Clomiphene in Men

[CognitiveNutrition]

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.

OBJECTIVE: 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. DESIGN AND SETTING: Longitudinal clinical investigation unit-based evaluation of the clinical and biochemical response to E-receptor blockade. PATIENT(S): 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). INTERVENTION(S): 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. sjwmd@yahoo.com sjwmd@yahoo.com

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.

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.

AIM: 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. andre.t.guay@lahey.org

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.

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. robert.s.tan@uth.tmc.edu

OBJECTIVE: 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.

[CognitiveNutrition]

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.

OBJECTIVE: 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.

Pol Tyg Lek. 1996 Feb;51(6-9):73-4.
[Results of tests with clomiphene and choriogonadotropin in men with oligozoospermia treated with longterm antiestrogens]

Medraś M, Terpiłowski L, Kiełkiewicz D, Winowski J, Ziotas G. Katedry i Kliniki Endokrynologii Akademii Medycznej we Wrocławiu.
The evaluation was made of the response to testosterone and oestradiol in the test (50 mg twice daily for 10 days) and HCG test (6000 units of Biogonadyl through 2 days) performed on 21 normospermic (fertile) males and on patients with normogonadotropic, idiopathic oligozoospermia, positively (12 patients) or negatively (24 males) reacting to the longterm Clostilbegyt treatment (50 mg daily for 240 days). It was shown that patients with oligozoospermia who do not react with an increase of spermatozoa during the longterm antioestrogen treatment had higher response of oestradiol in the dynamic test (+ 118.9%) than the normospermic males (+ 60.8%) or the oligozoospermic who showed positive semenologic response to the treatment (+ 58.8%). The similar reaction of oestradiol was shown in the HCG stimulation. In the hiperoestrogenism phenomenon the authors noticed the cause of lack of positive semenologic effects of the longterm antioestrogen treatment.

J Androl. 1991 Jul-Aug;12(4):258-63.
The effects of normal aging on the response of the pituitary-gonadal axis to chronic clomiphene administration in men.

Tenover JS, Bremner WJ. Department of Medicine, University of Washington School of Medicine, Seattle.

Serum androgens decline with age in normal men, despite normal or elevated bioactive serum gonadotropins, suggesting that primary testicular dysfunction occurs with aging. The authors further assessed the question of age-related testicular dysfunction by evaluating whether raising serum gonadotropins above the normal serum range for an extended time in healthy elderly men might result in bringing their gonadal function to a level similar to that found in young adult men. Five elderly (65 to 85 years old) and five young adult men (26 to 33 years old) were given 50 mg of clomiphene citrate (CC) twice a day for 8 weeks to stimulate gonadotropin production. During that time, testosterone (T), non-sex hormone-binding globulin bound T, and estradiol increased significantly in both age groups, while serum inhibin increased significantly only in the young adult men. The increases in serum androgens with CC administration were significantly greater in the young adult men than in the elderly men. These hormone changes occurred in the setting of serum gonadotropins that increased significantly in both age groups, although there was a tendency for the elderly men to have a smaller increase in luteinizing hormone. Despite 8 weeks of stimulation of the pituitary-gonadal axis by CC administration, the elderly men demonstrated significantly diminished testicular responses compared with the young adult men. Sertoli cell function, as determined by inhibin production, was more diminished in the elderly men than was Leydig cell function. These data strengthen the hypothesis that normal aging in men is accompanied by a decline in testicular function.

[CognitiveNutrition]

J Clin Endocrinol Metab. 1987 Dec;65(6):1118-26. Links
The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate.

Tenover JS, Matsumoto AM, Plymate SR, Bremner WJ. Geriatric Research, Education, and Clinical Center, Veterans Administration Medical Center, Seattle, Washington.

Serum testosterone (T) levels in men decline with age while serum LH levels, as measured by RIA, increase. To assess if the decline in serum T levels in healthy aging men is paralleled by an age-related decline in the bioavailable non-sex hormone-binding globulin (SHBG)-bound fraction of T and to determine whether there are age-related changes in LH secretion or LH control of T production, we studied 29 young (aged 22-35 yr) and 26 elderly (aged 65-84 yr) healthy men. All men had single random blood samples drawn, and 14 men in each age group underwent frequent blood sampling for 24 h, both before and after 7 days of clomiphene citrate (CC) administration. Both mean 24-h serum total T levels and non-SHBG-bound T were reduced in elderly men compared to those in young men (P less than 0.05), while estradiol and SHBG levels were similar in the 2 age groups. Serum FSH determined by RIA and LH by RIA and bioassay were higher in the elderly men compared to those in young men (P less than 0.05), but the ratios of LH bioactivity to immunoreactivity and the LH pulse frequency and amplitude were similar. After CC administration, mean serum total T and non-SHBG-bound levels in young men increased by 100% and 304%, respectively, while in older men these values increased by only 32% and 8%, respectively. However, CC-stimulated LH pulse characteristics and serum levels of estradiol, SHBG, FSH, and bioactive and immunoreactive LH were similar in the 2 groups. Thus, both at baseline and after CC stimulation, elderly men had significantly lower serum total T and non-SHBG-bound (bioavailable) T levels than did young men, despite similar or increased levels of bioactive LH and similar bioactive to immunoreactive LH ratios and LH pulse characteristics. These results suggest that major age-related changes in the hypothalamic-pituitary-testicular axis occur at the level of the testes and are manifested by decreased responsiveness to bioactive LH. Administration of CC to young and elderly men resulted in similar changes in LH pulse characteristics and LH bioactivity and immunoreactivity, suggesting preserved hypothalamic-pituitary responsiveness in the elderly.


J Clin Endocrinol Metab. 1987 Jun;64(6):1103-8.
Serum bioactive and immunoreactive follicle-stimulating hormone levels and the response to clomiphene in healthy young and elderly men.

Tenover JS, Dahl KD, Hsueh AJ, Lim P, Matsumoto AM, Bremner WJ.

Testicular function declines with normal aging, while serum immunoreactive LH and FSH levels increase. Since there are reports of an age-related decrease in the ratio of bioactivity to immunoreactivity (B/I ratio) for LH, we used a newly available bioassay for FSH to assess age-associated changes in the bioactivity and B/I ratio of FSH in man. Thirty-nine healthy men (23 young and 16 elderly) had single blood samples drawn. In addition, a subset of these men (12 young and 13 elderly) underwent frequent blood sampling for 24 h, both before and after 7 days of clomiphene citrate (CC) administration. Hourly blood samples from the 24-h sampling were pooled, and these, along with the single samples, were assayed for FSH by an in vitro bioassay system, using estrogen production by immature rat granulosa cells as the end point, and by RIA. Baseline single sample mean FSH, as measured by bioassay, was similar in young and elderly men [386 +/- 98 (+/- SEM) and 342 +/- 77 ng/mL, respectively]. Baseline mean FSH, measured by RIA, was significantly higher (P less than 0.001) in elderly men (234 +/- 31 ng/mL) than in young men (122 +/- 12 ng/mL). The baseline FSH B/I ratio based on single sampling was significantly lower (P less than 0.01) in elderly men (1.4 +/- 0.2) than in young men (2.7 +/- 0.3). In the men given CC and sampled for 24 h, mean bioactive FSH levels increased significantly in both the young (1180 +/- 282 ng/mL) and the elderly (992 +/- 227 ng/mL; P less than 0.01 for both values compared to baseline). Mean FSH by RIA also increased to similar levels in these young (217 +/- 34 ng/mL) and elderly (258 +/- 45 ng/mL) men. The FSH B/I ratio was 4.8 +/- 0.8 in young and 4.7 +/- 1.1 in elderly men after CC administration. We conclude that serum bioactive FSH levels are similar in elderly and young men, suggesting that the age-related decline in testicular function in man cannot be explained by a chronic deficiency in FSH stimulation; elderly men have a lower serum FSH B/I ratio than young men, which may reflect changes in the circulating form of FSH with aging; and administration of CC to young and elderly men increases both bioactive and immunoreactive serum FSH, implying preserved hypothalamic-pituitary responsiveness in the elderly.
Acta Endocrinol (Copenh). 1980 Oct;95(2):177-80
The effect of clomiphene citrate on pubertal gynaecomastia.
LeRoith D, Sobel R, Glick SM.

Clomiphene citrate 100 mg daily was used to treat 28 boys with pubertal gynaecomastia. Six failed to complete the course and of the remaining, 14 (64%) responded within 6 months of commencement of therapy. LH, FSH, testosterone and oestradiol levels rose during therapy. It is suggested that clomiphene affects gynaecomastia locally as an anti-oestrogen.

Int J Androl. 1980 Aug;3(4):417-28
Effect of clomiphene citrate on testicular steroid metabolism in man.

Carlstr?m K, Fredricsson B.

Administration of clomiphene citrate to males with normal peripheral testosterone levels increased the serum levels of FSH, LH, testosterone and low polar oestrogens and also the urinary excretion of LH, low polar oestrogens, dehydroepiandrosterone, androsterone and aetiocholanolone. No significant change was noted for the urinary excretion of 17-oxogenic steroids. Addition of clomiphene citrate (10(-4) to 2 X 10(-3) M) to incubations of [7-3H, 21-14C] progesterone with human testicular biopsy specimens in vitro caused a slight inhibition in the formation of 17 alpha-hydroxyprogesterone and a slightly increased formation of 20 alpha-hydroxy-4-pregnen-3-one but no measurable changes in the C19 steroid formation. The results support the hypothesis that there is selective action of clomiphene citrate upon the adrenal C19 steroid biosynthesis in the human male, combined with an indirect effect upon the testes via the hypothalamic-pituitary system. A direct effect on the gonadal steroidogenesis can, however, not be ruled out.

J Clin Endocrinol Metab. 1975 Jun;40(6):1114-6.
Pituitary-gonadal response to acute I.M. stimulation with clomiphene citrate in normal men.

Miechi HR, Turner D, Guitelman A, Aparicio NJ, Schwarzstein L.

In order to asses the effect of acute i.m. injection of clomiphene citrate (CC) on LH, FSH, and testosterone (T) secretion, five normal, fertile men received 5 mg of the drug dissolved in 2 ml 0.9% saline, while a further five were injected 10 mg of the same preparation. All tests were performed at 8 a.m. Blood samples were drawn at 0, 30, 60, 120 and 180 minutes of the injection. Serum LH, FSH, and T values were determined by the double antibody radioimmunoassay technique. A significant rise of the LH, FSH, and T levels was obtained in both groups. Peak LH values were obtained at 30 minutes (average), whereas FSH and T peaks occurred at 60 minutes. The 180-minute values were similar to basal. The results seem to indicate that intramsucularly administered CC could be useful, as a rapid test, in evaluating the function of the hypothalamic-pituitary-gonadal axis.

[jf1]

cliffs please!

[CognitiveNutrition]

Originally Posted by jackfast1

cliffs please!

LOL ok but give me alittle time to break it down.

[jf1]

Originally Posted by uniquenutrition

LOL ok but give me alittle time to break it down.

i also am interested in this product; the only things that bug me regarding the studies are the small sample size and lack of followup.
understandably, the company doesnt want to talk about adverse effects...

[CognitiveNutrition]

Originally Posted by jackfast1

i also am interested in this product; the only things that bug me regarding the studies are the small sample size and lack of followup.
understandably, the company doesnt want to talk about adverse effects...

Drugs should not be used long term. And this was for an unapproved use. It's hard to get funding for a drug for this purpose thus small sizes. But data is data.