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Cited by 102Hormonal and reproductive studiesSperm and Testicular FunctionHypothalamic control of reproductive hormones

A Randomized Prospective Double-Blind Comparison Trial of Clomiphene Citrate and Anastrozole in Raising Testosterone in Hypogonadal Infertile Men

Helo, Sevann, Ellen, Joseph, Mechlin, Clay, Feustel, Paul, Grossman, Michael, Ditkoff, Edward, McCullough, Andrew·2015·The Journal of Sexual Medicine
DOI 10.1111/jsm.12944
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Abstract

Aim: Clomiphene citrate (CC) and anastrozole (AZ) have been used off label to increase testosterone (T) in hypogonadal infertile men (HIM). Both medications have been shown to increase T with different effects on estradiol (E2) and T-to-E2 ratios. There are no reported randomized trials comparing CC and AZ to improve T levels in HIM. We aimed to establish equivalence of CC vs. AZ with respect to improvement in T levels in HIM. Methods: We randomized 26 HIM (T less than 350 ng/dL and normal luteinizing hormone [LH]). Patients were randomized to CC (25 mg/day) or AZ (1 mg/day) for 12 weeks. Hormones assayed were total T, free T, E2, LH, follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG). Patient-reported outcomes were the International Index of Erectile Function, Erection Hardness Scale, and the Androgen Deficiency in the Aging Male questionnaires. Blood tests and questionnaires were recorded at baseline, 6 and 12 weeks. Semen analyses were performed at baseline and 12 weeks. Results: T increased significantly from baseline in both groups at 6 and 12 weeks. There was a significantly larger increase in T and mean increase from baseline in CC vs. AZ (571 vs. 408 ng/dL, respectively). Whereas E-2 levels increased in the CC group, they decreased in the AZ group. Though both groups demonstrated an increase in T-to-E-2 ratio from baseline, statistic significance at 6 and 12 weeks was only achieved with AZ. Neither group demonstrated significant changes in seminal parameters or patient-reported outcomes. Conclusions: We failed to demonstrate equivalence of CC vs. AZ. CC resulted in significantly higher T levels than AZ. AZ resulted in a significantly larger increase in T/E-2 ratio than CC. No significant differences between CC and AZ on seminal parameters or patient-reported outcomes were demonstrated.

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  • Some studies have failed to show improvements in psychological or physiological parameters or symptoms of hypogonadism with AI-associated changes in testosterone levels and T:E2 ratios.

    “However, questions remain regarding the clinical significance of AI-associated changes in testosterone levels and T:E2 ratios, as some studies have failed to show improvements in psychological or physiological parameters or symptoms of hypogonadism with these associated changes (69,70).”

    From Non-testosterone management of male hypogonadism: an examination of the existing literature (2020) · cites this paper as [70]

  • The risk of developing a venous thrombo-embolic event seems to increase slightly when women are treated with SERMs.

    “The risk of developing a venous thrombo-embolic event seems to increase slightly when women are treated with SERMs.”

    From Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy (2020) · cites this paper as [66]

  • Studies with AIs in women with breast cancer show a slight increase in the incidence of venous thrombo-embolic events, although the incidence is slightly lower than in clomiphene citrate and tamoxifen.

    “Furthermore, studies with AIs in women with breast cancer show a slight increase in the incidence of venous thrombo-embolic events, although the incidence is slightly lower than in clomiphene citrate and tamoxifen [66].”

    From Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy (2020) · cites this paper as [66]

  • It is unclear if the increased venous thrombo-embolic event risk with SERMs also applies to men treated with SERMs.

    “However, it is unclear if this is also the case in men treated with SERMs [66].”

    From Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy (2020) · cites this paper as [66]

  • A randomized comparative trial of clomiphene citrate (25 mg/d) and anastrozole (1 mg/d) in 26 infertile men with functional central hypogonadism showed significantly higher levels of testosterone in the clomiphene citrate group than in the anastrozole group.

    “A randomized comparative trial of clomiphene citrate (25 mg/d) and anastrozole (1 mg/d) in 26 infertile men with functional central hypogonadism showed significantly higher levels of testosterone in the clomiphene citrate-group than in the anastrozole-group [66].”

    From Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy (2020) · cites this paper as [66]

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Authors
Helo, S., Ellen, J., Mechlin, C., Feustel, P., Grossman, M., Ditkoff, E., & McCullough, A.
Affiliations
  • Albany Medical Center Hospital (US)
  • Urology Associates of Central Missouri , Columbia, MO , USA
  • Albany Medical College (US)
  • CNY Fertility Center , Latham, NY , USA
Corresponding author
Helo, Sevann
ORCID
Venue
The Journal of Sexual Medicine
Publisher
Oxford University Press (OUP)
Published
2015-08-01
Volume
12
Issue
8
Pages
1761-1769
ISSN
  • 1743-6095 (ISSN-L)
  • 1743-6109
DOI
10.1111/jsm.12944
OpenAlex
W1530580940
Cited by
102
References
11
Citations by year
2026: 7 · 2025: 4 · 2024: 11 · 2023: 15 · 2022: 11 · 2021: 11 · 2020: 14 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 9 · 2015: 2
FWCI
6.09
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • The Journal of Sexual Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Capital Region Medical Research Foundation
  • Urological Institute of Northeastern New York
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
clomiphene citrate, anastrozole, hypogonadism, male infertility, testosterone, estradiol, semen parameters, erectile function
MeSH terms
Anastrozole, Clomiphene, Double-Blind Method, Fertility Agents, Male, Follicle Stimulating Hormone, Hormones, Humans, Hypogonadism, Infertility, Male, Luteinizing Hormone, Male, Nitriles, Prospective Studies, Testosterone, Triazoles, Treatment Outcome

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