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Random notes on Clomid

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From Dat:

From, Craig Niederberger MD FACS on July 2010:


Ever so often, I get asked questions from doctors, and I figure that here is a reasonable place to put how I answer the frequently asked ones. As with everything I write, it’s my opinion, and doctors opinions vary.

One question I get asked a lot is how to prescribe clomiphene for a male. Here’s how I do it.

First, clomiphene works by stimulating the pituitary. If the pituitary’s already in overdrive, clomiphene won’t help. So if a man’s LH is high, like 25 IU/L, I don’t prescribeclomiphene.

The next decision to make is what the target for therapy will be. If it’s augmenting a low testosterone level, then I’ll use the bioavailable testosterone calculation, As a reasonable threshold for total testosterone is 300 ng/dL and the portion of bioavailable testosterone ranges between 52% and 70%,1 I use the range between 156 ng/dL to 210 ng/dL as a lower limit of what is likely an adequate bioavailable testosterone level for a man. If the target for clomiphene therapy is stimulating the testis to make sperm, I use a higher threshold. If possible we try for twice as much, about 400 ng/dL for bioavailable and 600 ng/dl for total testosterone. It’s not always possible to achieve those levels.

I start with 25 mg clomiphene a day. As the pills come in 50 mg, and the half-life is relatively long, patients can take a pill every other day. Some prefer talking half a 50 mg pill daily.After two weeks, I have the patient get tests for testosterone, LH, albumin, SHBG (sex hormone binding globulin) and estradiol. In some instances, the estradiol will increase, but as long as the ratio of total testosterone to estradiol is greater than ten-to-one, that shouldn’t be a problem. If the estradiol increases substantially, other therapy, like an aromatase inhibitor, is preferred. If the testosterone is still low, then we’ll increase the clomiphene by 25 mg every other day or daily, and repeat the tests. I’ll increase the clomiphene to a maximum of 100 mg daily.

I believe that clomiphene works better if a man’s testosterone is low. That’s a good indication that there is a problem that may be corrected. If the testosterone is reasonable at the start, 400 ng/dL or more, then pushing it higher may not be as effective. But that’s my opinion, and as of present, scientific studies don’t definitively prove it right or wrong.

It’s important to note that clomiphene is “off-label” for use in the male. 
 

1S. Bhasin. Chapter 18: Testicular disorders. In: Kronenberg H. M., Melmed S., Polonsky K. S., and Reed Larsen P., eds. Williams Textbook of Endocrinology 11th ed. Philadelphia, W.B. Saunders Company, 2008; 647



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Interesting additional quote from the doctor:
 

You would expect from the pharmacology of these drugs that if an antiestrogen like clomiphene didn’t result in increase in downstream testosterone, an aromatase inhibitor like anastrozole wouldn’t either as both effectively prevent estradiol action on the pituitary. However, I have had patients who responded to anastrozole who didn’t to clomiphene, especially if estradiol was elevated.

 

People just don't seem to understand why Clomid is different then Nolva (Tamoxifen). In the early part of PCT you need what Clomid can bring to the table. 
 

Disparate effect of clomiphene and tamoxifen on pituitary gonadotropin release in vitro, E. Y. Adashi, A. J. Hsueh, T. H. Bambino and S. S. YenAJP - Endocrinology and Metabolism, Vol 240, Issue 2 125-E130

The direct effects of clomiphene citrate (Clomid), tamoxifen, and estradiol (E2) on the gonadotropin-releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in cultured anterior pituitary cells obtained from adult ovariectomized rats. Treatment of pituitary cells with Clomid or enclomid (10(-8) M) in vitro for 2 days resulted in a marked sensitization of the gonadotroph to GnRH as reflected by a 6.5-fold decrease in the ED50 of GnRH in terms of LH release from 2.2 x 10(-9) M in untreated cells to 3.6 x 10(-10) M. 

Treatment with E2 or Clomid also increased the sensitivity of the gonadotroph to GnRH in terms of FSH release by 4.3- and 3.3-fold respectively. 

Tamoxifen, a related antiestrogen, comparable to Clomid in terms of its ability to compete with E2 for pituitary estrogen receptors, was without effect on the GnRH-stimulated LH release at a concentration of 10(-7) M. Furthermore, tamoxifen, unlike Clomid, caused an apparent but not statistically significant inhibition of the sensitizing effect of E2 on the GnRH-stimulated release of LH. Our findings suggest that Clomid and its Enclomid isomer, unlike tamoxifen, exert a direct estrogenic rather than an antiestrogenic effect on cultured pituitary cells by enhancing the GnRH-stimulated release of gonadotropin.


So if Nolva (Tamoxifen) is used it will compete with E2 or Clomid for estrogen receptors. While E2 and Clomid have positive effects on GnRH-stimulated LH release, Nolva does not. Nolva just gets in the way early on. But may be fine at lower dose later.

 

Low Dose Clomid Therapy

The following study took things further and found Clomid to be effective due to inhibition at the estrogen receptor in the hypothalamus. So previously we have it acting on estrogen receptors and exerting an estrogenic effect which was a positive for GnRH stimulated LH release. Now we see it inhibits the estrogen receptors in the brain which probably reduces a negative feedback mechanism.
 

Clomiphene Citrate Effects on Testosterone/Estrogen Ratio in Male HypogonadismAhmad Shabsigh MDThe Journal of Sexual Medicine Volume 2, Issue 5, pages 716–721, September 2005

Conclusions

Clomiphene citrate effectively induces endogenous testosterone production via competitive inhibition of the hypothalamic estrogen receptor. Clomiphene citrate was able to increase serum testosterone and improve the testosterone/estrogen ratio. Clomiphene citrate was well tolerated and may be an alternative in the treatment of secondary hypogonadism in the aging male. Further studies are needed to confirm these findings and to define the optimal dose, long-term benefits, safety, and side effects. Other SERMs may also be investigated for their potential role in the management of secondary male hypogonadism.


So lets look more closely:
 

ABSTRACT

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 testostosterone 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.


Lets see if the body of the study wants to educate us. smile.gif
 

Introduction

Hypogonadism in aging males results in a steady decline in testosterone levels at a rate of 1% per year after age 40 years [1]. Testosterone deficiency has been implicated with decline in sexual function, loss of libido, osteoporosis, weight gain, muscle weakness, decreased lean body mass, diabetes mellitus, and cognitive changes [2]. The etiology of hypogonadism in the aging male is a combination of hypothalamus–pituitary axis dysfunction and primary testicular failure with decreased production of testosterone by Leydig cells [3].

The most common treatment of symptomatic late-onset hypogonadism is testosterone therapy with various transcutaneous, buccal, oral, and intramuscular delivery methods [2]. These delivery methods all share a common shortcoming. Because exogenous testosterone formulations cannot mimic the natural endogenous pathway of hypothalamus–pituitary hormonal axis, suppression of the hypothalamic–pituitary–gonadal axis is inevitable via a negative feedback mechanism [2]. Low levels of gonadotropin releasing hormone (GnRH), in turn, further decrease production of luteinizing hormone (LH) and follicular stimulating hormone (FSH) by the pituitary gland. The low LH levels translate to low testosterone production  by the Ledydig cells in the testes. The reduction in FSH results in suppression of spermatogenesis.

These endocrinologic changes are clinically manifested in reduction of both testicular size and sperm count. Moreover, excess testosterone from an external source can be metabolized to estradiol, which can result in gynecomastia. Other reported side effects include inadvertent contact contamination of spouse and children for gels and transdermal patches as well as hepatotoxities for oral formulations.

Hypogonadism in aging is also associated with increased body weight, adipose tissue, and estrogens, resulting from peripheral conversion of testosterone to estradiol. The negative feedback mechanism from excess estradiol results in a paradoxically low LH secretion from the pituitary despite a physiologically low testosterone level. The term secondary hypogonadism most accurately describes the predominant physiological process that occurs with aging [4].

Clomiphene citrate is a weak estrogen receptor antagonist and thus may be considered a selective estrogen receptor modulator (SERM). It competes with estradiol for the estrogen receptors at the level of the hypothalamus and blocks the normal negative feedback mechanism of circulating estradiol on the hypothalamus, preventing estrogen from limiting the production of GnRH [5]. The increase in GnRH level then stimulates the pituitary gland to release more FSH and LH, resulting in an increase in sperm and testosterone production by the testes [6].

The aim of this preliminary study was to determine whether clomiphene citrate is effective in stimulating this endogenous testosterone production pathway and in improving the testosterone/estrogen ratio. In addition, we will address the applicability of this medication as a therapeutic option for hypogonadism.
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Discussion

Male aging is associated with progressive decline in androgen production. This phenomenon has been described as andropause, male climacteric, or progressive androgen decline in the aging male. Because men do not experience an abrupt decrease and cessation of male hormone secretion that results in testicular failure, the term andropause is misleading [2]. As men age, alterations in the hypothalamus–pituitary–gonadal axis occur. This directly translates into decreased hypothalamic production of gonadotropins, starting a hormonal cascade resulting in decline of serum testosterone.

Male hypogonadism is a dynamic process that involves multiple organs, similar to the aging process itself. The age-related decline in testosterone is due to defects at all levels of the hypothalamic–pituitary–testicular axis: pulsatile GnRH secretion is attenuatedLH response to GnRH is reduced, and testicular response to LH is impaired. In the testes, histopathological studies have demonstrated changes consistent with senile atrophy, resulting in a decline in testosterone production by the Leydig cells [8]. This may explain the gradual rise of LH with aging. In the liver, sex hormone-binding globulin synthesis is increased, further reducing the net bioavailable and functional testosterone [9]. Perhaps the most dramatic changes occur at the hypothalamus–pituitary axis. The normal circadian rhythm is disrupted, and LH secretion is inhibited by negative feedback mechanism via estradiol. In fact, the term secondary hypogonadism refers to these men with functioning testes and relatively low levels of LH and testosterone [10–12].

Increase in visceral fat and obesity have been implicated as key contributors to secondary male hypogonadism [13]. It is well known that diabetic men consistently have testosterone levels approximately 20% lower than the general population. This low testosterone level may be attributed to altered insulin metabolism and resistance as a consequence of decreased muscle mass and increased fat [14].

Testosterone therapy has been used as a treatment for diminished libido and erectile dysfunction in hypogonadal men. The goal of testosterone therapy should be to maintain physiological levels of testosterone. In addition, it should ideally limit the conversion of testosterone to its metabolites such as dihydrotestosterone and estradiol. This will optimize the positive effects of testosterone, while curbing the side effects of its metabolites. Moreover, any testosterone therapy should try to mimic, rather than interfere with, the circadian rhythm of testosterone production [2].

Historically, hypogonadism has been treated with testosterone supplementation. Exogenous therapy with testosterone is the mainstay of therapy, and the emphasis is placed on improving the delivery system. As a result, many different exogenous testosterone preparations are commercially available [2]. They are in oral, injectable, and transdermal formulations. Each one of these delivery systems has advantages and disadvantages. Oral agents such as fluoxymesterone, methylterstosterone, and testosterone undecanoate have the convenience of being given orally. However, they can have significant hepatotoxic and gastrointestinal side effects. Liver function tests must routinely be performed to monitor for these changes. Furthermore, absorption and bioavailability are poor, and these oral testosterone therapy agents are not approved by the Food and Drug Administration (FDA) [15,16].

Intramuscular formulations of testosterone in cypionate or enanthate were the next products developed. This mode of delivery unfortunately leads to supraphysiological levels of testosterone in the first 72 hours of administration, followed by hypophysiological levels after 10–21 days. Obviously, maintenance of the normal circadian pattern of testosterone production is impossible with injectable preparations. This may, in fact, be more detrimental to the patient as he experiences more frequent swings in his testosterone levels [17,18]. There are also some data indicating an increase in hemoglobin levels and hypercoagulopathy associated with intramuscular formulations [19].

Transdermal testosterone therapy was the next generation of products made available. Its delivery system can maintain normal levels of testosterone and estradiol by applying them on the scrotal or nonscrotal skin. Normal testosterone levels can be maintained by using both types of patches. However, contact contamination to females and children is a major disadvantage with transdermal formulations [2,20,21]. Other side effects include gynecomastia, decreased sperm counts, softening, and decreased size of the testicles.

Clomiphene citrate (Clomid) was recently reclassified as an SERM because of its ability to compete with estradiol for the estrogen receptors at the level of the hypothalamus [22]. Clomiphene blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of GnRH. During clomiphene therapy, the frequency and amplitude of GnRH pulses increase, stimulating the pituitary gland to release more FSH and LH. Consequently, sperm and testicular testosterone productions are stimulated [5,23,24].

Faced with different problems associated with the currently available testosterone preparations, we sought a novel approach to manage patients with secondary male hypogonadism. We used a relatively low oral daily dose of clomiphene citrate (25 mg) in 36 men with a mean age of 39 years. All patients had low testosterone levels with an average testosterone level of 247.6 ng/dL. Patients were enrolled and followed prospectively. Serum levels of testosterone, estradiol, FSH, and LH were measured at the time of the initial visit and the first follow-up approximately 4–6 weeks later.

Testosterone levels increased by a mean of 146%. Similar changes were seen in both young and old patients. Of special interest is the observation that the T/E ratios increased in both groups, although this rise was significantly greater in the older population. This increase in the T/E ratio might be more important than total serum testosterone increase. No patients reported any side effects of clomiphene citrate including gynecomastia and nipple tenderness. In a recent article by Guay et al., 178 men with secondary hypogonadism and erectile dysfunction were treated with clomiphene citrate for 4 months. Both LH and free testosterone increased significantly in all patients. In this study 75% of patients had improvement of their erectile function [25].

The levels of testosterone have risen more in the men aged more than 40 years vs. men less than 40 years, from 251.4 ± 38.9 ng/dL to 579.7± 152.7 ng/dL, and from 242.2 ± 41.8 ng/dL to 652.4 ± 207.6, respectively. Tenover and Bremmer showed that, during a clomiphene challenge, testosterone rose more in younger than in older men. Of course, in their study the age differences were much greater. We cannot give a definite answer, but we can speculate that younger men have often an anxiety component to their low testosterone levels, via making adrenergic substances. This might be one explanation for the lower testosterone levels in the younger men and would be consistent with some of our anecdotal data [6].

Our study revealed promising results. Clomiphene citrate induces endogenous production of testosterone via competitive blockage of hypothalamic estrogen receptors. This effect presents a unique therapeutic opportunity for the management of hypogonadism in the aging male. Low dose, oral therapy with minimal side effects is an excellent substitute to transdermal or injectable testosterone alternatives. It enhances the endogenous androgen synthesis pathway while maintaining the natural circadian rhythm. This method of treatment is especially important in hypogonadal men with infertility, who wish to father children. Exogenous testosterone therapy suppresses spermatogenesis and the hypothalamic–pituitary–testicular axis and may cause testicular atrophy.

We understand that hypogonadism in aging males affect older patients. More than 20% of patients older than 60 years have signs and symptoms of hypogonadism. This phenomenon is usually caused by a combination of primary and secondary hypogonadism. Clomiphene citrate may offer an easy and practical solution for a subset of older patients with hypogonadism. Because this is a heterogeneous group of patients, we do not expect the same response in all older patients. This does not change the fact thatclomiphene citrate might be an excellent option for some men, especially those where secondary hypogonadism is a major component of their problem. Our future work will focus on the older patients with hypogonadism.

There are obvious limitations to this pilot study. Further investigation is needed to confirm the effectiveness of clomiphene citrate for the treatment of androgen deficiency in secondary male hypogonadism. Studies are needed to determine the optimal dose response in different age groups. Validated measurements of muscle strength, weight, sexual function, exercise tolerance, bone density, and mood changes are required before accepting clomiphene citrate as a standard of care for secondary hypogonadism. Long-term safety and efficacy data are not available, as well as clomiphene citrate effects on lipid metabolism. Lastly, other SERMs may function in a manner similar to clomiphene citrate and may also have benefits. We should mention that clomiphene citrate use for the treatment of hypogonadism is not approved by the FDA in the United States. This report clearly shows the short-term efficacy of clomiphene citrate in improving testosterone levels and the T/E ratio in the treatment of secondary male hypogonadism.


Summation of Clomid Therapy

Well if you read all of that then there is little more to say. If you want a summation of these studies here is a paragraph from a very recent thorough reviewEndocrine Aspects of Male Sexual DysfunctionsJacques Buvat MDThe Journal of Sexual Medicine Volume 7, Issue 4pt2, pages 1627–1656, April 2010

 

Shabsigh et al. [140] reported positive results in terms of T rise with clomiphene citrate (25 mg daily) in a study on 36 men with T deficiency (<3 ng/mL), thus confirming previous experiences of Guay et al. [141,142] in subjects with ED. However, an improvement of sexual symptoms was described by Guay et al. [141] in ED subjects only after prolonged therapy (four months). A recent study indicates that clomiphene is able to restore normal T and LH levels and to improve sperm motility and erectile function in most (70%) of male patients with prolactinomas and persistent hypogonadism under usual dopaminergic therapy [143].

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More recent study which compared the cost of Clomid therapy & Testosterone Gel Replacement Therapy. While it is interesting, what I choose to take out of it at the moment is simply another study demonstrating the effectiveness of low dose Clomid therapy.


Clomiphene Citrate and Testosterone Gel Replacement Therapy for Male Hypogonadism: Efficacy and Treatment CostFrederick Taylor MDThe Journal of Sexual Medicine Volume 7, Issue 1pt1, pages 269–276, January 2010
 

ABSTRACT

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


Lets see if we can learn anything from the Discussion section.
 

Discussion

The past decade has seen significant advancements in the study and understanding of male hypogonadism and the natural hormonal changes of the aging male [7–9]. As the understanding of the biologic effects of aging have advanced, so too has an understanding of the symptomatic effects that bring many men to seek treatment. Despite these important advances, controversy persists regarding the biochemical definition of hypogonadism. It is well understood that neither a low serum T, nor the presence of symptoms consistent with hypogonadism alone makes the clinical diagnosis. Rather, it is the combination of symptoms and a low or borderline low T that defines the clinical condition [10].Our current understanding of male hypogonadism precludes the definition of a serum T “cut-off”, above which no man can be considered hypogonadal and below which all men are hypogonadal. Without a well-defined biochemical T value required to diagnose hypogonadism, clinicians are left to weigh each patient individually with respect to his bothersome symptoms and serum T level. The American Society for Reproductive Medicine [11] suggests that total T levels below 200 ng/dL identify hypogonadism that warrants treatment, and that men with serum T levels between 200 ng/dL and 400 ng/dL may benefit from therapy. In addition, it has been advocated that in the face of symptoms of hypogonadism, but without clear biochemical evidence of low T, patients may benefit from a therapeutic trial of T supplementation [12]. The primary therapy for men with hypogonadism, regardless of age, has historically been via the administration of exogenous T. Although effective, exogenous T administration does not mimic normal circadian hormone release. In addition, although newer generations of T delivery products and methods have begun to address the issue of supraphysiologic dosing, several hurdles remain. Currently, there is no oral form of T therapy commercially available in the United States. Injectable formulations result in superphysiologic T levels, followed by a long and gradual decrease in serum concentration, with the inconvenience of a needle stick. T gels are generally well tolerated, albeit with the occasional skin irritation, and can be titrated to serum T levels. However, they carry a risk of contamination exposure to others, including children and pregnant women. In addition, all exogenously administered T carries the inherent effect of inhibition of the hypothalamic–pituitary axis with a decrease in endogenous T formation and, more importantly for hypogonadal men interested in fertility, a decrease in spermatogenesis.

Currently, CC is approved by the United States Food and Drug Administration (FDA) for the treatment of ovulatory dysfunction in women desiring pregnancy. CC has not been submitted to the FDA for study for use in the treatment of infertility or hypogonadism in men, and is consequently not FDA-approved for these uses. In spite of this, CC has been used in clinical practice for many years for the treatment of these conditions. Recent reports have demonstrated the efficacy of CC in treatment of male infertility [3,13], and the literature clearly supports the biochemical efficacy of CC in treatment of hypogonadism [2,14,15]. As a SERM, CC works to up-regulate endogenous hypothalamic function, resulting in increased serum LH and FSH levels, which in turn increase endogenous T production and spermatogenesis. The goal of CC treatment is to induce endogenous T production and spermatogenesis by presumed healthy testes, which are functioning but under-producing T. Our data certainly support the biochemical efficacy of CC in the treatment of hypogonadism, with an average increase in serum T of 210% from baseline.

Although recent literature demonstrates the biochemical efficacy of CC for the treatment of male hypogonadism, the issue of subjective outcomes is less clear. Guay et al. [16] demonstrated the biochemical efficacy of clomiphene citrate in men with secondary hypogonadism, but found no improvement in symptoms on the follow-up questionnaire. Subsequent publications, however, have suggested that CC may be effective in treating the sexual side effects of hypogonadism [15,17]. ADAM questionnaires were administered to the majority of our hypogonadal patients at their initial visit. A follow-up telephone ADAM questionnaire was then administered by a single investigator to gauge the symptom response. Overall, we demonstrate a symptomatic improvement in the hypogonadal patients treated with CC, and no patients reported a worse ADAM score. In addition, in order to assess the sexual response of the patients to therapy, questions 1 and 7 of the ADAM questionnaire were considered and scored separately. In doing so, we found that the patient's sexual function was statistically significantly improved with therapy.

Recent basic science research has begun to expand an understanding of the role of estrogen receptors in prostate cancer [18–21]. As a SERM, there is understandably some interest in the effect that CC may have on peripheral estrogen receptor activation, and, consequently, downstream estrogen-related effects. Literature does exist to suggest a link between estrogen receptor activation (particularly estrogen receptor α) and the development of prostate cancer [18,22–24]. In addition, Bang-Ping et al. [25] demonstrated that, in vitro, CC administration to the PC3 prostate cancer cell line resulted in increased intracellular calcium concentration. Regulated calcium concentrations are essential for normal cell survival, whereas increased intracellular calcium concentrations can cause cell death. Thus, the possibility exists that CC may be tumoricidal to prostate cancer cells. In addition and perhaps most tellingly, there were no changes in pre- and posttreatment PSA values in our patient cohort who were taking CC with up to 40 months of continuous treatment.

Male hypogonadism has been suggested as a cause of osteopenia and osteoporosis, particularly in older men [26–28]. T appears to be protective against the development of osteopenia and osteoporosis; however, the mechanism of protection is not well established and is likely due to peripheral aromatization of T to estradiol [27,29]. Estrogen prevents bone loss and thus is a mainstay to prevent postmenopausal osteopenia and osteoporosis [30,31]. SERMs have been shown to have agonist effects on bone estrogen receptors, and have shown efficacy in the treatment of osteopenia and osteoporosis in postmenopausal women [30,32]. In addition, CC has been shown to have estrogen agonist effects on bone and to prevent osteoporosis in a rat model [33–35]. Although further studies need to be done, it is possible that CC may protect against the development of osteopenia and osteoporosis in men with hypogonadism due to its estrogen agonist effect on bone receptors.

Conclusion

CC represents a viable treatment option for men with hypogonadism demonstrating biochemical and clinical efficacy with no side effects and lower cost as compared with TGRT.More study via prospective, large-scale, multicenter trials assessing hypogonadal symptom response to CC would provide additional support for its use in the hypogonadal male without an elevated serum LH.


Clomid may protect against prostate cancer and support bone health. It may be a viable alternative to exogenous testosterone therapy.

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A deafening silence to this thread, the methodology and outcomes for these studies are beyond reproach yet to date this treatment for males remains off label and impossible to get here in NZ....well that's been my experience, I have tried to get GP's and Endos to prescribe for me all to no avail.

My purpose for this is to start a family as the TRT treatment I am on has made me functionally sterile, even though all studies to date have said this is a safe therapy no one will prescribe and overseas internet ordering has just resulted in seizure at the border.

In NZ there seems to be no accountability for outcomes, my reason for saying this is that my right to have children and my ability to become a complete family is being curtailed by the NZ government in the form of MED safe and Pharmac. Where will the Endo or the GP be at the end of my regret filled life at not being able to fore full an expected normal human right ie having children.

If any one out there knows of a way that I can get Clomiphene Citrate or it's generics please let me know.

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Hey Guys, been reading this forums and others for a few months now, and honestly Daz's infinite wisdom has helped me be in a position tonchallenge my so called specialist. Been on trt a couple months, reandron which was ok for the first shot until the side effects kicked in on the second, had some alternatives thrown at me until ive  now come to realise our gp's and specialists just do not know enough about this subject to help us. I imagine the demographics and population number means they do not have multitudes of these cases to work on whereas overseas counterparts may deal with it more commonly. My trt issue was medical and not AAS use related, but in my recent experience have seriously considered the thought of following what most on here have said 'get some good stuff and pin that @#$%' comes to mind. I found that trt here keeps you sub par bare minimal T, no emphasis on estradiol levels nor their willingness to combat it, on top of it as above when question fertility, testicular atrophy (lets be honest a small pair of steel raisins doesnt compare to a big pair of steel cajones) when asked about anti-estrogens,HCG,Tamoxifen or anything related to restoring/reversing affects to your manlihood so you can wear that leopard print daisy dukes short shorts to the beach with pride is met by blank stares. I also questioned my ability to procreate as this is something near to my heart,and was told that although trt 'shuts some people down a bit' that i would still be able to have children,couple months down the line no no pregnant mrs and the doc reckons its cant be me at fault,demanded a fertility tests and have 0 fellas....end result is my endo basically chemically neutered me then refuses to assist with reversal of it,will not advise on stopping trt especially with no basic pct which probably isnt required at the low doses ive had but at the same time without assistance of normal restorations. As Rich Piana would say 'dick to ball ratio' is a concern of course but fatherhood is the primary. @Daz69 i know ive annoyed you with questions already but would appreciate it if you could in your wisdom, suggest a good protocol for a person in my case to either go on cycle and pct off like an aas user or stop trt and somehow abracadabra so hcg/nolvadex/clomid whatever you think would be best to sort out the twig and berries and give my child a sibling. Thanks @Daz69 you have been a great source of help in knowlegdge

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