Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics

Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism : Pharmacodynamics and Pharmacokinetics / Ronald Wiehle, Glenn R. Cunningham, Nelly Pitteloud, Jenny Wike, Kuang Hsu, Gregory K. Fontenot, Michele Rosner, Andrew Dwyer, Joseph Podolski

  • BJUI 112 (2013) 8 (December), p. 1188-1200
  • PMID: 23875626
  • PMCID: PMC4155868
  • DOI: 10.1111/bju.12363


Objectives: To determine the pharmacodynamic (PD) profile of serum total testosterone levels (TT) and luteinizing hormone (LH) in men with secondary hypogonadism following initial and chronic daily oral doses of enclomiphene citrate in comparison to transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate (Androxal®) in comparison to transdermal testosterone on other hormones and markers in men with secondary hypogonadism.

Patients and methods: This was a randomized, single blind, two-center phase II study to evaluate three different doses of enclomiphene citrate (6.25mg, 12.5mg and 25 mg Androxal®), versus AndroGel®, a transdermal testosterone, on 24-hour LH and TT in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (ITT Population), but 4 men had T levels >350 ng/dL at baseline. Forty-four men completed the study per protocol (PP population). All subjects enrolled in this trial had serum TT in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions. TT and LH levels were assessed each hour for 24 hours to examine the effects at each of three treatment doses of enclomiphene versus a standard dose (5 grams) of transdermal testosterone (AndroGel). In the initial profile TT and LH were determined in a naïve population following a single initial oral or transdermal treatment (Day 1). This was contrasted to that seen after six weeks of continuous daily oral or transdermal treatment (Day 42). The pharmacokinetics of enclomiphene was performed in a select subpopulation. Serum samples were obtained over the course of the study to determine levels of various hormones and lipids.

Results: After six weeks of continuous use, the mean ± SD concentration of TT at Day 42 C0hrTT, was 604 ± 160 ng/dL for men taking the highest of dose of enclomiphene citrate (enclomiphene, 25 mg daily) and 500 ± 278 ng in those men treated with transdermal testosterone. These values were higher than Day 1 values but not different from each other (p = 0.23, T-test). All three doses of enclomiphene increased C0hrTT, CavgTT, CmaxTT, CminTT and CrangeTT. Transdermal testosterone also raised TT, albeit with more variability, and with suppressed LH levels. The patterns of TT over 24 hour period following six weeks of dosing could be fit to a non-linear function with morning elevations, mid-day troughs, and rising night-time levels. Enclomiphene and transdermal testosterone increased levels of TT within two weeks, but they had opposite effects on FSH and LH Treatment with enclomiphene did not significantly affect levels of TSH, ACTH, cortisol, lipids, or bone markers. Both transdermal testosterone and enclomiphene citrate decreased IGF-1 levels (p<0.05) but suppression was greater in the enclomiphene citrate groups.

Conclusions: Enclomiphene citrate increased serum LH and TT; however, there was not a temporal association between the peak drug levels and the Cmax levels LH or TT. Enclomiphene citrate consistently increased serum TT into the normal range and increased LH and FSH above the normal range. The effects on LH and TT persisted for at least one week after stopping treatment.

Original document


Research / Study
12 July 2013
Cunningham, Glenn R.
Dwyer, Andew
Fontenot, Gregory K.
Hsu Kuang
Pitteloud, Nelly
Podolski, Joseph
Rosner, Michele
Wiehle, Ronald
Wike, Jenny
United States of America
Other organisations
Centre Hospitalier Universitaire Vaudois (CHUV) - Lausanne University Hospital
Doping classes
S1. Anabolic Agents
S4. Hormone And Metabolic Modulators
Luteinizing hormone (LH)
Selective estrogen receptor modulators (SERMS)
Medical terms
Health effects
Hormone replacement therapy (HRT)
Document category
Scientific article
Document type
Pdf file
Date generated
10 January 2022
Date of last modification
18 January 2022
  • Legal Source
  • Education
  • Science
  • Statistics
  • History
Country & language
  • Country
  • Language
Other filters
  • ADRV
  • Legal Terms
  • Sport/IFs
  • Other organisations
  • Laboratories
  • Analytical aspects
  • Doping classes
  • Substances
  • Medical terms
  • Various
  • Version
  • Document category
  • Document type
Publication period