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Tamoxifen en clomid literatuuroverzicht

Topic in 'Anabolen' gestart door Galen, 3 jul 2012.

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  1. Galen

    Galen Peter Bond Super Mod Elite Member Topic Starter

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    Notes: Er staan hele rare spelfouten in de tekst hier op het forum door het copy pasten vanuit de PDF. Kon het ook copy pasten vanuit m'n TEX file maar dan moest ik al die latex shit er weer uit halen. De PDF is uiteraard ook gewoon toegevoegd. Dit is overigens puur bedoeld als overzicht van beide SERMs.

    Tamoxifen and clomiphene for the bodybuilder: a literature overview
    GetXXL
    July 3, 2012

    Abstract
    Tamoxifen and clomiphene are selective estrogen receptor modulators (SERMs), commonly used as post cycle therapy (PCT) after a cycle of (androgenic) anabolic steroids (AAS), to restore testosterone levels. In this article I have gathered relevant clinical trials in which the results of these SERMs on hormone levels were measured in men.

    Introduction
    Tamoxifen (trade names: Nolvadex, Istubal and Valodex) was first discovered in 1962 by Dr. Arthur L. Walpole [1]. And it was some 11 years later in 1973, until it first hit the market, being approved by the Committee on the Safety of Medicines in the United Kingdom, marketed under the brandname Nolvadex. Four years later, in 1977, similar approval was given in the United States
    of America by the Food and Drug Administration (FDA). Clomiphene (trade names: Clomid, Milophene and Serophene) was first discovered in 1956 by the Merrel company [2]. In 1967 the FDA approved clomiphene for clinical usage. Since approval, both substances have been used for the treatment of breast cancer and induction of ovulation, and till date, they still are being widely used for this purpose. The purpose of this article, however, is to display the results of both substances on hormonal levels in men. In 1975 the first review appeared evaluating these drugs, termed antioestregens, in which also the role of these drugs in male fertility was reviewed [3]. Knowledge bout both the drugs and the effects on men were very limited at the time. Luckily, in the years to come, both drugs have been intensively been researched, also in men.

    Literature overview
    Using both PubMed and Google Scholar, I have gathered as much relevant studies as possible on the subject. In table 1 I have outlined the relevant studies concerning the effect on testosterone (T) levels. When provided, the effect on free testosterone (FT) levels is included.

    Willis et al.[5] was the oldest study I could obtain, published in 1977. They measured the hormonal effects of tamoxifen in 9 oligospermic men. 10 mg tamoxifen was given daily to the subjects for 6 months. After 4 months, blood samples were taken, and a significant increase in testosterone was measured. This study, also conducted a short term (7 days) trial of tamoxifen in 5 normal men. On this short term, with only 10 mg daily, a significant increase in testosterone was observed, however, the authors note that no change in basal LH, FSH or gonadotrophin response to GnRH was produced during the short trial. The authors speculate that tamoxifen might stimulate the gonad directly, or alter its sensitivity to gonadotrophin, or that it has some effect on prolactin secretion. Vermeulen et al.[4] was the second oldest study I could obtain concerning the subject. The study, published in 1978, was the very rst to measure hormonal effects in normal men treated with either SERM. The study evaluated the effects of both SERMs in a short term trial of 10 days on normal men, resulting in comparable effects on testosterone, LH and FSH levels. However, the pituitary response to GnRH after the administration of clomiphene, was characterized by a decrease in the LH response, the authors report. This was not the case for tamoxifen. The decreased response might very well be due to the high dosage (150 mg daily) used in the study, as later trials showed no decreased response to GnRH at lower dosages. They also conducted two longer term trials. One of 6 weeks, in which 20 mg of tamoxifen was given to 4 normal men every day. An enhanced response of both LH and FSH was observed compared to the 10 days of treatment, and testosterone levels also further raised. The other one was a 9 month trial in which 20 mg of tamoxifen was given to 21 oligospermic men. The authors observed that FSH levels tended to decline after prolonged tamoxifen treatment. But also in these patients; testosterone, LH and FSH were significantly increased.
    Years passed, and many more trials were conducted in which the hormonal effects were being measured after treatment with either SERM, as can be seen in table 1. Unfortunately, I was unable to find any study measuring the hormonal effects of tamoxifen on hypogonadal men. However, it is unlikely that, due to the nature of the drug, hypogonadal men would not benefit from it.

    Luckily, there are five trials in which the hormonal effects of clomiphene on hypogonadal men were measured [10][11][12][18][19].
    Guay et al. [11] conducted a double blind placebo-controlled trial with clomiphene in which 17 men, diagnosed with secondary hypogonadism, were given 50 mg of clomiphene three times a week, for 2 months. LH, FSH and testosterone all increased significantly. The increase of testosterone after 2 months was almost identical to the increase measured after 1 month (with a negligible decrease after the first month). In this trial, free testosterone was also measured, which rose parallel to total testosterone. In a further secondary analysis, the patients were separated by men with or without diabetes, hypertension or both. The stimulated total testosterone level was not dierent in the two groups, but the free testosterone level showed a trend toward significance (P < 0.11) in men without diabetes or hypertension, the authors note. Yet due to the small sample size, it is hard to proof significance and further studies are warranted to draw conclusions.

    In 2003, Guay et al. conducted a bigger trial, with not 17, but 173 hypogonadal men. The protocol remained the same, 50 mg of clomiphene three times a week, except for 4 months this time, instead of 2. The increase in free testosterone was comparable to that of the previous conducted study. An increase in free testosterone of 78% and 104% were measured in the previous and this study, respectively (total testosterone was not measured in the 2003 trial). The moderate difference can most likely be contributed to the longer duration of the 2003 trial. Both studies do note a significant association between increasing age and a decreasing response to clomiphene. In the 2003 trial, even after correction for several clinical predictors, this association was still very strong. Furthermore, of all clinical predictors of patient response, only diabetes approached statistical significance. Patiens with diabetes were 55% less likely than patients without diabetes to respond to clomiphene therapy (P = 0:06), the authors note. Notably, cigarette smokers had no difference in response compared to nonsmokers. Whereas the patients in both studies of Guay et al. were relatively old (mean of 60 years for the 1995 trial and 54 years for the 2003 trial), the mean of the age of the hypogonadal men in the study performed by Shabsigh et al. [10] in 2005, was 39 years. As was stated by Guay et al. there is an association between increasing age and decreasing response to clomiphene. Furthermore, there appears to be a steady decline of testosterone with age in men [24]. A recent study suggests this may be due to accumulating age-related co-morbidities [25]. Nevertheless, the association remains.

    Shabsigh et al. report an increase in testosterone of 146% after 4-6 weeks of 25 mg clomiphene daily. The slight positive increase between this study and Guay et al. (2003) might partly be due to the mean age difference between both studies. However, both studies do also differ in dosing protocol (50 mg three times a week in Guay et al. vs 25 mg every day in Shabsigh et al.) and duration (2 months in Guay et al. vs 4-6 weeks in Shabsigh et al). Although the latter isn't likely to positively influence the testosterone levels. Furthermore, as stated before, the difference is small. Unfortunately, Shabsigh et al. did not report free testosterone levels.

    Another notable study is the trial conducted by Tenover et al. [16] in 1991. The patients (n=10) were in normal health and received 100 mg clomiphene daily for 2 months. An increase in total testosterone of 233% was observed, and furthermore, an extreme increase of non-coïtus hormone-binding globulin bound testosterone (nSHBG-T) of 961% was observed. The goal of the study was to assess the question of age-related testicular dysfunction by evaluating whether raising serum gonadotropins above normal serum range for an extended time in healthy elderly men might result in bringing their gonadal function to a similar level of that found in young adult men. For this study, 5 healthy young adult men (mean age 29 years) and 5 healthy older men (mean age 73 years) were recruited. And indeed, if we look at the raise in nSHBG-T after 2 months of clomiphene, the response is hugely dierent between both groups. The 961% increase noted before, is the average of both groups, if we would only observe the young men, an increase of 1410% in nSHBG-T comes to light. Although the elderly men also had a big increase in nSHBG-T (512%), there still remains a big gap between both age groups. Total testosterone in the young men and elderly men increased with 268% and 198% respectively. As androgen clearance does not increase with normal aging, the lower serum levels of androgens in the elderly men suggest decreased Leydig Cell production, the authors note.

    Last, but certainly not least are the two remaining trials I haven't discussed yet in which clomiphene was given to hypogonadal men. And that isn't the only thing these two have in common; they also have a very long treatment phase.

    In 2011, Katz et al.[18] published a study in which 86 hypogonadal men were evaluated, given 25 mg clomiphene every other day and titrated to 50 mg every other day. The mean age of the patients was 29 years old, and the mean duration of the study was 19 months. The patients were generally very healthy. Total testosterone, free testosterone, oestradiol, LH and FSH were all increased significantly after treatment. Notably, SHBG remained the same throughout the treatment. As can be seen in table 1, testosterone increased with 152% and free testosterone with 332%. It should be noted that although both testosterone and oestradiol increased, the relative increase of oestradiol was higher, leading to a testosterone : oestradiol ratio of 12.4 at last follow-up, while the ratio was 7.4 at baseline. However, no patient developed gynaecomestia. There were no major side effects recorded from the treatment and no patient ceased treatment because of adverse events. Clomiphene is an effective and safe alternative to testosterone supplementation therapy in hypogonadal men, the authors conclude.

    A similar study to that of Katz et al. was published in 2012, by Moskovic et al.[19]. 46 hypogonadal men received clomiphene treatment and the mean age was 44 years (slightly older than in Katz et al.) A total of 46 patients had 12 months of clomiphene treatment, 37 patients had >2 years' treatment and 29 patients had >3 years' treatment. After 1 year of treatment, testosterone was increased with 168%. The testosterone levels, however, dropped slightly over the next 24 months of treatment. Additionally, bone densitometry results were collected for all patients to define their bone mineral density. At baseline, 28% of patients had normal bone densitometry at baseline, this rose to 50%, 48% and 55% at years 1, 2 and 3 respectively. The propertion of patients with osteoporosis was 13% at baseline and 6%, 6% and 3% respectively at the follow-up time points. Patients were free of side-effects, suggesting that clomiphene is effective in long-term management of hypogonadism, the authors note, in line with the findings of Katz et al.

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    References
    [1] Jordan VC, The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole. Breast Cancer Research and Treatment 11:197-209 (1988).
    [2] Macklon NS, Stouer RL, Giudice LC, Fauser BC, The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev 2006; 27: 170-207.
    [3] Lunan CB, Klopper A, Antioestrogens: a review. Clinical Endocrinology (1975) 4, 551-572.
    [4] Vermeulen A, Comhaire F, Hormonal eects of an antiestrogen, Tamoxifen, in normal and oligospermic men. Fertility and Sterility, Vol. 29, No. 3, March 1978.
    [5] Willis KJ, London DR, Bevis MA, Butt WR, Lynch SS, Holder G, Hormonal effects of tamoxifen in oligospermic men. J. Endocr. (1977), 73, 171-178.
    [6] Dony JMJ, Smals AGH, Rolland R, Fauser BCJM, Thomas CMG, Effect of lower versus higher doses of tamoxifen on pituitary-gonadal function and sperm indices in oligozoospermic men. Andrologia 17 (4): 369-378 (1985).
    [7] Kadioglu TC, Koksal IT, Tunc M, Nane I, Tellaloglu S, Treatment of idiopathic and postvaricocelectomy oligozoospermia with oral tamoxifen citrate. BJU Int. 1999 Apr;83(6):646-8.
    [8] Kadioglu TC, Oral tamoxifen citrate treatment is more eective in normogonadotropic patients who have follicle-stimulating hormone levels within the lower half of normal. Int Urol Nephrol (2009) 41:773-776.
    [9] Birzniece V, Sata A, Sutanto S, Ho KKY, Neuroendocrine regulation of growth hormone and androgen axes by selective estrogen receptor modulators in healthy men. J Clin Endocrinol Metab 95: 5443-5448, 2010.
    [10] Shabsigh A, Kang Y, Shabsign R, Gonzalez M, Liberson G, Fisch H, Golubo E, Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716-721.
    [11] Guay AT, Bansal S, Heatley GJ, Eect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 80: 3546-3552, 1995.
    [12] Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E, Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit? International Journal of Impotence Research (2003) 15, 156{165.
    [13] Adamopoulos DA, Vassilopoulos P, Kapolla N, Kontogeorgos L, The effect of clomiphene citrate on coïtus hormone binding globulin in normospermic and oligozoospermic men. Int J Androl. 1981 Dec;4(6):639-45.
    [14] Adamopoulos DA, Nicopoulou S, Kapolla N, Karamertzanis M, Andreou E, The combination of testosterone undecanoate with tamoxifen citrate enhances the effects of each agent given independently on seminal parameters in men with idiopathic oligozoospermia. Fertil Sterile 1997;67:756-62.
    [15] Tenover JS, Matsumoto AM, Plymate SR, Bremner WJ, The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate. J Clin Endocrinol Metab 65: 1118, 1987.
    [16] Tenover JS, Bremner WJ, The effects of normal aging on the response of the pituitary-gonadal axis to chronic clomiphene administration in men. J Androl 1991;12:258-263
    [17] Buvat J, Ardaens K, Lemaire A, Gauthier A, Gasnault JP, Buvat-Herbaut M, Increased sperm count in 25 cases of idiopathic normogonadotropic oligospermia following treatment with tamoxifen. Fertil Steril. 1983 May;39(5):700-3.
    [18] Katz DJ, Nabulsi O, Tal R, Mulhall JP, Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU Int. 2011 Nov 1.
    [19] Moskovic DJ, Katz DJ, Akhavan A, Park K, Mulhall JP, Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU Int. 2012 Mar 28.
    [20] Cakan M, Aldemir M, Topcuoglu M, Altug U, Role of testosterone/estradiol ratio in predicting the ecacy of tamoxifen citrate treatment in idiopathic oligoasthenoteratozoospermic men. Urol Int. 2009;83(4):446-51.
    [21] Novoa FJ, Boronat M, Carrillo A, Tapia M, Daz-Cremades J, Chirino R, Effects of tamoxifen on lipid prole and coagulation parameters in male patients with pubertal gynecomastia. Horm Res. 2002;57(5-6):187-91.
    [22] Clarke SC, Schoeld PM, Grace AA, Metcalfe JC, Kirschenlohr HL, Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation. 2001 Mar 20;103(11):1497-502.
    [23] Krause W, Holland-Moritz H, Schramm P, Treatment of idiopathic oligozoospermia with tamoxifen: a randomized controlled study. Int J Androl. 1992 Feb;15(1):14-8.
    [24] Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001 Feb;86(2):724-31.
    [25] Sartorius G, Spasevska S, Idan A, Turner L, Forbes E, Zamojska A, Allan C, Ly L, Conway A, McLachlan R, Handelsman D, Serum Testosterone, Dihydrotestosterone and Estradiol Concentrations in Older Men Self-Reporting Very Good Health:The Healthy Man Study. Clin Endocrinol (Oxf). 2012 May 7
     
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  2. Nomen Nescio

    Nomen Nescio Died Twice. Elite Member

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  3. suwardi

    suwardi Ripped Bodybuilder

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    in for later dankje
     
  4. Cools

    Cools Colossal Veteran +10 jaar member

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  5. Antonios

    Antonios Cool Novice

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    Off topic: Mijn moeder gebruikt ook tamoxifen. Dat zou de kans dat haar borstkanker terug komt verkleinen.

    Thanks voor het leesvoer! :)
     
  6. MrJ

    MrJ 10 year + member Elite Member +15 jaar member

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    Top stukje dit! :thumb:
     
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    Peanuthead95 Vrouwen oppik artiest Elite Member

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    Mooi geschreven stukje, verdient een bump.
     
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