Clomid For Men With Low Testosterone
by Jeffrey Dach MD
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For Part Two, Click Here.
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A Case Report
A 37 year old professional athlete and bodybuilder arrived in my office complaining of low testosterone symptoms of low libido, erectile dysfunction, chronic fatigue, and mood disorder. He admitted to anabolic steroid abuse in the past, and now sought medical intervention to “restore his testosterone to normal.”
A few years ago, he had married and fathered a child, and he now wanted to devote more time to his family, but complained of a lack of energy to do so. He also wanted to preserve fertility, as he wanted more children. Previous medical doctor’s lab studies showed low testosterone levels, all below 300 ng/dl, and low FSH and LH levels as well.
Upper left image : cropped portions of an anonymous body builder, courtesy of wikimedia commons. This image is an illustration only, and not an actual patient in any clinic.
Diagnosis and Treatment
After our usual workup, and the obvious diagnosis of hyopogonadal hypogonadism, treatment was started with HCG (human chorionic gonadotropin), an LH analog which stimulates testicular testosterone production. The patient wished to retain fertility which contra-indicated the use of Testosterone preparations.
Shortly after starting the HCG injections, the patient reported an immediate improvement in mood and energy, lasting about one week. However, this improvement was short lived and lasted only one week, after which he reported a recurrence of more severe low testosterone symptoms, worse than before.
Paradoxical Response with Lower Testosterone Levels
Repeat labs at 6 weeks showed testosterone levels had actually dropped lower to the 150 ng/dl range. FSH and LH were undetectable. My diagnosis at this point was hypothalamic suppression, and the HCG was discontinued.
Switch to Clomiphene was Sucessful
Treatment with Clomid (clomiphene 25 mg tablet daily) was started. Six weeks later, the patient reported “feeling like my old self” with improved energy, libido and mood. Repeat labs 6 weeks after starting the Clomid showed testosterone levels of 832 ng/dl, and LH and FSH had increased as well. Serum estrogen was quite high at 72 pg/ml. Anastrazole was added to the treatment program with follow up normalization of estrogen levels.
What Happened in this Patient ?
Why was there a paradoxical response to HCG ? The answer is in the feedback mechanism illustrated by the diagram to the left.
The hypothalamus produces gonadotropin releasing hormone (GnRH), which in turn stimulates pituitary production of LH and FSH (leutinizing hormone and follicle stimulating hormone). LH and FSH then travel to the testicle to induce testosterone(LH) and sperm production (FSH). \
Image upper left: Pituitary feedback control of LH, FSH and Testosterone from Estrogen (E2). Diagram is courtesy of Dr Rochira , Eur J Endocrinol. 2006 Oct;155(4):513-22.(1)
Estrogen Receptors in the Hypothalamus Control the Whole Thing
In the female, estrogen receptors in the hypothalamus control releasing hormone (GnRH) as well as pituitary LH and FSH production. The Male of the species has this same estrogen receptor in the hypothalamus which controls LH and FSH production. Blocking this hypothalamic estrogen receptor can be accomplished with clomiphene, a drug FDA approved for use in women. Clomiphene use in males is “off label” use, however.
The drug then “tricks” the hypothalamus to produce more releasing hormone (GnHR), which in turn travels to the pituitary gland to increase LH and FSH production. LH and FSH in turn increase testosterone production, and sperm production, thus maintaining and enhancing fertility.
In our patient, the hypothalamic Estrogen receptors were set to shut off at a relatively low estrogen level. The drug “reset ” this to a higher level, allowing more LH, FSH which then stimulated testosterone production.
The advantage of this treatment approach is that it does not impair fertility. For younger males who wish to maintain or enhance fertility this is a good option.
Aromatase Conversion of Testosterone to Estrogen
Some men are “preferential aromatizers”, meaning there is increased conversion of testosterone to estrogen via the aromatase pathway. This explains in some, the paradoxical response to HCG which may initially raised testosterone levels. However, upon conversion to estrogen, the increased estrogen level then shuts off the hypothalamic production of GnHR, which in turn may cause very low levels of LH and FSH, explaining the paradoxical low testosterone levels after HCG treatment in some.
In this scenario, Clomiphene is an excellent treatment, which successfully raises testosterone levels while preserving fertility. Because of preferential conversion of testosterone to estrogen in some men, elevated estrogen levels may require the addition of an aromatase inhibitor such as anastrazole (also called Arimidex).
Estrogen Feedback Regulates Hypothalamus
In a 2006 report in the European Journal of Endocrinology by Dr Rochira from Italy showed that the feedback of gonadotropins (GnRH from the hypothalamus) is regulated by estrogens that come from the aromatization of testosterone. He studied two males with absent estrgoen from a genetic deficiency in the aromatase enzyme. When these two subjects were given topical Estradiol, this suppressed levels of GnRH, LH, FSH and testosterone, which decreased significantly. (1)
Clomiphene: How does it work ?
Clomiphene binds to and “blocks” the estrogen receptor sites in the hypothalamus (reference). This stimulates the production of GnRH, gonadotropins.
Click Here for excellent discussion of pathophysiology of hypothalamic pituitary axis.
Conclusion: Clomiphene for men with low testosterone is a viable option for younger males who wish to maintain fertility. Use in males is “off-label”.
Articles with Related Interest:
This article is Part One,
For Part Two, Click Here.
For Part Three Click Here
Links and References
Eur J Endocrinol. 2006 Oct;155(4):513-22.
Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback. Rochira V, Zirilli L, Genazzani AD, Balestrieri A, Aranda C, Fabre B, Antunez P, Diazzi C, Carani C, Maffei L.
Source Integrated Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy.
BACKGROUND: In men, the feedback of gonadotropins is regulated by estrogens that come from the aromatization of testosterone, but the relative contribution to the inhibition of LH and FSH secretion by the amount of locally produced estrogens within the hypothalamus and/or the pituitary, and the amount of circulating estrogens still remains unknown.
OBJECTIVE:In order to evaluate the effect of regulation induced by estradiol on the hypothalamic-pituitary-gonadal (HPG) axis, we studied the pulsatility of LH and FSH in two aromatase-deficient men (called subject 1 and subject 2), in which the production rate of estrogen (both local and circulating) is completely, or at least severely, impaired.
DESIGN:FSH and LH were evaluated in terms of their pulsated secretion and as GnRH-stimulated secretion in two phases: phase 1, before estrogen treatment; and phase 2, during estrogen treatment with 25 microg transdermal estradiol twice weekly.
METHODS:Blood samples were taken during phase 1 and phase 2 at 0800 h for basal measurements of LH, FSH, inhibin B, testosterone, and estradiol. The analysis of the pulsatility of LH and FSH was performed by sampling every 10 min for 8 h in the two phases. Gonadotropin response to GnRH-stimulation test was studied by serial standard sampling after 100 microg GnRH i.v. bolus in phases 1 and 2.
RESULTS:Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5 +/- 0.7 in phase 1, 4.5 +/- 0.7 in phase 2) and amplitudes (3.5 +/- 0.006 in phase 1, 1.9 +/- 0.4 in phase 2) of peaks, whereas FSH showed only a conspicuous reduction in serum levels and a trend towards the reduction of the amplitudes of its peaks without modification of the frequency of the pulses.
Both testosterone and gonadotropins decreased during phase 2, whereas estradiol reached the normal range in both subjects.
Transdermal estradiol treatment significantly lowered the peaks of both serum LH and FSH after GnRH as well as the incremental area under the curve after GnRH administration in both subjects. Basal serum inhibin B levels were slightly higher before transdermal estradiol treatment (phase 1) than during estrogen treatment (phase 2) in both subjects.
CONCLUSIONS:The administration of estrogen to aromatase-deficient men discloses the effects of circulating estrogens on LH secretion, exerted both at pituitary level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulsed amplitude, and at hypothalamic level as shown by the reduction of the frequency of LH pulses. The present study, coupling the outcomes of basal, GnRH-stimulated and the pulsatile evaluation of LH and FSH secretion in two aromatase-deficient men, demonstrates that circulating estrogens play an inhibitory role in LH secretion by acting on the hypothalamus and the pituitary gland of men. The discrepancy among testosterone levels, the arrest of spermatogenesis and a slightly inappropriate respective increase of serum FSH (lower than expected) suggests a possible role of estrogens in the priming and the maturation of HPG axis in men, an event that has never occurred in these two subjects as a consequence of chronic estrogen deprivation.
BJU Int. 2012 Mar 28. Clomiphene citrate is safe and effective for long-term management of hypogonadism.
Moskovic DJ, Katz DJ, Akhavan A, Park K, Mulhall JP.
Sexual & Reproductive Medicine Program, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Clomiphene citrate (CC) has previously been documented to be efficacious in the treatment of hypogonadism. However little is known about the long term efficacy and safety of CC. Our study demonstrates that CC is efficacious after 3 years of therapy. Testosterone levels and bone mineral density measurement improved significantly and were sustained over this prolonged period. Subjective improvements were also demonstrated. No adverse events were reported.
OBJECTIVE: To assess the efficacy and safety of long-term clomiphene citrate (CC) therapy in symptomatic patients with hypogonadism (HG).
PATIENTS AND METHODS:Serum T, oestradiol and luteinizing hormone (LH) were measured in patients who were treated with CC for over 12 months. • Additionally, bone densitometry (BD) results were collected for all patients. Demographic, comorbidity, treatment and Androgen Deficiency in Aging Men (ADAM) score data were also recorded.
• Comparison was made between baseline and post-treatment variables, and multivariable analysis was conducted to define predictors of successful response to CC.
• The main outcome measures were predictors of response and long-term results with long-term CC therapy in hypogonadal patients. RESULTS:The 46 patients (mean age 44 years) had baseline serum testosterone (T) levels of 228 ng/dL.
• Follow-up T levels were 612 ng/dL at 1 year, 562 ng/dL at 2 years, and 582 ng/dL at 3 years (P < 0.001).
• Mean femoral neck and lumbar spine BD scores improved significantly.
• ADAM scores (and responses) fell from a baseline of 7 to a nadir of 3 after 1 year. • No adverse events were reported by any patients. CONCLUSIONS:Clomiphene citrate is an effective long-term therapy for HG in appropriate patients.
• The drug raises T levels substantially in addition to improving other manifestations of HG such as osteopenia/osteoporosis and ADAM symptoms.
BJU Int. 2011 Nov 1. Outcomes of clomiphene citrate treatment in young hypogonadal men. Katz DJ, Nabulsi O, Tal R, Mulhall JP. Source Male Sexual and Reproductive Medicine Programme, Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Hypogonadism is a prevalent problem, increasing in frequency as men age. It is most commonly treated by testosterone supplementation therapy but in younger patients this can lead to testicular atrophy with subsequent exogenous testosterone dependency and may impair spermatogenesis.
Clomiphene citrate (CC) may be used as an alternative treatment in these patients with hypogonadism when maintenance of fertility is desired. This study shows that CC is a safe and efficacious drug to use as an alternative to exogenous testosterone. Not only have we validated previous findings of other papers but have proven our findings over a much longer period (mean duration of treatment 19 months). This prospective study is the largest to date assessing both the objective hormone response to CC therapy as well as the subjective response based on a validated questionnaire.
OBJECTIVE:To prospectively assess the andrological outcomes of long-term clomiphene citrate (CC) treatment in hypogonadal men.
PATIENTS AND METHODS:We prospectively evaluated 86 men with hypogonadism (HG) as confirmed by two consecutive early morning testosterone measurements
• The cohort included all men with HG presenting to our clinic between 2002 and 2006 who, after an informed discussion, elected to have CC therapy. CC was commenced at 25 mg every other day and titrated to 50 mg every other day.
The target testosterone level was 550 ± 50 ng/dL.
• Testosterone (free and total), sex hormone binding globulin, oestradiol, luteinizing hormone and follicle stimulating hormone were measured at baseline and during treatment on all patients. Once the desired testosterone level was achieved, testosterone/gonadotropin levels were measured twice per year.
• To assess subjective response to treatment, the androgen deficiency in aging males (ADAM) questionnaire was administered before treatment and during follow-up.
RESULTS: patients’ mean (standard deviation [sd]; range) age was 29 (3; 22-37) years. Infertility was the most common reason (64%) for seeking treatment. The mean (sd) duration of CC treatment was 19(14) months.
• At the last evaluation, 70% of men were using 25 mg CC every other day, and the remainder were using 50 mg every other day.
• All mean testosterone and gonadotropin measurements significantly increased during treatment.
• Subjectively, there was an improvement in all questions (except loss of height) on the ADAM questionnaire. More than half the patients had an improvement in at least three symptoms.
• There were no major side effects recorded and the presence of a varicocele did not have an impact on the response to CC.
CONCLUSION:Long-term follow-up of CC treatment for HG shows that it appears to be an effective and safe alternative to testosterone supplementation in men wishing to preserve their fertility
J Sex Med. 2010 Jan;7(1 Pt 1):269-76. Epub 2009 Aug 17.
Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: efficacy and treatment cost.
Taylor F, Levine L. Rush University Medical Center-Department of Urology, Chicago, IL, USA.
INTRODUCTION:The efficacy of oral clomiphene citrate (CC) in the treatment of male hypogonadism and male infertility (MI) with low serum testosterone and normal gonadotropin levels has been reported.
AIM:The aim of this article is to evaluate CC and testosterone gel replacement therapy (TGRT) with regard to biochemical and clinical efficacy and cost. MAIN OUTCOME MEASURES:The main outcome measures were change in serum testosterone with CC and TGRT therapy, and change in the androgen deficiency in aging male (ADAM) questionnaire scores with CC therapy.
METHODS:Men receiving CC or TGRT with either Androgel 1% or Testim 1% for hypogonadism (defined as testosterone < 300 ng/mL) or MI were included. Serum values were collected 1-2 months after treatment initiation and semi-annually thereafter. Retrospective data collection was performed via chart review. Subjective follow up of patients receiving CC was performed via telephone interview using the ADAM questionnaire.
RESULTS:A hundred and four men (65 CC and 39 TGRT) were identified who began CC (50 mg every other day) or TGRT (5 g). Average age (years) was 42(CC) vs. 57 (TGRT). Average follow up was 23 months (CC, range 8-40 months) vs. 46 months (TGRT, range 6-149 months).
‘Average posttreatment testosterone was 573 ng/dL in the CC group and 553 ng/dL in the TGRT group (P value < 0.001). The monthly cost of Testim 1% (5 gm daily) is $270, Androgel 1% (5 gm daily) is $265, and CC (50 mg every other day) is $83. Among CC patients, the average pretreatment ADAM score was 4.9 vs. 2.1 at follow up (P < 0.05). Average pretreatment ADAM sexual function domain score was 0.76 vs. 0.23 at follow up (P < 0.05). There were no adverse events reported.
CONCLUSION:CC represents a treatment option for men with hypogonadism, demonstrating biochemical and clinical efficacy with few side effects and lower cost as compared with TGRT.
The Journal of Clinical Endocrinology & Metabolism January 1, 2011 vol. 96 no. 1 38-52 Why Is Androgen Replacement in Males Controversial? Glenn R. Cunningham and Shivani M. Toma Baylor College of Medicine and St. Luke’s Episcopal Hospital, Houston, Texas 77030 2009
IDrugs. 2009 Feb;12(2):109-19.
Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men. Hill S, Arutchelvam V, Quinton R. Department of Clinical Pharmacology & Therapeutics, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.
Enclomiphene (Androxal), in development by Repros Therapeutics Inc, is a non-steroidal estrogen receptor antagonist that promotes gonadotropin-dependent testosterone secretion by the testes. Enclomiphene constitutes the trans-stereoisomer of clomiphene citrate, a drug that has been widely prescribed for several decades for the treatment of female ovulatory dysfunction. Because of the antagonistic effects of enclomiphene, the drug has the potential to increase serum testosterone levels in men with secondary hypogonadism by restoring physiological endogenous testosterone secretion while maintaining testicular volume and, potentially, spermatogenesis. In clinical trials conducted to date, enclomiphene demonstrated significant efficacy in the physiological restoration of testosterone levels in males with secondary hypogonadism. The compound also exhibited an unanticipated favorable effect on fasting plasma glucose; this result has been accompanied by rapidly accumulating evidence from other researchers for a bidirectional relationship between low serum testosterone and obesity/metabolic syndrome (syndrome X) in men. Short-term clinical safety data for enclomiphene have been satisfactory and equivalent to safety data for testosterone gels and placebo.
Enclomiphene demonstrates promise in the management of secondary hypogonadism associated with obesity, metabolic syndrome and, possibly, infertility, and should undergo placebo-controlled, randomized clinical trials for these indications.
Expert Opin Investig Drugs. 2009 Dec;18(12):1947-55. Clomiphene citrate and enclomiphene for the treatment of hypogonadal androgen deficiency. Kaminetsky J, Hemani ML. NYU Langone Medical Center – Department of Urology, New York, New York 10016, USA.
Hypogonadism has a number of important clinical consequences related to androgen deficiency and impaired spermatogenesis. The cause of this condition is multifactorial and can result from hypothalamic, pituitary or gonadal dysfunction as well as factors that affect hormonal signaling along the hypothalamic-pituitary-gonadal axis. While testosterone replacement is the most common treatment, it canparadoxically lead to infertility, and may be a less physiologic therapy for patients with secondary hypogonadism due to pituitary dysfunction. Clomiphene citrate, and its derivatives, may allow for restoration of gonadal function by restoring physiologic pituitary function in a subset of patients with hypogonadism.
Fertil Steril. 2006 Nov;86(5):1513.e5-9. Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate. Ioannidou-Kadis S, Wright PJ, Neely RD, Quinton R. Department of Endocrinology, Royal Victoria Infirmary and University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom.
Inhibition of pituitary gonadotropin secretion in men by T is principally mediated by aromatization to estrogen (E), which inhibits hypothalamic secretion of GnRH. We hypothesized that adult-onset isolated hypogonadotropic hypogonadism (IHH) might result from an altered central set-point for E-mediated negative feedback. Longitudinal clinical investigation unit-based evaluation of the clinical and biochemical response to E-receptor blockade.
A 31-year-old man presenting with an 18-month history of sexual dysfunction resulting from severe adult-onset IHH (LH 1.7 U/L, FSH 2.0 U/L, T 3.5 nmol/L). Initial therapy with 50 mg of clomiphene citrate (CC) three times a day for 7 days, with overnight LH pulse profiling and 9 am T levels evaluated at baseline and on completion. A 2-month washout period, followed by low-dose maintenance therapy (25-50 mg/d) for 4 months.
MAIN OUTCOME MEASURE(S):Baseline and stimulated T levels and LH pulsatility; effect on sexual function.
RESULT(S):Clomiphene therapy resulted in complete normalization of pulsatile gonadotropin secretion, serum T level, and sexual function. CONCLUSION(S):Isolated hypogonadotropic hypogonadism may result from an acquired defect of enhanced hypothalamic sensitivity to E-mediated negative feedback. Whereas direct T replacement therapy can further suppress endogenous gonadotropin secretion, treating IHH men with gonadotropins can stimulate endogenous T secretion and enhance fertility potential. On theoretical grounds, reversal of gonadotropin deficiency with CC might be expected to have a similar biological effect.
Fertil Steril. 2006 Dec;86(6):1664-8. Epub 2006 Sep 27.
Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate.
Whitten SJ, Nangia AK, Kolettis PN. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Alabama, Birmingham, Alabama 35249-7333, USA.
OBJECTIVE: To review the management of male hypogonadotropic hypogonadism (HH) and evaluate the efficacy of clomiphene citrate (CC). DESIGN:Retrospective review.
SETTING:Two university-based urology clinics.
PATIENT(S):Ten patients referred for male infertility evaluation.
INTERVENTION(S): Patients were treated with either clomiphene citrate or injectable gonadotropins.
MAIN OUTCOME MEASURE(S): Changes in seminal parameters, gonadotropin levels, serum testosterone, and pregnancy.
RESULT(S): Ten men who were evaluated for infertility were diagnosed with HH. Four had Kallmann’s syndrome, four idiopathic HH, and two panhypopituitarism. Eight patients were azoospermic, and two were oligospermic on presentation. Three of the four men with adult-onset idiopathic HH responded to CC alone with increases in testosterone, FSH, and LH. Semen parameters in this group also improved, and two of the three men achieved pregnancies with CC alone. Out of the ten men actively attempting conception, four pregnancies were achieved. Three pregnancies (two with CC and one with gonadotropins) were in men diagnosed with adult-onset idiopathic forms of HH.
CONCLUSION( S): Select patients with adult-onset idiopathic forms of HH may benefit from a trial of clomiphene citrate.
2003 Clomid Restores T after steroid abuse
Fertil Steril. 2003 Jan;79(1):203-5. Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Tan RS, Vasudevan D. Department of Family and Community Medicine, University of Texas Health Sciences Center, Houston, Texas 77030, USA. To report a case of symptomatic hypogonadism induced by the abuse of multiple steroid preparations that was subsequently reversed by clomiphene. DESIGN: Case report.
SETTING:University-affiliated andrology practice within family practice clinic.
PATIENT(S):A 30-year-old male.
INTERVENTION(S): Clomiphene citrate, 100-mg challenge for 5 days, followed by treatment at same dose for 2 months.
MAIN OUTCOME MEASURE(S): Clinical symptoms, androgen decline in aging male questionnaire, total T, FSH, LH.
RESULT(S): Reversal of symptoms, normalization of T levels with LH surge, restoration of pituitary-gonadal axis.
CONCLUSION(S): Clomiphene citrate is used typically in helping to restore fertility in females. This represents the first case report of the successful use of clomiphene to restore T levels and the pituitary-gonadal axis in a male patient. The axis was previously shut off with multiple anabolic steroid abuse.
Fertil Steril. 1997 Apr;67(4):783-5. Idiopathic hypogonadotropic hypogonadism in a male runner is reversed by clomiphene citrate. Burge MR, Lanzi RA, Skarda ST, Eaton RP. University of New Mexico School of Medicine, Department of Medicine/Endocrinology-5ACC, Albuquerque 87131, USA.
To assess the efficacy of estrogen antagonist therapy on the function of the hypothalamic-pituitary-testicular axis in a young male runner with significant morbidity attributable to idiopathic hypogonadotropic hypogonadism.
DESIGN: An uncontrolled case study.
SETTING: The outpatient endocrinology clinic of a university tertiary referral center. PATIENT(S): A 29-year-old male who has run 50 to 90 miles per week since 15 years of age and who presented with a pelvic stress fracture, markedly decreased bone mineral density, and symptomatic hypogonadotropic hypogonadism.
INTERVENTION(S): Clomiphene citrate (CC) at doses up to 50 mg two times per day over a 5-month period.
MAIN OUTCOME MEASURE(S): Serum concentrations of LH, FSH, and T before and after CC therapy, as well as clinical indicators of gonadal function.
RESULT(S): Barely detectable levels of LH and FSH associated with hypogonadal levels of T were restored to the normal range with CC therapy.
The patient experienced improved erectile function, increased testicular size and sexual hair growth, and an improved sense of well being.
CONCLUSION(S): Exercise-induced hypogonadotropic hypogonadism exists as a clinical entity among male endurance athletes, and CC may provide a safe and effective treatment option for males with debilitating hypogonadism related to endurance exercise.
J Sex Med. 2005 Sep;2(5):716-21. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism.
Shabsigh A, Kang Y, Shabsign R, Gonzalez M, Liberson G, Fisch H, Goluboff E. Department of Urology, NY Presbyterian Medical Center, New York, NY, USA.
Symptomatic late-onset hypogonadism is associated not only with a decline in serum testosterone, but also with a rise in serum estradiol.
These endocrine changes negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Currently, the most common treatment is exogenous testosterone therapy. This treatment can be associated with skin irritation, gynecomastia, nipple tenderness, testicular atrophy, and decline in sperm counts.
In this study we investigated the efficacy of clomiphene citrate in the treatment of hypogonadism with the objectives of raising endogenous serum testosterone (T) and improving the testosterone/estrogen (T/E) ratio.
METHODS: Our cohort consisted of 36 Caucasian men with hypogonadism defined as serum testosterone level less than 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate and followed prospectively. Analysis of baseline and follow-up serum levels of testosterone and estradiol levels were performed.
RESULTS: The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 +/- 39.8 ng/dL and 32.3 +/- 10.9, respectively. By the first follow-up visit (4-6 weeks), the mean testosterone level rose to 610.0 +/- 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). There were no side effects reported by the patients.
CONCLUSIONS: Low dose clomiphene citrate is effective in elevating serum testosterone levels and improving the testosterone/estradiol ratio in men with hypogonadism. This therapy represents an alternative to testosterone therapy by stimulating the endogenous androgen production pathway.
Int J Impot Res. 2003 Jun;15(3):156-65. Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit? Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E. Center for Sexual Function (Endocrinology), Peabody, Massachusetts 01960, USA.
Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate, but with a modest effect on sexual function. We wondered if longer treatment would produce improved results.
A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone (P<0.001) and free testosterone (P<0.001) occurred in all patients.
Multivariable analysis showed that responses decreased significantly with aging (P<0.05). Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED.For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.
The off-label use of clomiphene tablets in young males to relieve symptoms of low testosterone is becoming more popular because it preserves fertility, and is less expensive and more convenient than testosterone injections. Best results are obtained in males of child bearing ages (30 – 50 yrs of age) with hypothalamic dysfunction, (ie. low FSH/LH, and good testicular reserve which can respond to FSH/LH stimulation) Before starting clomiphene, the patient should be conversant with the adverse effects of treatment.
Above left image: Retina of the left eye shows retinal vein occlusion resulting in hemorrhages and exudates marked by Green Arrows, courtesy of wikimedia commons.
Review of the Medical Literature on Adverse Effects of Clomiphene
Dr Viola from Capetown South Africa reviewed the medical literature on common adverse effects of clomiphene treatment, mostly in women. She found 35 articles on the topic and published her report in 2011. She found that blurred visual and other visual effects were most commonly reported about 1.5% of the time.(1)
“Visual adverse events with the use of CC in clinical studies was reported as 1.5%. These include blurred vision, photophobia, diplopia, scotomata, phosphenes and periphlebitis.”(1)
Dr. Viola also reported on central retinal vein occlusion as an adverse effect of clomipene.(1)
Central Retinal Vein Occlusion in a Male
Although a number of reports of retinal vein occlusion have been reported in women using clomiphene (Clomid) as a fertility treatment to induce ovulation, only one is reported in a 35 year old male undergoing fertility treatment with Clomiphene. This male patient had an underlying inherited thrombophilia, with Factor V Leiden and MTHFR polymorphism.(2) His retinal vein occlusion, due to thrombosis of the vein, was treated with Plavix (clopidogrel) with recovery. Dr Politou suggests young men should be screened for Factor V Leiden before starting Clomiphene.
Visual Disturbances-Blurred Vision
Dr. Purvin from Methodist Hospital in Indiana reported on visual disturbances from Clomiphene in three women undergoing fertility treatment for 4-12 months.(9)
” All three patients experienced prolonged afterimages (palinopsia), shimmering of the peripheral field, and photophobia while undergoing treatment with clomiphene. The results of the neuro-ophthalmologic examination and electrophysiologic studies were normal in all three patients. Unlike previously reported cases, visual symptoms did not resolve on cessation of treatment. Patients remain symptomatic from 2 to 7 years after discontinuing treatment with the medication.”(9)
“The most common side-effect is without question blurred vision; while this may be a problem for some Clomid users it will dissipate once use is discontinued. “(9)
One case of bilateral uveitis (inflammation of the eye) was described in a 30 year old female on clomiphene.(8) One case of elevated liver enzymes was reported (7)
In women undergoing fertility treatment with prolonged high dose Clomiphene, various central nervous system adverse effects have been reported including induction of psychosis, nervousness, sleeplessness, headaches, visual disturbances, vertigo.(3,4,5)
Psychological Effects on Mood
In a 2005, large self-reported survey of women on Clomiphene and HMG adverse psychological effects were reported including, Irritability, mood swings, and feeling down.(6)
Estrogen and HyperCoagulable State
Most adverse effects of clomiphene are reported for female fertility treatment using high dose Clomiphene. I would speculate that most of the adverse effects are due to high estrogen levels known to cause hypercoagulable state.(10,11)
Anastrazole to Keep Estrogen Levels Low and Prevent Hypercoagulation.
Adverse effects from off-label use of clomiphene is less commonly reported in the medical literature in males than in females, possibly because of the lower dosage used. Females dosage is 50-200 mg per day, while for males, we use the lower dosage of 12.5 mg every other day up to 25 mg per day.
Estrogen and Hypercoagulable State
For female patients undergoing fertility treatment to induce ovulation, elevated estrogen is part of the desired outcome. Estrogen levels may rise by a factor of one hundred (100 times higher than pre-treatment levels), inducing a hypercoagulable state.(10,11) Quite the opposite in males, clomiphene induced elevated estrogen is an undesirable side effect, preventable with an aromatase inhibitor (anastrazole).
In males, central retinal vein occlusion with underlying inherited thrombophila mutation has been reported.(2) The authors say the causal mechanism is unknown. I would differ, and suggest the cause is high estrogen induced by clomiphene stimulation. High estrogen causes a hypercoagulable state.(10,11) An aromatase inhibitor (anastrazole) prevents the high estrogen level, and therefore prevent the rare thrombotic complication, such as the retinal vein occlusion in the inherited thrombophilia male patient. (2) I would suggest a prudent practice would be to use an aromatase inhibitor with the clomiphene.