Alternatives to testosterone replacement: Clomiphene ( Clomid )

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Nelson Vergel

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Clomiphene Citrate (CC)


Like HCG, CC was originally designed for female infertility. Approved by the FDA in 1967 it has since become an inexpensive generic drug. It is a selective estrogen receptor modulator comprised of a 38%/62% racemic mixture of cis and trans isomers, zuclomiphene and enclomiphene, respectively.30 It has antagonistic effects on the estrogen receptors in the hypothalamus and the pituitary thereby increasing endogenous gonadotropin releasing hormones, LH and FSH. It ability to increase LH in men was recognized as early at 1968 31 As with all SERMs organ estrogen agonistic effects are also possible. In a study aimed at using CC challenges to diagnose hypogonadotropic hypogonadism, Paulsen demonstrated significant increases in LH,FSH and T in normal older men taking 50 mgs of CC twice a day.32 Sherins et
al33 were able show the CC was able to block the LH and FSH suppression that occurs with exogenous T and estrogen administration, thus demonstrating that estrogen was the primary inhibitory hormone on GnRH , LH and FSH. Over the ensuing decades, CC was used to increase male fertility with mixed results. Though an increase in T and estrogen level was consistently demonstrated, no consistent effect of seminal parameters or pregnancy rates was observed. A 6 month multicenter international placebo controlled study cast doubts on the efficacy of CC on idiopathic male infertility. It is important to realize that in the international study, the infertile population was eugondal with the mean baseline T levels of 481ng dl-1. Well controlled studies in the hypogonadal infertile male are lacking, despite the high prevalence of secondary hypogonadism in this group of men.

Tenover et al34 looked at an 8 week trial of CC (50mg BID) in 5 healthy older and 5 young eugonadal men (mean age 73 vs 29; mean baseline T 518 vs 498) and demonstrated that older men both increased LH and FSH and T and E-2. Though levels of T were significantly lower in the older group, the levels achieved in both groups were well above levels that are achieved with many current day exogenous treatments. Lim observed normalization of testosterone levels in 5 hypogonadal uremic men with uniform increase in libido, sexual potency, and a general sense of well-being using 100 mg of CC daily for as long as 12 months. The normalization of T continued for 4-5 months after discontinuation of therapy. Plasma estradiol levels were elevated at baseline and did not change significantly from baseline.35

Guay el al36 challenged 21 older men with erectile dysfunction and secondary hypogonadism with 50 mg CC bid for 7 days and normalized their T, demonstrating that at that at least in the short term, the concept of testosterone restoration was possible in older men. He then expanded the concept with an eight week double blind placebo controlled crossover study in older men (mean age 62) with secondary hypogonadism and erectile dysfunction (documented with nocturnal penile tumescence scan (NPT). No improvement was seen in NPT or sexual function questionnaires in the group as a whole. When the study population was split between younger and older groups (mean age 53 and 66respectively) in a post hoc analysis, not surprisingly, the differences between the treatment groups with the sexual function questionnaires and NPT testing achieved statistical significance. The older men were more likely to
have “end organ” disease” refractory to hormonal manipulation. This was the first demonstration that CC could not only normalize T levels in SHGD but result in symptomatic improvement. 37 Guay then began treating men in his practice
with SHGD with CC (50 mg) three times a week. He reported an observational series of 173 men with ED and SHGD treated for 4 months. The diagnosis of ED was based on self-report and not a validated questionnaire and a placebo arm was lacking. The outcome was measured as “responder” to treatment (successful intercourse >75% of the time), partial responder (successful intercourse 50%-75% of the time) and non-responder. As in his previous studies, LH, FSH and free testosterone levels increased. Sexual function improved in 75% and did not change in 25%. Age and vascular co- morbidities negatively affected the response rates. 38

Taylor et al in an observational study compared the biochemical efficacy of CC to exogenous gel treatment (TRT) in 104 men (65 CC vs 39 on TRT). The groups were not strictly identical but demonstrated comparable increases in testosterone with a 182 $ monthly savings in the CC group. PSA levels and HCT did not significantly change in follow up (23 months)39 Moskovic demonstrated an excellent chemical response in a younger cohort of 29 men (mean age 44) followed for three years on CC 25 mgs every other day. In addition, despite an unusually high percentage of men with altered bone mineral density at baseline (75%) BMD normalized at one year in 25%. No improvement in BMD was observed after the first year. Though estradiol increased significantly no gynecomastia or breast tenderness occurred. No side effects were reported.40

The efficacy of CC in relieving the symptoms of hypogonadism is often anecdotally reported as being inferior to exogenous therapy without the support of randomized double blind studies. Katz et al retrospectively looked at symptom relief with CC (25mg every other day) in 86 young (mean age 29) hypogonadal men, most of whom were presenting for infertility (57 %) over a 4 year period at a Sloan Kettering andrology practice. The men were followed for a mean of 19 months. Surprisingly the median number of positive baseline responses on the androgen deficiency in aging males (ADAM) questionnaire was 5 that dropped to 2. These “generally very healthy” young men started at a mean T level of 192 ng dl-1 and increased their T to 485 (despite a target treatment level of 550 ng dl-1). The symptoms that showed significant increases included “decreased libido, lack of energy, decreased life enjoyment, sad/grumpy, decreased sports performance”.41 The lack of a placebo arm weakens the strength of the study. Further support of the efficacy of CC in relieving hypogonadal symptoms comes from a retrospectively gathered observational comparative study from Baylor by Ramasamy. In examining the effect of CC vs replacement therapy on hypogonadal symptoms, nosignificant differences were seen in between T injections, T gels or CC. T levels were highest with injections (1104 ng dl-1) vs CC (504 ng dl-1) or the gels (412 ng dl-1).42 The lack of a difference in symptom relief supports the concept that symptom relief may be tied to a threshold level that is achieved with TRES and TREP. Unfortunately pre-treatment quantitative ADAM scores (QADAM) were not reported and the QADAM has not been fully psychometrically validated.

Recently there has been interest in the trans isomer of CC (EC). Distinct differential pharmacokinetics of the two isomers have been demonstrated.43 Though the Cmax, and Tmax were comparable, the AUC for the isomers was dramatically different after a single dose administration of 50 mgs of CC in women with polycystic ovaries. At 456 hours, ZC was detected in 9/9 patients vs 1/9 for EC.44 The half-life of EC is 7-8 hrs. 45 EC was evaluated in an early proof of concept randomized, open-label, fixed dose, active-control (7EC and 5 exogeous gel), two-center phase IIB study in 12 men with secondary hypogonadism treated previously with topical testosterone. After T discontinuation of exogenous T, T levels in both groups average 165ng dl-1. After treatment T levels increased in both groups to over 540 ng dl-1 but decreased to baseline after cessation of treatment suggesting that the hypothalamic testicular axis reverts to its pretreatment state and continued therapy is necessitated. Whereas sperm counts were increased in all men on EC at 6 months only 2 of 5 of gel patients increased their sperm concentrations to over 20 million per ml. GTP increased only in the EC arm.46 In follow up clinical trials, safety and clinical efficacy were comparable to a gel preparation while preserving sperm counts. Sperm counts were decreased in the men treated with gels. Side effects were comparable to CC. The most significant adverse events were hot flushes (10%), visual disturbances headaches, nausea and vomiting. Aside from the hot flushes, all events occurred in less than 5% of the study population. 47 The ease of use, low side effect profile, therapeutic efficacy and preservation of fertility, make EC if approved an attractive therapeutic alternative to standard TREP.

Source: http://www.asiaandro.com/news/upload/20141020-aja2014.316 FOF.pdf
 
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