Author's Accepted Manuscript

A Comparison of Secondary Polycythemia in Hypogonadal Men Treated with

Clomiphene Citrate versus Testosterone Replacement: A Multi-institutional Study

Karen M. Wheeler , Ryan P. Smith , Raj A. Kumar , Shaan Setia , Raymond A.

Costabile , Parviz K. Kavoussi

PII: S0022-5347(16)31612-3
DOI: 10.1016/j.juro.2016.10.068
Reference: JURO 14118

To appear in: The Journal of Urology

Please cite this article as: Wheeler KM, Smith RP, Kumar RA, Setia S, Costabile RA, Kavoussi PK, A
Comparison of Secondary Polycythemia in Hypogonadal Men Treated with Clomiphene Citrate versus
Testosterone Replacement: A Multi-institutional Study, The Journal of Urology® (2016), doi: 10.1016/
j.juro.2016.10.068.

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 ACCEPTED MANUSCRIPT

Running Title: Polycythemia in clomiphene vs testosterone

Title: A Comparison of Secondary Polycythemia in Hypogonadal Men Treated with Clomiphene

Citrate versus Testosterone Replacement: A Multi-institutional Study.

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Authors: Karen M. Wheeler1; Ryan P. Smith1; Raj A. Kumar 2; Shaan Setia1; Raymond A. Costabile1; Parviz
K. Kavoussi3

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1. University of Virginia, Department of Urology
2. University of Central Florida, Burnett School for Biomedical Sciences

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3. Austin Fertility and Reproductive Medicine, Department of Reproductive Urology

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Communicating Author:
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Karen Wheeler

kmw8g@virginia.edu
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University of Virginia
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PO Box 800422

Charlottesville VA 22908
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Abstract

Purpose To evaluate the relative prevalence of secondary polycythemia in hypogonadal men

treated with either clomiphene citrate (CC) or testosterone replacement therapy (TRT).

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Materials and Methods: In this retrospective, multi-institutional study, we included 188 CC-

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and 175 TRT-treated men with symptomatic hypogonadism. Overall prevalence and odds ratios

of secondary polycythemia in CC versus TRT treatment were primarily measured as were

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baseline characteristics. Subset analysis included polycythemia rates amongst different types

of TRT.

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Results and Conclusions: Overall, TRT treated men were older than CC treated men (51.5 vs 38

years of age respectively). TRT treated men had longer treatment durations than CC treated
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men, 19.6 months vs 9.2 months respectively. The mean changes in hematocrit were 3.0 % and
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0.6%, and the mean changes in serum testosterone (T) were 333.1 ng/dL and 367.6 ng/dL in
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TRT-treated and CC-treated men, respectively. The prevalence of polycythemia in men on TRT

was 11.2% versus 1.7% in men treated CC (p=0.0003). This significance remained after
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correction for age, site, smoking history, and pre-treatment hematocrit via logistic regression.

The prevalence of polycythemia in men treated with CC is markedly lower than that of TRT
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treated men. The improvement in absolute serum T levels was similar to TRT treated men.
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There is not a significant risk of polycythemia in men treated with CC for hypogonadism.

Keywords: Hypogonadism, Clomiphine Citrate, Testosterone replacement, Polycythemia

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Introduction:

The incidence of hypogonadism ranges widely between 2.1 and 12.8% 1 with an

estimated 0.8-1.6% yearly decline in total testosterone in middle-aged men and the rates of

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testosterone use have considerably risen 2. Presenting symptoms of hypogonadism commonly

include decreased energy, decreased libido, depressed mood, decreased muscle mass, and

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increased body fat 3. The most common treatment for men with hypogonadism is testosterone

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replacement therapy (TRT). Exogenous TRT may result in side effects such as gynecomastia and

mastodynia, acne, polycythemia, and testicular atrophy 3-5. Exogenous TRT has an inhibitory

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effect on the hypothalamic-pituitary-gonadal (HPG) axis, thereby decreasing production of
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luteinizing hormone (LH) and follicle stimulating hormone (FSH), both of which play significant

roles in local testicular steroidogenesis and spermatogenesis, respectively. Treatment of men

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with hypogonadism with TRT typically impairs spermatogenesis, may adversely impact
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subsequent fertility, and may induce testicular atrophy. TRT is not recommended in
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hypogonadal men who wish to maintain fertility potential, or are actively attempting to achieve

pregnancy.
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Clomiphene Citrate (CC) is a selective estrogen receptor modulator which blocks the
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effects of estrogens in the hypothalamus resulting in increased production of LH and FSH by the
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anterior pituitary gland with subsequent increased serum and intratesticular testosterone

production. CC was initially developed and FDA approved to treat female infertility, but has

been used off-label for many years to treat hypogonadism in infertile men.
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A common side effect of exogenous TRT is an elevation in red blood cells, or secondary

polycythemia. Thrombotic risks of testosterone therapy have come under increased scrutiny

since the release of a new label warning by the FDA in 2014 6. The literature reports a relative

risk of polycythemia in TRT treated patients as high as 3.5 fold with TRT 7,8, although sub-group

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analyses suggest a lower risk with transdermal routes of administration, and higher risk with

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intramuscular injection 9 . In general, unmanaged polycythemia has the potential to lead to

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jaundice, pruritus, cerebrovascular accidents, thrombosis, or bleeding. Management of

secondary polycythemia involves phlebotomy and discontinuation of TRT, and may ultimately

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require decreasing TRT dosing after polycythemia has resolved, or considering other modalities
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of treatment if the patient is on intramuscular injections, which has the highest rates of

polycythemia among TRT modalities. Patients on TRT should have hemoglobin and hematocrit
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levels monitored regularly 10. CC increases serum testosterone levels, however, there is no data
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regarding the potential for secondary polycythemia on CC, and whether hemoglobin and
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hematocrit levels should be monitored in these men, which is not the current standard practice

pattern 11.
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Methods and Materials:

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Study Population and Study Design. We performed a retrospective cohort analysis of men who
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received TRT or CC. Prior to our study, we performed a power calculation assuming an

incidence of polycythemia of 5% to 10% for TRT-treated individuals and a difference of 3%,

resulting in a need for approximately 220 patients per arm at 80% power. After IRB approval,

retrospective analysis of symptomatic patients who were evaluated and found to be

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hypogonadal defined by a total testosterone level less than 300 ng/dl, by Urologists at the

University of Virginia and Austin Fertility & Reproductive Medicine, between 1/1/2004 –

12/31/2014 with diagnoses of hypogonadism or male infertility (ICD-9 codes 257.2 or V72.84),

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resulted in 175 men treated with CC and 188 treated with exogenous TRT. Hypogonadal,

symptomatic patients were treated with CC if they desired to maintain fertility potential or if

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they did not like the idea of decreasing the function of the HPG axis regardless of desire of

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fertility preservation after counseling on the mechanisms of TRT vs CC. The standard CC dosing

was 25 mg daily, which was titrated up to 50 mg daily if the testosterone level did not reach

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eugonadal levels (>300 ng/dl) after one month of treatment. TRT modalities included
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intramuscular injections, transdermal gel, and subcutaneous pellet insertions. Testosterone

levels and hemoglobin and hematocrit were obtained one month after initiating treatment,
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regardless of modality of treatment, and checked at 6 month intervals following the first post-
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treatment lab test for the duration of treatment (follow up intervals between 1 and 11 years).
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Gonadotropins were checked in all patients prior to treatment and had to be in normal lab

reference ranges to be deemed as candidates for CC. Patients who were undergoing periodic
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phlebotomy were excluded.

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Outcomes and Statistics. The primary outcome analyzed was prevalence and odds ratio of
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secondary polycythemia (defined as a hematocrit >52%) in patients treated with CC versus TRT.

Although specific guidelines use a hematocrit of 54 as the definition of polycythemia, we

selected a more conservative hematocrit to help guide the need for hematocrit screening prior

to being in a higher risk category. Secondary outcomes included absolute changes in mean

serum testosterone levels (ng/dL). Descriptive statistics are reported as means with standard
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deviations (SD) and quartiles (Q1-Q3) are added as indicated. As the route of testosterone

administration, age, duration of treatment and smoking status have all been associated with

increased incidence rates of secondary polycythemia 12-14, logistic regression was used to adjust

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for these baseline characteristics as well as the location of the patient (Austin is 780 feet above

sea level, Charlottesville is 594 feet above sea level). Comparisons between each treatment

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arm were analyzed using t-tests and Chi-squared tests as appropriate. SAS 9.4 software was

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used for analysis.

Results:

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CC treated men were significantly younger, had a slightly lower BMI, and were on

treatment for a shorter amount of time compared to TRT treated men (Table 1.). The
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percentage of patients that were active smokers and the ratio of men treated at each site were

comparable.
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The pre-treatment hemoglobin and hematocrit levels were clinically similar between

both arms. Although the small difference did reach statistical significance, this was presumably
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due to sample size. There was no statistically significant difference in the post-treatment

hemoglobin and hematocrit levels between the two treatment groups. There were no adverse
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sequelae in men who developed polycythemia. Pre-treatment and post-treatment serum

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testosterone levels were significantly higher in the CC arm as compared to the TRT group (p-

value 0.031; 0.025 respectively; Table 2.). Despite the slightly higher pre-treatment

testosterone, the change in testosterone was greater in the CC group (368 [95%CI: 337 – 399])
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versus the TRT group (333 [99%CI; 290 – 376]), although this was not statistically significant (p-

value 0.20).

A univariate analysis of the secondary polycythemia rate versus treatment modality

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revealed a significantly higher rate in the TRT group versus the CC group. A subset analysis of

the TRT group revealed significant differences between the route of TRT and the rate of

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secondary polycythemia. The highest rate of secondary polycythemia was 19% for the intra-

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muscular injection route, 12.5% for subcutaneous pellets, and 5.4% for transdermal gels (p-

value 0.03). Although a hematocrit of 52% was used as the cutoff for polycythemia as the

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primary end point, a secondary analysis revealed 3.7% of T treated men and 0% of CC treated
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men increased hematocrit levels to greater than 54%, which is used as the cutoff of

polycythemia by specific guidelines (p=0.0095).

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Given the significant differences between CC and TRT baseline characteristics and
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baseline hemoglobin, hematocrit, and testosterone levels, a logistic regression was performed
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to account for these differences (Table 3). Following this analysis, pre-treatment hematocrit
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and CC versus TRT treatment were the only variables that remained significant. Each increase

in pre-treatment hematocrit of 5% increases your risk of polycythemia. Furthermore, use of CC

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compared to TRT associated with 87% decrease in the odds of polycythemia even after
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adjustment for factors in this model.

Discussion:

To our knowledge, this is the first large-scale study to evaluate the rates of secondary

polycythemia in CC treated men in comparison to TRT treated men. There was a significantly
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lower rate of secondary polycythemia in symptomatic, hypogonadal men treated with CC as

compared to TRT. This result reached a post-hoc power of 96% despite not achieving our pre-

planned number of patients. This difference remained on regression analysis after correction

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for age, treatment site, pre-treatment hematocrit, and active smoking. Additionally, we found

a significant increase in serum testosterone levels in CC treated men that was comparable to

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TRT treated men.

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CC has been commonly used for many years as a treatment for hypogonadism in men

wishing to maintain fertility potential. It has generally been accepted as a safe drug, but there

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is a paucity of data evaluating potential adverse effects, especially compared to treatment with
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TRT 15. Reported side effects on CC include headache, dizziness, visual changes, gynecomastia,

and testicular enlargement 11. Small studies have noted paradoxically reduced testosterone
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levels while on CC treatment 16. There are also case reports of men who develop azoospermia
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while on CC 17, although the majority of studies find either no significant change in semen
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parameters or improvement in semen parameters and fertility rates after CC treatment 15.

Taylor and Levine did secondarily look at hemoglobin, cholesterol, and PSA levels after CC and
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TRT treatment and found no significant increase in either treatment group 18. Polycythemia is
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a known potential side effect of TRT, however, practice patterns on checking hemoglobin and
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hematocrits serially for patients on CC vary from practitioner to practitioner because the

paucity of data.

Many studies have described significant increases in serum testosterone with CC

treatment 11,19. These prior studies have revealed comparable increases in serum testosterone
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levels in hypogonadal men treated with CC compared to TRT 18,20. CC has also been compared

to other estrogen receptor modulators and has proven to be more effective in increasing

testosterone levels 21. The majority of other CC studies have focused on sperm parameters and

fertility rates after treatment 16,22-24, and have found significant increases in both following CC

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treatment. Additionally, Moskovic et.al. noted an increase in bone mineral density with CC

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treatment 11.

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In addition to biochemical outcomes, there is a large body of literature interrogating the

satisfaction of hypogonadism treatment with CC treatment. Many use the androgen deficiency

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in aging men (ADAM) questionnaire and have found an increase in satisfaction with CC
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treatment. Katz and Ramasamy et al. found comparable increases in score to TRT treated men
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. However, Patel et.al. reported fatigue and worsening mood symptoms in men on CC 16.
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CC’s improvement of erectile function in younger men has also been reported 25.
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Recently, enclomiphene, the trans-isomer of clomiphene citrate has been investigated

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to treat hypogonadal men 24. Results from open label 23 and phase II trials 26 have also shown
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similar increases in serum testosterone as compared to topical testosterone.

Limitations to our study include that it is a retrospective study and practice patterns or
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other environmental factors may confound the results. There are some differences between
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the treatment groups. These differences are addressed by performing regression analysis for

predictors of secondary polycythemia. Pre-treatment hematocrit was also a predictor of post-

treatment polycythemia, which is logical and should give pause if a patient has baseline high

hematocrit or hemoglobin. The ratio of patients from each site was also not perfectly matched,
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with more TRT treated patients from UVA and more CC treated patients from Austin. This was

corrected for in our regression.

The use of a hematocrit of 52% hematocrit as a definition for secondary polycythemia

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may seem arbitrary. However, the Endocrine Society identifies a hematocrit of >50% as a

reason not to start testosterone therapy and a level of >54% as a reason to stop therapy 27.

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Other endocrinology societies also indicate a level of 52-55% as a reason to stop testosterone

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therapy, while acknowledging the lack of evidence for a specific cut-off value 28. Larger, clinical

trials looking at levels of clinically relevant polycythemia also use a cut-off of 52% 9. Thus, we

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chose a hematocrit level of 52% as a cut-off. Additionally, using a higher hematocrit cut-off for
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polycythemia, 54%, there was a rate of 3.7% in T treated patients and 0% in CC treated patients

(p=0.0095).
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This study does not address the underlying biochemical reasons for an increased
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polycythemia prevalence in TRT treated men. The mechanisms of action are different between
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CC and TRT in increasing serum testosterone levels. Aromatization of testosterone to estradiol

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with either treatment and association with polycythemia was not evaluated in the study and

requires further study.

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Conclusion:
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Treatment of hypogonadal men with CC does not significantly increase the risk of

secondary polycythemia while it does improve serum testosterone to eugonadal levels,

comparable to TRT. This suggests that serial hemoglobin and hematocrit monitoring is not

indicated in men treated with CC as it is in TRT treated men, assuming that the risk of
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thrombosis seen in TRT treated men with secondary polycythemia is due to an increase in

erythrocyte number only.

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Table 1: Baseline characteristics

Clomiphene Testosterone Replacement P-value

Age – mean (SD*) 38.2 (10.4) 51.5 (12.6) <0.0001
BMI – cm/kg3 (SD) 27.5 (4.3) 29.0 (5.3) 0.012
Smoking History – % active 6.9% 8.0% 0.70

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Site - UVA/Austin 25/150 85/103 <0.0001
Treatment duration – months (SD) 9.2 (8.8) 19.6 (22.8) <0.0001
*SD = standard deviation

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Table 2: Hemoglobin and hematocrit and serum testosterone parameters

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Testosterone
Clomiphene p-value
Replacement
Hematocrit – % (Q1-Q3; SD*)

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Pre 44.6 (43.0 – 46.6; 3.4) 43.1 (41.6 – 45.9; 4.6) 0.0009
Post 45.1 (43.4 – 47.0; 3.0) 45.7 (43.2 – 48.1; 5.0) 0.14
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Hemoglobin – ng/dL (Q1-Q3; SD)
Pre 15.1 (14.5 – 15.9; 1.1) 14.7 (14.1 – 15.7; 1.5) 0.003
Post 16.2 (14.6 – 16.0; 10.9) 15.4 (14.5 – 16.5; 1.7) 0.33
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Testosterone – ng/dL (Q1-Q3; SD)

Pre 259 (192 – 322; 207) 236 (169 – 281; 114) 0.031
Post 627 (479 – 732; 207) 568 (367 – 736; 283) 0.025
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Polycythemia (>52% Hct) - % 1.7 % 11.2 % 0.0002

Route of TRT 0.03
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Intramuscular 19%
Subcutaneous pellets 12.5%
Transdermal 5.4%
*Q1-Q3 indicates 1st and 3rd quintiles; SD = standard deviation
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Table 3: Multivariable logistic regression analysis for polycythemia between CC and TRT.
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OR (95% CI) p-value

Age 0.98 (0.94 – 1.0) 0.48
Site 0.94 (0.19 – 4.7) 0.94
Active Smoking 2.9 (0.58 – 14) 0.70
Duration of Treatment 1.0 (0.96 – 1.0) 0.70
Pre-Treatment Hct * 4.1 (1.8 – 9.2) 0.0006
CC versus TRT 0.13 (0.03 – 0.58) 0.007
*For every 5 point increase in pre-treatment Hct, your chance of polycythemia increases 4-fold.
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Key Definitions for Abbreviations:

CC = Clomiphene Citrate

TRT = Testosterone Replacement Therapy

T = Testosterone

PT
HPG = Hypothalamic-Pituitary-Gonadal

LH = Luteinizing Hormone

RI
FSH = Follicle Stimulating Hormone

SC
ADAM = Androgen Deficiency in Aging Men

U
AN
M
D
TE
C EP
AC