MP76-07
COMPARISON OF THE EFFECTS OF ORAL ENCLOMIPHENE CITRATE AND TOPICAL TESTOSTERONE GELS TREATMENT ON SERUM HORMONES, ERYTHROCYTOSIS, LIPIDS, AND PROSTATE SPECIFIC ANTIGEN
Alexander W. Pastuszak*, Houston, TX; Ronald D. Wiehle, Gregory Fontenot, Joseph Podolski, The Woodlands, TX; Larry I. Lipshultz, Houston, TX
INTRODUCTION AND OBJECTIVES: Testosterone therapy (TTh) is often the mainstay for hypogonadism treatment. Adverse ef- fects of TTh include lipid abnormalities, erythrocytosis, and increases in prostate specific antigen (PSA).
Enclomiphene citrate (En) can raise T levels, but its effects on lipids, erythrocytosis, and PSA are unknown relative to TTh. Here, we compare effects of topical T gels and oral En in hypogonadal men on serum hormones, lipids, erythrocytosis, and PSA.
METHODS: Data from 11 prospective, randomized, blinded Phase 2/3 trials of oral En, placebo, and T gels were analyzed. Men with secondary hypogonadism based on two morning serum evaluations for total T (TT) <300 ng/dL and low-to-normal LH were enrolled; 130 men on T gels, 290 on placebo, and 953 on En completed the study protocols. TT, dihydrotestosterone (DHT), estradiol (E), hemoglobin (Hgb), hematocrit (Hct), PSA, total cholesterol (Tchol), triglycerides (TG), LDL- Chol, and HDL-Chol were evaluated at baseline (BL) and during regular follow-up for up to 1 year, and compared using a mixed model linear regression for repeated measures.
RESULTS: Both T gels and En raised serum TT, DHT and E levels, with a more significant increase in TT and E levels in men on En (En TT: 216 64 vs. 450 182 mg/dL at BL and 12 months; T gels
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TT: 231 74 vs. 379 187 ng/dL at BL and 12 months), and a slower return to baseline after treatment was discontinued. In contrast, Hgb and Hct were higher in men on T gels (Hct 49.3% at 12 months) than En (46.9% at 12 months), although only one patient discontinued T gel due to erythrocytosis (Hct >54%); no erythrocytosis occurred in men taking En. Small, clinically insignificant increases in mean PSA were
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observed with En (0.8 vs. 1.2 ng/mL at BL and 12 months) that were not observed in men on T gels (0.9 vs. 0.8 ng/mL at BL and 12 months). Decreases in TChol (En: 190 vs. 178 mg/dL; T gel 193 vs. 190 mg/dL at BL and 12 months), HDL-Chol (En: 49 vs. 41 mg/dL; T gel 42 vs. 42 mg/dL at BL and 12 months) and LDL-Chol (En: 106 vs. 101 mg/dL; T gel 115 vs. 117 mg/dL at BL and 12 months) were observed with both En and T gels, with more significant changes with En. Effects on triglycerides were variable and inconsistent for both En and T gels.
CONCLUSIONS: En therapy results in more significant and sustained increases in TT and E, as well as more significant and sus- tained decreases in TChol, HDL-Chol and LDL-Chol, than T gel therapy. Clinically insignificant effects on PSA, Hgb, and Hct are observed. En may represent an effective, low-risk treatment option for androgen deficient men with few adverse effects.
Source of Funding: AWP is a National Institutes of Health (NIH) K12 Scholar supported by a Male Reproductive Health Research Career (MRHR) Development Physician-Scientist Award (HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program (to Dolores J. Lamb).
MP76-08
SERUM LEVELS OF ENCLOMIPHENE AND ZUCLOMIPHENE IN HYPOGONADAL MEN ON LONG-TERM CLOMIPHENE CITRATE TREATMENT
Sevann Helo*, Joseph Mahon, Albany, NY; Joseph Ellen, Richmond, VA; Greg Fontenot, Kuang Hsu, Ronald Wiehle, The Woodlands, TX; Paul Feustel, Charles Welliver, Andrew McCullough, Albany, NY
INTRODUCTION AND OBJECTIVES: Clomiphene citrate (CC) is a non-steroidal selective estrogen receptor modulator (SERM) that increases testosterone (T) production by blocking negative feedback inhibition of estradiol on the hypothalamic pituitary axis. It is used off label to treat hypogonadal men (HM) and exists as a 60/40 % racemic mixture of the stereoisomers
enclomiphene (EN) and zuclomiphene (ZU), respectively. EN is a potent estrogen receptor antagonist reaching peak plasma concentration (Tmax) in 4 hours (hrs), with a half-life (T1/2) of 8 hrs. ZU is an estrogen receptor agonist that reaches a Tmax in 7 hrs, with T1/2 greater than 40 hrs. A study evaluating the relative concen- trations of EN and ZU in HM on long-term CC therapy has never been performed. Our aim was to evaluate the serum concentrations of each isomer in HM on long-term CC treatment.
METHODS: With institutional review board approval we recruited HM currently on CC treatment to have serum EN and ZU concentration levels drawn. All patients were on generic CC 25 mg daily for a minimum of 6 weeks. Patient characteristics, hormone levels, and duration of treatment were reviewed. EN and ZU serum concentration levels were obtained for each patient using liquid chromatography-mass spectrometry with a Kinetex XB-C18 reverse phase column.
RESULTS: A total of 15 men were enrolled from June 2015 to August 2015. Mean patient age was 42, mean BMI 31.8, and mean duration of treatment 31.5 months; 12 men were treatment naive. Mean T increase was 31.2% from baseline. Although CC was administered as a 3:2 EN:ZU racemic mixture, prolonged treatment resulted in a 1:27 EN:ZU ratio of serum concentration. Patient age, BMI, duration of treatment and serum T levels were not predictive of EN or ZU concentrations.
CONCLUSIONS: After prolonged treatment with CC in HM, ZU is the predominant isomer present in serum. Given the vastly different biochemical properties of EN and ZU, this study supports the need for development of a pure SERM for the treatment of HM.