

90.

730.

820.

750.

140.

540.

410.

770.

230.

550.

14P

osttr

eatm

ent

2.2

0.18

0.23

0.45

0.04

0.18

0.14

0.27

0.04

0.41

0.04

Pva

lue

1.24

E-0

82.

85E

-05

<0.0

50.

160.

16<0

.05

0.00

58.

07E

-05

<0.0

50.

040.

08

AD

AM

=an

drog

ende

ficie

ncy

inag

ing

mal

e.

272 Taylor and Levine

J Sex Med 2010;7:269–276

with respect to his bothersome symptoms andserum T level. The American Society for Repro-ductive Medicine [11] suggests that total T levelsbelow 200 ng/dL identify hypogonadism that war-rants treatment, and that men with serum T levelsbetween 200 ng/dL and 400 ng/dL may benefitfrom therapy. In addition, it has been advocatedthat in the face of symptoms of hypogonadism, butwithout clear biochemical evidence of low T,patients may benefit from a therapeutic trial of Tsupplementation [12]. The primary therapy for

men with hypogonadism, regardless of age, hashistorically been via the administration of exog-enous T. Although effective, exogenous T admin-istration does not mimic normal circadianhormone release. In addition, although newer gen-erations of T delivery products and methods havebegun to address the issue of supraphysiologicdosing, several hurdles remain. Currently, there isno oral form of T therapy commercially availablein the United States. Injectable formulations resultin superphysiologic T levels, followed by a longand gradual decrease in serum concentration, withthe inconvenience of a needle stick. T gels aregenerally well tolerated, albeit with the occasionalskin irritation, and can be titrated to serum Tlevels. However, they carry a risk of contaminationexposure to others, including children and preg-nant women. In addition, all exogenously admin-istered T carries the inherent effect of inhibitionof the hypothalamic–pituitary axis with a decreasein endogenous T formation and, more importantlyfor hypogonadal men interested in fertility, adecrease in spermatogenesis.

Currently, CC is approved by the United StatesFood and Drug Administration (FDA) for thetreatment of ovulatory dysfunction in womendesiring pregnancy. CC has not been submitted tothe FDA for study for use in the treatment ofinfertility or hypogonadism in men, and is conse-quently not FDA-approved for these uses. In spiteof this, CC has been used in clinical practice formany years for the treatment of these conditions.Recent reports have demonstrated the efficacy ofCC in treatment of male infertility [3,13], and theliterature clearly supports the biochemical efficacyof CC in treatment of hypogonadism [2,14,15]. Asa SERM, CC works to up-regulate endogenoushypothalamic function, resulting in increasedserum LH and FSH levels, which in turn increaseendogenous T production and spermatogenesis.The goal of CC treatment is to induce endogenousT production and spermatogenesis by presumedhealthy testes, which are functioning but under-producing T. Our data certainly support thebiochemical efficacy of CC in the treatment ofhypogonadism, with an average increase in serumT of 210% from baseline.

Although recent literature demonstrates the bio-chemical efficacy of CC for the treatment of malehypogonadism, the issue of subjective outcomes isless clear. Guay et al. [16] demonstrated the bio-chemical efficacy of clomiphene citrate in men withsecondary hypogonadism, but found no improve-ment in symptoms on the follow-up questionnaire.

Figure 4 Clomiphene citrate patient pre- and posttreatmentandrogen deficiency in aging male scores.

Figure 5 Clomiphene citrate patient pre- and posttreatmentandrogen deficiency in aging male scores.

Table 3 Post-treatment parameters

CC patients

Pretreatment Posttreatment P valueHemoglobin (gm/dL) 15 14.5 0.42PSA (ng/mL) 0.78 0.98 0.14Total cholesterol (mg/dL) 171 203 0.4

TGRT patients

Pretreatment Posttreatment P valueHemoglobin (gm/dL) 14.9 15.2 0.38PSA (ng/mL) 0.95 1.14 0.25Total cholesterol

(mg/dL)199 182 0.19

CC = clomiphene citrate; TGRT = testosterone gel replacement therapy;PSA = prostate-specific antigen.

Efficacy and Treatment Cost 273

J Sex Med 2010;7:269–276

Subsequent publications, however, have suggestedthat CC may be effective in treating the sexual sideeffects of hypogonadism [15,17]. ADAM question-naires were administered to the majority of ourhypogonadal patients at their initial visit. Afollow-up telephone ADAM questionnaire wasthen administered by a single investigator to gaugethe symptom response. Overall, we demonstrate asymptomatic improvement in the hypogonadalpatients treated with CC, and no patients reporteda worse ADAM score. In addition, in order to assessthe sexual response of the patients to therapy, ques-tions 1 and 7 of the ADAM questionnaire wereconsidered and scored separately. In doing so, wefound that the patient’s sexual function was statis-tically significantly improved with therapy.

Recent basic science research has begun toexpand an understanding of the role of estrogenreceptors in prostate cancer [18–21]. As a SERM,there is understandably some interest in the effectthat CC may have on peripheral estrogen recep-tor activation, and, consequently, downstreamestrogen-related effects. Literature does exist tosuggest a link between estrogen receptor activation(particularly estrogen receptor a) and the develop-ment of prostate cancer [18,22–24]. In addition,Bang-Ping et al. [25] demonstrated that, in vitro,CC administration to the PC3 prostate cancer cellline resulted in increased intracellular calcium con-centration. Regulated calcium concentrations areessential for normal cell survival, whereas increasedintracellular calcium concentrations can cause celldeath. Thus, the possibility exists that CC may betumoricidal to prostate cancer cells. In addition andperhaps most tellingly, there were no changes inpre- and posttreatment PSA values in our patientcohort who were taking CC with up to 40 monthsof continuous treatment.

Male hypogonadism has been suggested as acause of osteopenia and osteoporosis, particularlyin older men [26–28]. T appears to be protectiveagainst the development of osteopenia andosteoporosis; however, the mechanism of protec-tion is not well established and is likely due toperipheral aromatization of T to estradiol [27,29].Estrogen prevents bone loss and thus is a main-stay to prevent postmenopausal osteopenia andosteoporosis [30,31]. SERMs have been shown tohave agonist effects on bone estrogen receptors,and have shown efficacy in the treatment ofosteopenia and osteoporosis in postmenopausalwomen [30,32]. In addition, CC has been shown tohave estrogen agonist effects on bone and toprevent osteoporosis in a rat model [33–35].

Although further studies need to be done, it ispossible that CC may protect against the develop-ment of osteopenia and osteoporosis in men withhypogonadism due to its estrogen agonist effect onbone receptors.

Conclusion

CC represents a viable treatment option for menwith hypogonadism demonstrating biochemicaland clinical efficacy with no side effects and lowercost as compared with TGRT. More study via pro-spective, large-scale, multicenter trials assessinghypogonadal symptom response to CC wouldprovide additional support for its use in thehypogonadal male without an elevated serum LH.

Corresponding Author: Frederick Taylor, MD,Urology, Rush University Medical Center, 1725 W.Congress Parkway, Suite 348, Chicago, IL 60612,USA. Tel: +312-942-6447; Fax: +312-942-4005; E-mail:frederick_taylor@rush.edu

Conflict of Interest: None.

Statement of Authorship

Category 1(a) Conception and Design

Frederick Taylor; Laurence Levine(b) Acquisition of Data

Frederick Taylor; Laurence Levine(c) Analysis an Interpretation of Data

Frederick Taylor; Laurence Levine

Category 2(a) Drafting the Manuscript

Frederick Taylor; Laurence Levine(b) Revising It for Intellectual Content

Frederick Taylor; Laurence Levine

Category 3(a) Final Approval of the Completed Manuscript

Frederick Taylor; Laurence Levine

References

1 Morales A, Heaton JP, Carson CC. Andropause: Amisnomer for a true clinical entity. J Urol2000;163:705–12.

2 Shabsigh A, Kang Y, Shabsign R, Gonzalez M,Liberson G, Fisch H, Goluboff E. Clomiphenecitrate effects on testosterone/estrogen ratio in malehypogonadism. J Sex Med 2005;2:716–21.

274 Taylor and Levine

J Sex Med 2010;7:269–276

3 Hussein A, Ozgok Y, Ross L, Niederberger C. Clo-miphene administration for cases of nonobstructiveazoospermia: A multicenter study. J Androl 2005;26:787–91.

4 Whitten SJ, Nangia AK, Kolettis PN. Selectpatients with hypogonadotropic hypogonadism mayrespond to treatment with clomiphene citrate. FertilSteril 2006;86:1664–8.

5 Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr.A pharmacological review of selective oestrogenreceptor modulators. Hum Reprod Update 2000;6:212–24.

6 Morley JE, Charlton E, Patrick P, Kaiser FE,Cadeau P, McCready D, Perry HM 3rd. Validationof a screening questionnaire for androgen deficiencyin aging males. Metabolism 2000;49:1239–42.

7 Mitchell R, Hollis S, Rothwell C, Robertson WR.Age related changes in the pituitary-testicular axis innormal men; lower serum testosterone results fromdecreased bioactive LH drive. Clin Endocrinol(Oxf) 1995;42:501–7.

8 Vermeulen A, Kaufman JM. Ageing of thehypothalamo-pituitary-testicular axis in men. HormRes 1995;43:25–8.

9 Mulligan T, Frick MF, Zuraw QC, Stemhagen A,McWhirter C. Prevalence of hypogonadism inmales aged at least 45 years: The HIM study. Int JClin Pract 2006;60:762–9.

10 Morales A, Morley JE, Heaton JP. Androgen defi-ciency in the aging male. In: Wein A, Kavoussi L,Peters C, Partin A, Novick A, ed. Campbell-WalshUrology, 9th ed., Saunders: Philadelphia; 2007:850–62.

11 Practice Committee of American Society for Repro-ductive Medicine and Society for Male Reproduc-tion and, Urology. Androgen deficiency in the agingmale. Fertil Steril 2008;90:S83–7.

12 Black AM, Day AG, Morales A. The reliability ofclinical and biochemical assessment in symptomaticlate-onset hypogonadism: Can a case be made for a3-month therapeutic trial? BJU Int 2004;94:1066–70.

13 Sigman M, Jarow JP. Male infertility. In: Wein A,Kavoussi L, Peters C, Partin A, Novick A, ed.Campbell-Walsh Urology, 9th ed., Saunders: Phila-delphia; 2007:609–53.

14 Tan RS, Vasudevan D. Use of clomiphene citrate toreverse premature andropause secondary to steroidabuse. Fertil Steril 2003;79:203–5.

15 Guay AT, Jacobson J, Perez JB, Hodge MB,Velasquez E. Clomiphene increases free testosteronelevels in men with both secondary hypogonadism anderectile dysfunction: Who does and does not benefit?Int J Impot Res 2003;15:156–65.

16 Guay AT, Bansal S, Heatley GJ. Effect of raisingendogenous testosterone levels in impotent menwith secondary hypogonadism: Double blindplacebo-controlled trial with clomiphene citrate.J Clin Endocrinol Metab 1995;80:3546–52.

17 Ioannidou-Kadis S, Wright PJ, Neely RD, QuintonR. Complete reversal of adult-onset isolatedhypogonadotropic hypogonadism with clomiphenecitrate. Fertil Steril 2006;86:1513.e5–9.

18 Ellem SJ, Risbridger GP. Treating prostate cancer:A rationale for targeting local oestrogens. Nat RevCancer 2007;7:621–7.

19 Ellem SJ, Schmitt JF, Pedersen JS, Frydenberg M,Risbridger GP. Local aromatase expression inhuman prostate is altered in malignancy. J ClinEndocrinol Metab 2004;89:2434–41.

20 Cussenot O, Azzouzi AR, Nicolaiew N, Fromont G,Mangin P, Cormier L, Fournier G, Valeri A, LarreS, Thibault F, Giordanella JP, Pouchard M, ZhengY, Hamdy FC. Cox A and Cancel-Tassin G, Com-bination of polymorphisms from genes related toestrogen metabolism and risk of prostate cancers:The hidden face of estrogens. J Clin Oncol 2007;25:3596–602.

21 Cancel-Tassin G, Latil A, Rousseau F, Mangin P,Bottius E, Escary JL, Berthon P, Cussenot O. Asso-ciation study of polymorphisms in the human estro-gen receptor alpha gene and prostate cancer risk.Eur Urol 2003;44:487–90.

22 Leav I, Lau KM, Adams JY, McNeal JE, Taplin ME,Wang J, Singh H, Ho SM. Comparative studies ofthe estrogen receptors beta and alpha and the andro-gen receptor in normal human prostate glands, dys-plasia, and in primary and metastatic carcinoma. AmJ Pathol 2001;159:79–92.

23 Fromont G, Yacoub M, Valeri A, Mangin P, Vallan-cien G, Cancel-Tassin G, Cussenot O. Differentialexpression of genes related to androgen and estro-gen metabolism in hereditary versus sporadic pros-tate cancer. Cancer Epidemiol Biomarkers Prev2008;17:1505–9.

24 Price D, Stein B, Sieber P, Tutrone R, Bailen J,Goluboff E, Burzon D, Bostwick D, Steiner M.Toremifene for the prevention of prostate cancerin men with high grade prostatic intraepithelialneoplasia: Results of a double-blind, placebo con-trolled, phase IIB clinical trial. J Urol 2006;176:965–70.

25 Jiann B, Lu Y, Chang H, Huang J, Jan C. Effect ofclomiphene on Ca2+ movement in human prostatecancer cells. Life Sci 2002;70:3167–78.

26 Tuck SP, Datta HK. Osteoporosis in the aging male:Treatment options. Clin Interv Aging 2007;2:521–36.

27 Tuck SP, Francis RM. Testosterone, bone andosteoporosis. Front Horm Res 2009;37:123–32.

28 Bain J, Brock G, Kuzmarov I. International consult-ing group, Canadian society for the study of theaging male: Response to health Canada’s positionpaper on testosterone treatment. J Sex Med 2007;4:558–66.

29 Francis RM. The effects of testosterone onosteoporosis in men. Clin Endocrinol (Oxf)1999;50:411–4.

Efficacy and Treatment Cost 275

J Sex Med 2010;7:269–276

30 Riggs BL, Melton LJ 3rd. The prevention and treat-ment of osteoporosis [see comment] [erratumappears in N Engl J Med 1993;328:65; author reply66; PMID: 8416278]; N Engl J Med 1992;327:620–7.

31 Rossouw JE, Anderson GL, Prentice RL, LaCroixAZ, Kooperberg C, Stefanick ML, Jackson RD,Beresford SA, Howard BV, Johnson KC, KotchenJM, Ockene J, Writing Group for the Women’sHealth Initiative Investigators. Risks and benefits ofestrogen plus progestin in healthy postmenopausalwomen: Principal results From the Women’s HealthInitiative randomized controlled trial. JAMA 2002;288:321–33.

32 Delmas PD, Bjarnason NH, Mitlak BH, RavouxAC, Shah AS, Huster WJ, Draper M, ChristiansenC. Effects of raloxifene on bone mineral density,

serum cholesterol concentrations, and uterineendometrium in postmenopausal women. N Engl JMed 1997;337:1641–7.

33 Chakraborty PK, Brown JL, Ruff CB, Nelson MF,Mitchell AS. Effects of long-term treatment withestradiol or clomiphene citrate on bone mainte-nance, and pituitary and uterine weights in ovariec-tomized rats. J Steroid Biochem Mol Biol 1991;40:725–9.

34 Uyar Y, Koltan SO, Pogun S, Vatansever S, CaglarH. The effect of clomiphene citrate on osteoporosisin ovariectomized rats. Arch Gynecol Obstet2008;278:107–14.

35 Young RL, Goldzieher JW, Chakraborty PK,Panko WB, Bridges CN. Qualitative differences inestrogenic/antiestrogenic effects of clomiphene andzuclomiphene. Int J Fertil 1991;36:291–5.

276 Taylor and Levine

J Sex Med 2010;7:269–276