Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis

21 Dec 2021

Clomiphene citrate for men with hypogonadism : a systematic review and meta-analysis / Manou Huijben, M. Tycho W.T. Lock, Vincent F. de Kemp, Laetitia M.O. de Kort, H.M.K. van Breda

  • Andrology (21 December 2021), p. 1-19
  • PMID: 34933414
  • DOI: 10.1111/andr.13146


Abstract

Background: Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first-choice therapy, with several side effects, including negative feedback of the hypothalamic-pituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism, clomiphene citrate is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of clomiphene citrate therapy for men with hypogonadism.

Methods: The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with clomiphene citrate. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument, was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic and lipid profile, side effects, safety aspects.

Results: We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone increased with 2.60 (95% CI 1.82-3.38) during clomiphene citrate treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males questionnaire, whose improved during treatment. Reported side effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported.

Conclusion: Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. Clomiphene citrate has few reported side effects and good safety aspects.

Clomiphene citrate-induced severe hypertriglyceridemia

20 Apr 2009

Clomiphene citrate-induced severe hypertriglyceridemia / Hamiyet Yilmaz Yaşar, Ozden Ertuğrul

  • Fertility and Sterility 92 (2009) 1 (1 July), p. 396.E7-396.E8
  • PMID: 19380127
  • DOI: 10.1016/j.fertnstert.2009.03.069


Abstract

Objective: To report a case of severe hypertriglyceridemia associated with clomiphene citrate (CC) treatment.

Design: Case report.

Setting: A patient referred to an endocrinology clinic of a state hospital.

Patient(s): A 29-year-old, overweight woman with a history of polycystic ovary syndrome who had been given clomiphene citrate (CC) for ovulation induction and presented with severe hypertriglyceridemia. She had a family history of type 2 diabetes and hyperlipidemia.

Intervention(s): Clomiphene citrate treatment was discontinued, and gemfibrozil treatment at a dose of 1,200 mg/d was started.

Main outcome measure(s): Serum lipid levels.

Result(s): With the discontinuation of CC treatment and start of a specific lipid-lowering agent, the patient's lipid profile improved. After 3 months, CC therapy was restarted, and again severe hypertriglyceridemia developed, which resolved with the previous treatment strategies.

Conclusion(s): Clomiphene citrate should be used cautiously in women having risk factors for dyslipidemia, and, even in the presence of a normal lipid profile, lipid levels should be closely monitored when CC treatment is instituted.

Clomiphene Citrate for the Treatment of Hypogonadism

3 Dec 2018

Clomiphene Citrate for the Treatment of Hypogonadism / Karen M. Wheeler, Devang Sharma, Parviz K. Kavoussi, Ryan P. Smith, Raymond Costabile

  • Sexual Medicine Reviews 7 (2019) 2 (April), p. 272-276
  • PMID: 30522888
  • DOI: 10.1016/j.sxmr.2018.10.001


Abstract

Introduction: Clomiphene citrate (CC) is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men since the 1970s. It acts centrally to increase secretion of luteinizing hormone and follicle-stimulating hormone, thereby increasing testosterone production and serum levels. Unlike testosterone replacement therapy, CC does not suppress the hypothalamic-pituitary-gonadal axis, preserving intratesticular testosterone production and spermatogenesis. This is especially useful in treating hypogonadal men who are interested in fertility.

Aim: To review the literature regarding the use of CC in the setting of hypogonadism.

Methods: A review of the relevant literature through September 2018 was performed via PubMed.

Main outcome measure: The data regarding the efficacy and safety of CC when used in the setting of hypogonadism is summarized.

Results: Although results are mixed, many studies show CC reduces symptoms in hypogonadal men. Studies have also shown improvement in erectile function and bone mineral density, as well as a reduction in body mass index. There have been few studies investigating fertility rates in hypogonadal men treated with CC, but a metaanalysis of these shows significant improvement in fertility rates. Several studies show improvement in semen parameters. Few studies have investigated adverse effects of the drug. Reports include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. Despite these reports, CC is generally considered to be safe and well tolerated.

Conclusion: CC is safe and effective and should remain in the armament of urologists treating hypogonadal men, especially men interested in preservation of fertility.

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

12 Jul 2013

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


Abstract

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.

Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone

17 Jul 2014

Enclomiphene citrate stimulates testosterone production while preventing oligospermia : a randomized phase II clinical trial comparing topical testosterone / Ronald D. Wiehle, Gregory K. Fontenot, Jenny Wike, Kuang Hsu, Jennifer Nydell, Larry Lipshultz

  • Fertility and Sterility 102 (2014) 3 (September), p. 720-727
  • PMID: 25044085
  • DOI: 10.1016/j.fertnstert.2014.06.004


Abstract

Objective: To determine the effect of enclomiphene citrate in men with secondary hypogonadism.

Design: Phase II clinical trial.

Setting: Community dwelling men making visits to physician offices.

Patient(s): Men with secondary hypogonadism.

Intervention(s): Oral administration of enclomiphene citrate or 1% topical T gel.

Main outcome measure(s): Luteinizing hormone, FSH, T, and semen analysis.

Result(s): Treatment with enclomiphene citrate resulted in increased morning serum T, E2, and LH levels similar to those obtained with a topical T gel in men with secondary hypogonadism. Follicle-stimulating hormone and LH were increased with enclomiphene, and sperm counts were conserved.

Conclusion(s): Enclomiphene citrate reverses the two hallmarks of secondary hypogonadism, namely, low serum total T and low or inappropriately normal LH while preserving sperm production.

Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement

23 Oct 2015

Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone : restoration instead of replacement / Edward D. Kim, Andrew McCullough, Jed Kaminetsky

  • BJUI 117 (2017) 4 (April), 677-685
  • PMID: 26496621
  • DOI: 10.1111/bju.13337


Abstract

Objectives: To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism.

Patients and methods: Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (AndroGel(®) 1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18-60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (≤300 ng/dL; ≤10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2-10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study.

Results: TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group.

Conclusions: Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained.

Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment

11 Aug 2016

Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment / Sevann Helo, Joseph Mahon, Joseph Ellen, Ron Wiehle, Gregory Fontenot, Kuang Hsu, Paul Feustel, Charles Welliver, Andrew McCullough

  • BJUI 119 (2017) 1 (January), 171-176
  • PMID: 27511863
  • DOI: 10.1111/bju.13625


Abstract

Objectives: To determine the relative concentrations of enclomiphene (ENC) and zuclomiphene (ZUC) isomers in men with hypogonadism on long-term clomiphene citrate (CC) therapy, and to determine whether patient age, body mass index (BMI) or duration of therapy were predictive of relative concentrations of ENC and ZUC.

Patients and methods: Men already receiving CC 25 mg daily therapy for secondary hypogonadism for a minimum of 6 weeks were recruited to have their ENC and ZUC levels assessed. Total testosterone, free testosterone, oestradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) before initiation of and while on CC therapy were recorded for all patients. Patient demographics including age, BMI and medical comorbidites were recorded. Serum samples were obtained at the time of enrolment to determine ENC and ZUC concentrations.

Results: A total of 15 men were enrolled in the period from June 2015 to August 2015. The median (range) patient age was 36 (22-70) years, BMI 32.0 (21.1-40.3) kg/m2 and duration of treatment 25.9 (1.7-86.6) months. Baseline median total testosterone, oestradiol and LH levels were 205.0 ng/dL, 17.0 pg/mL and 4.0 mlU/mL, respectively. The post-treatment median total testosterone, oestradiol and LH level increased to 488.0 ng/dL, 34.0 pg/mL and 6.1 mIU/mL, respectively (all P<0.001). The median ENC and ZUC concentrations were 2.2 and 44.0 ng/mL, respectively. After at least 6 weeks of CC therapy, the median ZUC: ENC serum concentration ratio was 20:1. On linear regression analysis. patient age, BMI, duration of treatment and serum testosterone levels were not predictive of ENC or ZUC concentrations.

Conclusions: Long-term CC therapy resulted in a significant alteration of ENC and ZUC concentrations, with ZUC as the predominant isomer. Given the vastly different biochemical and toxicological properties of ENC and ZUC, this study supports the need for the development of a pure selective oestrogen receptor antagonist for the treatment of men with hypogonadism.

Hypothalamic-Pituitary-Testicular Axis Effects and Urinary Detection Following Clomiphene Administration in Males

5 Oct 2018

Hypothalamic-Pituitary-Testicular Axis Effects and Urinary Detection Following Clomiphene Administration in Males / Geoffrey D. Miller, Chad Moore, Vinod Nair, Brian Hill, Stuart E. Willick, Alan D. Rogol, Daniel Eichner

  • Journal of Clinical Endocrinology & Metabolism 104 (2019) 3 (March), p. 906-914
  • PMID: 30295816
  • DOI: 10.1210/jc.2018-01159


Abstract

Context: Clomiphene is a performance-enhancing drug commonly abused by males in sport, but the extent to which testosterone increases in healthy males following its use is unknown. In addition, evidence suggests that clomiphene, a mixture of cis- and trans-isomers zuclomiphene and enclomiphene, is detectable in urine for months following use; the isomer-specific urinary detection window has yet to be characterized in a controlled study.

Objective: To determine the effect of once-daily, 30-day clomiphene treatment on serum testosterone and gonadotropin levels in the subject population studied and the urinary clearance and detection window of clomiphene isomers following administration for antidoping purposes.

Participants and design: Twelve healthy males aged 25 to 38 years, representing a recreational athlete population, participated in this open-label, single-arm study.

Intervention: Oral clomiphene citrate (50 mg) was self-administered once daily for 30 days. Serum and urine samples were collected at baseline and at days 7, 14, 21, 28, 30, 32, 35, 37, 44, 51, and 58; urine collections continued periodically up to day 261.

Results: Mean testosterone, LH, and FSH levels increased 146% (SEM, ±23%), 177% (±34%), and 170% (±33%), respectively, during treatment compared with baseline. Serum drug concentrations and urinary excretion were nonuniform among individuals as isomeric concentrations varied. The zuclomiphene urinary detection window ranged from 121 to >261 days.

Conclusions: Clomiphene significantly raised serum testosterone and gonadotropin levels in healthy men and thus can be abused as a performance-enhancing drug. Such abuse is detectable in urine for ≥4 months following short-term use.

Enclomiphene citrate: A treatment that maintains fertility in men with secondary hypogonadism

7 May 2019

Enclomiphene citrate : A treatment that maintains fertility in men with secondary hypogonadism / Joshua A. Earl, Edward D. Kim

  • Expert Review of Endocrinology & Metabolism 14 (2019) 3 (May), p. 157-165
  • PMID: 31063005
  • DOI: 10.1080/17446651.2019.1612239


Abstract

Hypogonadism is an important issue among the male population. Treatments such as exogenous testosterone have become very popular. One of the adverse effects of testosterone is its suppression of fertility. This has lead to the use of alternative therapies such as selective estrogen receptor modulators (SERMs) that aim to correct hypogonadism without reducing fertility. Areas covered: The SERM, clomiphene citrate, which is approved by the FDA for the treatment of ovarian dysfunction, has been shown to have beneficial effects on male hypogonadism. Clomiphene citrate exists as a mixture of both the cis-isomer (zuclomiphene) and the trans-isomer (enclomiphene). The literature has suggested that most of the beneficial effects of clomiphene are due to the trans-isomer enclomiphene. Zuclomiphene contributes little to the intended outcomes. The purpose of this drug profile is to examine the available literature on the trans-isomer enclomiphene.

Expert opinion: Enclomiphene has been shown to increase testosterone levels while stimulating FSH and LH production. Initial studies demonstrated that enclomiphene maintains the androgenic benefit of clomiphene citrate without the undesirable effects attributable to zuclomiphene. This article reviews the difficulties associated with the FDA approval of a new molecular entity related to the treatment of hypogonadism.

Is competitive body-building pathological? Survey of 984 male strength trainers

10 May 2020

Is competitive body-building pathological? Survey of 984 male strength trainers / Ian Steele, Harrison Pope, Eric J. Ip, Mitchell J. Barnett, Gen Kanayama

  • BMJ Open Sport & Exercise Medicine 6 (2020) 1, e000708
  • PMID: 32419952
  • PMCID: PMC7223260
  • DOI: 10.1136/bmjsem-2019-000708


Abstract

Objectives: Hundreds of thousands, if not millions, of individuals worldwide engage in competitive body-building. Body-building often attracts derogatory characterisations such as as 'bizarre' or 'narcissistic,' or a 'freak show', seemingly implying that it is associated with pathology. Few studies have compared psychological features in competitive bodybuilders versus recreational strength trainers.

Methods: Using logistic regression with adjustment for age and race, we compared 96 competitive bodybuilders ('competitors') with 888 recreational strength trainers ('recreationals'), assessed in a prior internet survey, regarding demographics; body image; use of anabolic-androgenic steroids (AAS), other appearance-enhancing and performance-enhancing drugs (APEDs), and classical drugs of abuse; history of psychiatric diagnoses; and history of childhood physical/sexual abuse.

Results: Competitors reported a higher lifetime prevalence of AAS (61 (63.5%) vs 356 (10.1%), p<0.001) and other APED use than recreationals but showed very few significant differences on other survey measures. AAS-using competitors were more likely than AAS-using recreationals to have disclosed their AAS use to a physician (31 (50.8%) vs 107 (30.0%), p=0.003). Both groups reported high levels of body image concerns but did not differ from one another (eg, 'preoccupation with appearance' caused significant reported distress or impairment in important areas of functioning for 18 (18.8%) competitors vs 132 (15.4%) recreationals, p=0.78). No significant differences were found on the prevalence of reported childhood physical abuse (9 (9.4%) vs 77 (8.8%), p=0.80) or sexual abuse (4 (4.2%) vs 39 (4.5%), p=0.83). Competitors reported a lower lifetime prevalence of marijuana use than recreationals (38 (39.6%) vs 514 (57.9%), p=0.001).

Conclusion: Aside from their APED use, competitive bodybuilders show few psychological differences from recreational strength trainers.

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