Treating Low Testosterone with Clomid, hCG and Aromatase Inhibitors: A Review of the Data

[madman]

Abstract

Testosterone deficiency is defined as a total testosterone level <300 ng/dL confirmed on two early morning lab draws. Testosterone therapy has historically been offered to men with symptomatic testosterone deficiency in the form of injections, gels, or pellets. However, these treatments are invasive or have undesirable effects including the risk of drug transference. Additionally, testosterone therapy has been associated with increases in hematocrit and controversy remains regarding the risk of cardiovascular and thromboembolic events while on testosterone therapy. As such, much interest has recently been focused on alternative treatment options for testosterone deficiency in the form of orally-administered medications with more favorable side effect profiles. Lifestyle modifications and varicocelectomy have been shown to raise endogenous testosterone production. Similarly, SERMs and aromatase inhibitors (AIs) have been shown to raise testosterone levels safely and effectively. Human chorionic gonadotropin (hCG) remains the only FDA-approved non-testosterone treatment option for testosterone deficiency in men. However, this medication is expensive and requires patient-administered injections. Over-the-counter herbal supplements and designer steroids remain available though they are poorly studied and are associated with the potential for abuse as well as increased hepatic and cardiovascular risks. This review aims to discuss the existing treatment alternatives to traditional testosterone therapy, including the efficacy, safety, and side effects of these options. The authors suggest that the SERM clomiphene citrate (CC) holds the greatest promise as a nontestosterone treatment option for testosterone deficiency.




Conclusions

Given the prevalence of testosterone deficiency in men, and the desire to avoid testosterone therapy and its associated effects on testicular volume, spermatogenesis, and the HPG axis with possible adverse side effects, much work has been done to identify safe and efficacious alternative treatment options. Lifestyle modifications are safe and have been shown to increase endogenous testosterone production and should be offered to all men desiring treatment for testosterone deficiency. Varicocelectomy, with further study, may become a valid treatment option in the presence of a clinical varicocele. While numerous compounds exist marketed towards “boosting testosterone,” data on the safety and efficacy of these are poor, and these are not currently recommended as treatments for testosterone deficiency. Gonadotropins, including hCG (the only non-testosterone agent FDA-approved for the treatment of male hypogonadism), are effective, but costly and require administration via injection. AIs may also raise testosterone levels but may be associated with decreases in bone mineral density if used long-term. SERMs, including clomiphene citrate, appear to be highly effective at producing physiologic testosterone levels and appear to be well tolerated and safe when used long-term. Consideration may be given to offering clomiphene citrate to men with symptomatic testosterone, regardless of the patient’s desire to preserve fertility. While studies exist suggesting that many of these treatment options are well tolerated and efficacious, further prospective studies must be conducted to support their use as first-line treatment options in the management of testosterone deficiency.

 

[madman]

Figure 1 Hypothalamus-pituitary-gonadal axis. The hypothalamus releases GnRH in a pulsatile fashion, which stimulates the anterior pituitary to release LH and FSH to stimulate testosterone production and spermatogenesis in the testis. Testosterone negatively feeds back on the pituitary to suppress LH release. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone.

 

[madman]

Figure 2 The effect of exogenous testosterone on the HPG axis. Exogenous testosterone suppresses the release of GnRH and LH, resulting in testicular atrophy and suppression of spermatogenesis. HPG, hypothalamic-pituitary-gonadal; GnRH, gonadotropinreleasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone.

 

[madman]

Figure 3 Steroid regulation pathway. Adapted from Kovac JR, Pan M, Arent S, et al. Dietary Adjuncts for Improving Testosterone Levels in Hypogonadal Males. Am J Mens Health 2016;10:NP109-17. copyright © 2016 by © SAGE Publications; Reprinted by Permission of SAGE Publications, Inc.

 

[madman]

Figure 4 Sites of action of SERMs, aromatase inhibitors, and hCG in the HPG axis. SERMs, selective estrogen receptor modulators; hCG, human chorionic gonadotropin; HPG, hypothalamic-pituitary-gonadal; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone.

 

[DS3]

Excellent post @madman.

Aside from the vital and intriguing information regarding the efficacy and sustainability of alternative testosterone treatments for hypogonadal men, is there data regarding the subjective response rates of men using these alternative forms of therapy? For example, it is known that Clomiphene Citrate is efficacious for producing physiological increases in testosterone in hypogonadal men. However, it is also known, anecdotally, that Clomid makes a lot of men (no idea a speculative %) feel terrible during treatment, others feel no positive subjective benefits nor negative, and yet others report positive effects (this latter group appears to be a small %).

Is there any evidence on the subjective positive treatment outcomes of these alternative treatments?

 

[DS3]

I found one study conducted by Ranjith Ramasamy, Jason M. Scovell, Jason R. Kovac, Larry I. Lipshultz.

American Urological Association

What is interesting is how they note that subjective differences in treatment outcomes were not observed.

However, 2014 was the same year that I went to Dr. Lipshultz to start TRT.

After HCG/Clomid therapy for 4 months, he asked me how I was feeling subjectively (including energy, libido, drive, strength, etc.), to which I replied negatively as I didn't feel well. He told me, "Yea, that's what a lot of patients tell me. It just doesn't seem like the Clomid and/or HCG creates the same subjective experience that exogenous T creates."

Interesting how he acknowledged that, anecdotally, a sizeable portion of his patients who he has originally put on the HCG/Clomid combo (or Clomid mono) do not report positive symptom relief, yet the study he helped conduct determined there was no subjective difference.

Really leads me to say, "Hmm...is it just that their sample wasn't fully representative of the average male experience on various forms of TRT? Were there flaws in the study? Or is there some underlying agenda inherent with how the study was conducted/reported?

 

[DS3]

I am sure this video has been widely seen among Excel Male members, but the first 5 minutes are critical in discussing how men on Clomid often do not feel well and that one major issue is the blocking of estrogen in the brain and the negative impact that creates on libido.

Estradiol in Men: Interview with Urology Professor Dr Ranjith Ramasamy

Nelson Vergel, founder of ExcelMale.com and DiscountedLabs.com and author of Testosterone: A Man's Guide, interviews Dr Ranjith Ramasamy. Dr Ramasamy is the Director of Male Reproductive Medicine and Surgery as well as an Assistant professor in Department of Urology at the University of Miami...

www.excelmale.com

 

[madman]

Excellent post @madman.

Aside from the vital and intriguing information regarding the efficacy and sustainability of alternative testosterone treatments for hypogonadal men, is there data regarding the subjective response rates of men using these alternative forms of therapy? For example, it is known that Clomiphene Citrate is efficacious for producing physiological increases in testosterone in hypogonadal men. However, it is also known, anecdotally, that Clomid makes a lot of men (no idea a speculative %) feel terrible during treatment, others feel no positive subjective benefits nor negative, and yet others report positive effects (this latter group appears to be a small %).

Is there any evidence on the subjective positive treatment outcomes of these alternative treatments?

The SERM most studied in the treatment of testosterone deficiency is clomiphene citrate (CC). CC has long been used as a treatment to restore testosterone levels and promote or preserve spermatogenesis in men with testosterone deficiency desiring to preserve fertility, and multiple studies have shown that CC effectively raises testosterone to eugonadal levels (50-56). This medication is an oral compound administered at doses ranging from 25 mg every other day, to 50 mg daily, based on testosterone response. Moskovic et al. reported on 29 men with a baseline total testosterone level of 228±48 ng/dL treated for >3 years with CC. They demonstrated improvements in testosterone to a mean of 582±227 ng/dL (P<0.001), as well as significant improvements in ADAM questionnaire response (P=0.01) and mean BMI (P<0.05) (50). Similarly, Taylor and Levine demonstrated that compared to testosterone gel therapy, CC treatment resulted in equivalent, significant improvements in testosterone levels at a fraction of the cost, as well as significant improvements in ADAM questionnaire scores. No patients discontinued CC treatment due to side effects, and no adverse events on CC were reported. Additionally, patients on CC treatment did not experience changes in hemoglobin, PSA, or cholesterol levels while on treatment (51). Ramasamy et al. have also demonstrated that quantitative ADAM scores were similar among patients treated with CC as compared to those treated with testosterone gels or injections, with improvements in testosterone levels while on CC treatment to physiologic levels (54).

Still, CC has not historically been offered as a first line treatment for testosterone deficiency in men not desiring fertility preservation given its off-label use and lack of long term data regarding safety and efficacy. In the setting of these limitations, ongoing studies are being conducted to establish long-term treatment outcomes. CC is well tolerated. Rare side effects include headaches, visual changes, and gynecomastia (50). Additionally, CC use has shown to have significantly less risk of increased hematocrit as compared to testosterone therapy (57). Preliminary data on men treated for testosterone deficiency on CC for as long as 7 years show that over 80% of men achieve testosterone levels >450 ng/dL, with 78% of men reporting subjective improvement in hypogonadal symptoms, and only 9% reporting side effects from CC treatment with no significant adverse events (58). This data together suggests that CC may be a safe and effective treatment option for the long-term management of testosterone deficiency, and consideration should be made to offering this therapy to men as a first-line treatment option for testosterone deficiency, regardless of the patient’s desire for fertility preservation.

Enclomiphene citrate (EC) is a trans-isomer of CC and is not currently FDA approved in the United States. Like CC, EC has been shown to raise testosterone and gonadotropin levels, while preserving spermatogenesis (59). Additionally, EC treatment may deliver the androgenic effects of CC without the side effects associated with CC, though further studies need to be conducted to determine if EC has clinically superior selectivity (60).

Like CC, tamoxifen has been shown to increase testosterone and gonadotropin levels, and preserve spermatogenesis, and this SERM is an acknowledged alternative treatment option for testosterone deficiency in men (1,61). Tamoxifen has been used to stimulate gonadotropin production, and to treat gynecomastia in the setting of anabolic steroid-induced hypogonadism or hCG treatment (62). However, the adverse effects associated with tamoxifen appear to be greater than those associated with CC use, including gastrointestinal distress, venous thromboembolic events, and other cardiovascular outcomes (63). As such, tamoxifen is less commonly used for the treatment of testosterone deficiency.




When searching the literature it would seem from the studies done using CC as an alternative treatment for hypogonadal men that many end up experiencing improvements in low-t symptoms with minimal side effects.

Judging by the amount of men we see on the forums that use CC as sole therapy to treat hypogonadism the overall beneficial effects tend be a hit or miss as some do feel better (not many), others feel not much difference and many end up feeling horrible.

There is still lack of long-term data regarding the safety and efficacy of CC aside from preliminary data on men that were treated for low-t using CC for up to 7 years with a large percentage of those men reporting subjective improvement.

Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism. - PubMed - NCBI

Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism.


Abstract

PURPOSE:
Clomiphene citrate may be used as an off label treatment of hypogonadism. There are few long-term data on clomiphene citrate efficacy and safety when administered for more than 3 years. We assessed improvements in testosterone and hypogonadal symptoms while on clomiphene citrate for extended periods.

MATERIALS AND METHODS:
We performed a retrospective review to identify patients treated with clomiphene citrate for hypogonadism (baseline testosterone less than 300 ng/dl) at a total of 2 institutions from 2010 to 2018. We assessed the duration of clomiphene citrate therapy, serum testosterone levels, symptom improvement and clomiphene citrate side effects.

RESULTS:
A total of 400 patients underwent clomiphene citrate treatment for a mean ± SD of 25.5 ± 20.48 months (range 0 to 84). Of the patients 280 received clomiphene citrate for 3 years or less (mean 12.75 ± 9.52 months) and 120 received it for more than 3 years (mean 51.93 ± 10.52 months). Of men on clomiphene citrate for more than 3 years 88% achieved eugonadism, 77% reported improved symptoms and 8% reported side effects. Estradiol was significantly increased following clomiphene citrate treatment. Results did not significantly differ between patients treated for more than 3, or 3 or fewer years. The most common side effects reported by patients treated more than 3 years included changes in mood in 5, blurred vision in 3 and breast tenderness in 2. There was no significant adverse event in any patient treated with clomiphene citrate.

CONCLUSIONS:
Clomiphene citrate is not typically offered as primary treatment of hypogonadism in men who do not desire fertility preservation. These data demonstrate that clomiphene citrate is safe and effective with few side effects when used as long-term treatment of hypogonadism.








Enclomiphene (EC) may very well be more effective overall.....let alone minimize any potential side-effects but again rigorous long-term studies are lacking.

Enclomiphene citrate: A treatment that maintains fertility in men with secondary hypogonadism

ABSTRACT Introduction: Hypogonadism is an important issue among the male population. Treatments such as exogenous testosterone have become very popular. One of the adverse effects of testosterone is its suppression of fertility. This has led to the use of alternative therapies such as selective...

www.excelmale.com

Use of tamoxifen and aromatase inhibitors have their own potential downfalls and although many try either hCG mono or clomid.....those using hCG mono tend to not feel as good overall compared to trt.

 

[ajax31]

There's very little discussion on this board about another option - Toremifine (Fareston).

 

[ajax31]

View attachment 9505
Figure 1 Hypothalamus-pituitary-gonadal axis. The hypothalamus releases GnRH in a pulsatile fashion, which stimulates the anterior pituitary to release LH and FSH to stimulate testosterone production and spermatogenesis in the testis. Testosterone negatively feeds back on the pituitary to suppress LH release. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone.

@Cataceous made an interesting comment in the following post that androgen negative feedback at the pituitary is minimal (it's mostly estrogen there).

Pituitary restart while on TRT: promising initial results with GnRH plus enclomiphene

TL;DR: Over a period of seven weeks, treatment with GnRH and enclomiphene raised LH and FSH from around 0.1 mIU/mL to about 1.0 mIU/mL, even though TRT and hCG dosing were continued. Subjective results have been encouraging. I had written previously on the subject of GnRH suppression on TRT...

www.excelmale.com

 

[Cataceous]

@Cataceous made an interesting comment in the following post that androgen negative feedback at the pituitary is minimal (it's mostly estrogen there).
...

I think in @madman's quote they're simply not bothering to mention that the negative feedback of testosterone at the pituitary is via its prior conversion to estradiol; estradiol follows testosterone. And if you think about it, if androgens significantly inhibited gonadotropin production at the pituitary then SERMs like clomiphene wouldn't work.

Interestingly, it appears that androgens do cause negative feedback at the pituitary for prolactin production.

 

[DS3]

I think in @madman's quote they're simply not bothering to mention that the negative feedback of testosterone at the pituitary is via its prior conversion to estradiol; estradiol follows testosterone. And if you think about it, if androgens significantly inhibited gonadotropin production at the pituitary then SERMs like clomiphene wouldn't work.

Interestingly, it appears that androgens do cause negative feedback at the pituitary for prolactin production.

Question: I’ve been thinking about this for a while and don’t have an answer (also, admittedly haven’t researched it for lack of time)...Why do androgens such as Primobolan, Masteron, or Anavar also lead to shutdown of the HPGA when they don’t convert to estrogen? I understand and appreciate the negative feedback induced by estrogen (and this being the theoretical reason why exogenous T shuts you down). However, is this the only factor influencing HPGA shutdown? If so, why do DHT derivatives also lead to shutdown?

 

[Cataceous]

Question: I’ve been thinking about this for a while and don’t have an answer (also, admittedly haven’t researched it for lack of time)...Why do androgens such as Primobolan, Masteron, or Anavar also lead to shutdown of the HPGA when they don’t convert to estrogen? I understand and appreciate the negative feedback induced by estrogen (and this being the theoretical reason why exogenous T shuts you down). However, is this the only factor influencing HPGA shutdown? If so, why do DHT derivatives also lead to shutdown?

Androgens have a direct suppressive effect on the hypothalamus, which reduces GnRH output. Not the most recent work, but:

... Development of this negative feedback loop is essential for homeostatic maintenance of circulating testosterone concentrations in males; exactly how this is affected is not entirely understood, nevertheless androgen feedback at the level of both the hypothalamus and the pituitary has become the widely accepted paradigm. ... [But] data from clinical studies on patients with hypogonadotrophic hypogonadism suggest that, while testosterone feedback is required for control of GnRH release by the hypothalamus, aromatisation of testosterone to estradiol is sufficient for control of LH secretion by the pituitary [8–10], suggesting the primary site of androgen feedback in human males is the hypothalamus.​

[1]

 

[madman]

Question: I’ve been thinking about this for a while and don’t have an answer (also, admittedly haven’t researched it for lack of time)...Why do androgens such as Primobolan, Masteron, or Anavar also lead to shutdown of the HPGA when they don’t convert to estrogen? I understand and appreciate the negative feedback induced by estrogen (and this being the theoretical reason why exogenous T shuts you down). However, is this the only factor influencing HPGA shutdown? If so, why do DHT derivatives also lead to shutdown?

All AAS will lead to the shutdown of the HPG axis (even non-aromatizing AAS) due to a direct suppressive effect on the hypothalamus (reduction in GnRH output).

The HPG axis is very sensitive to sex steroids and when using exogenous AAS the hypothalamus will recognize these elevated/excess levels which in turn leads to a shutdown resulting in the suppression of natural endogenous testosterone/sperm production.

AAS can also bind the androgen receptor inside target cells and bring into play the same negative feedback effects as endogenous testosterone.

Also, although some of the milder non-aromatizing oral AAS such as oxandrolone (Anavar), methenolone (Primobolan), stanozolol (Winstrol), mesterolone (Proviron) have been shown to be less suppressive under some therapeutic conditions it because of the therapeutic doses used/duration of therapy and just to be clear this is tossed out the window when any AAS are taken in high enough supra-physiological doses.



WILLIAM LLEWELLYN'S
ANABOLICS

Some of the more potent anabolic/androgenic steroids, including testosterone, nandrolone, trenbolone, and oxymetholone, appear to be more suppressive of testosterone release than many other AAS drugs. This may be explained in part by the additional estrogenic or progestational activity inherent in these steroids, as estrogens and progestins both also provide negative feedback inhibition of testosterone release 306 307. It is important to note, however, that all anabolic/androgenic steroids are capable of suppressing testosterone secretion. This includes primarily anabolic compounds such as methenolone and oxandrolone, which are normally regarded as milder in this regard. While these compounds may be less inhibitive of testosterone synthesis under some therapeutic conditions when taken in the supratherapeutic doses necessary for physique- or performance-enhancement, significant atrophy and suppression are common, and distinctions less pronounced.


The HPTA Axis In the human body, the Hypothalamic-Pituitary-Testicular Axis (HPTA) controls testosterone biosynthesis. The HPTA is a tightly regulated system of checks and balances that works to assure the correct level of testosterone is maintained. We can look at this regulating process as having three levels. At the top is the hypothalamic region of the brain, which releases GnRH (Gonadotropin-Releasing Hormone) when it senses a need for more testosterone. GnRH sends a signal to the second level of the axis, the pituitary, to produce Luteinizing Hormone (LH). LH, in turn, sends a message to the Leydig’s cells in the testes (level three) to secrete testosterone. Given this role, LH is regarded as the primary direct messenger controlling testosterone synthesis. Testosterone and other sex steroids that are produced as a result of this LH stimulation serve as a counterbalance. They provide negative feedback to lower the secretion of LH and testosterone, preventing overproduction. Synthetic anabolic steroids, of course, send the same negative feedback. The serum level of testosterone is, therefore, a reflection of both positive and negative stimulation fighting each other for hormonal control.

The Hypothalamic-Pituitary-Testicular Axis: The hypothalamus releases Gonadotropin- Releasing Hormone (GnRH), which stimulates the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This (primarily LH) promotes the release of testosterone from the testes. Androgens, as well as estrogens and progestins, in turn, cause negative feedback inhibition at the hypothalamus and pituitary, lowering the output of gonadotropins and testosterone when too much hormone is present.




Reproductive (Male)

Fertility

Anabolic/androgenic steroid use may impair fertility. The human body strives to maintain balance in its sex hormone levels (homeostasis). This balance is regulated largely by the hypothalamic-pituitary-testicular axis (HPTA), which is responsible for controlling the production of testosterone and sperm. The administration of anabolic/androgenic steroids provides additional sex steroid(s) to the body, which the hypothalamus can recognize as excess. It responds to this excess by reducing signals that support the production of pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH normally stimulate the release of testosterone by the testes(gonads) and also increase the quantity and quality of sperm. When LH and FSH levels drop, testosterone levels, sperm concentrations, and sperm quality may all be reduced.


Testicular Atrophy

Anabolic/androgenic steroids may produce atrophy (shrinkage) of the testicles. Testosterone is synthesized and secreted by the Leydig cells in the testes. Its release is regulated by the hypothalamic-pituitary-testicular axis, a system that is very sensitive to sex steroids. When anabolic steroids are administered, the HPTA will recognize the elevated hormone levels and respond by reducing the synthesis of testosterone. If the testes are not given ample stimulation, over time they will atrophy, a process that can involve both a loss of testicular volume and shape. This atrophy may or may not be obvious to the individual. In some cases, the testes will appear normal even though their functioning is insufficient. In other cases, shrinkage is very apparent. Visible testicular atrophy is one of the most common side effects of steroid abuse, appearing in more than 50% of all anabolic/androgenic steroid abusers.
300 301












Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use
J Abram McBride and Robert M Coward


Both TRT and AAS use can lead to suppression of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in a diminution of spermatogenesis and potential infertility. Spontaneous recovery of spermatogenesis after cessation of TRT or AAS is possible but may take several months to several years, and in some cases may be permanent.13,14,15,16 Taken together, the rising use of TRT and AAS in young- to middle-aged men, in conjunction with a societal shift toward greater paternal age,17 is creating an environment where clinicians are increasingly likely to encounter men seeking treatment for infertility related to prior TRT and/or AAS use or treatment for hypogonadism with interest in preserving their fertility. Meanwhile, men present to infertility specialists for vasectomy reversal (VR) at an average age of 41 (n = 1300), some of whom may also suffer from hypogonadism and report current or previous TRT use.18 Therefore, clinicians need to be keenly aware of the effects of TRT and AAS on spermatogenesis and what treatment options are available to reverse these effects to restore spermatogenesis.


NORMAL SPERMATOGENESIS
Normal spermatogenesis is dependent on appropriate signaling from the HPG axis. This signaling initially consists of a pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus via the portal system to the pituitary gland where stimulation results in gonadotropin release. Luteinizing hormone (LH) from the pituitary stimulates Leydig cells in the testis to produce testosterone and leads to intratesticular production of insulin-like growth factor 1 (IGF-1), which plays an integral role in Leydig cell LH receptor upregulation, steroidogenesis, and maturation.19,20 Follicle-stimulating hormone (FSH) from the pituitary stimulates Sertoli cells in the testis, which supports spermatogonial differentiation and maturation. Both FSH and maintenance of high intratesticular testosterone (ITT) levels (50–100 fold higher than serum) in response to LH are critical for normal spermatogenesis to occur.21,22,23,24 Historically, Sertoli cell-produced androgen-binding protein was thought to be responsible for such high ITT levels, but recent data suggest that other factors are also involved.25 Interestingly, animal studies have demonstrated that the absence of FSH signaling results in impaired spermatogenesis whereas loss of sufficiently high ITT levels results in the absence of spermatogenesis.26

Regulation of the HPG axis occurs via feedback inhibition. Endogenous testosterone directly inhibits GnRH and LH release at the hypothalamus and pituitary levels, respectively, leading to downstream attenuation of testosterone production. Testosterone also indirectly regulates gonadotropin secretion via estrogen, derived from testosterone conversion peripherally by aromatase enzyme. Estrogen exhibits a greater effect on LH secretion than FSH although additional FSH feedback inhibition occurs with inhibin B secreted from Sertoli cells. Inhibin B levels have been considered a surrogate for spermatogenesis; for example, men with spermatogenetic defects express lower inhibin B levels.27 Additional autocrine, paracrine, and endocrine factors within the hypothalamus, pituitary, and testis can function to further modulate the HPG axis in complex ways including endocannabinoids, GnRH, kisspeptin, norepinephrine, growth hormone, interleukins, and TGF-β.28 Therefore, the HPG axis represents a dynamic, but tightly regulated, system at multiple levels resulting in spermatogenesis, among other things.


INFLUENCE OF EXOGENOUS ANDROGENS ON SPERMATOGENESIS
The use of exogenous androgens can influence the HPG axis by similar mechanisms as endogenous testosterone by exerting negative feedback in a dose- and duration-dependent fashion, resulting in reductions in ITT, blunting of FSH production, and ultimately decrease or complete cessation of spermatogenesis.29 Data specifically describing the natural history of unassisted spermatogenesis recovery after long-term TRT are lacking, but such information can be extrapolated from the male contraceptive literature.16 Multiple and international trials using various testosterone preparations have been performed and demonstrate a median time to spermatogenesis suppression to <1 × 106 ml-1 sperm within 3.5 months. Alternatively, the same data demonstrate a median time to recovery of 20 × 106 ml-1 sperm ranging from 3 to 6 months, with probability estimates suggesting recovery in 67%, 90%, 96%, and 100% of men at 6, 12, 16, and 24 months, respectively, after discontinuation of testosterone exposure.13 These data also suggest that a longer exposure to exogenous testosterone, Asian ethnicity, and older age may result in a prolonged recovery time after treatment cessation.13,30,31,32 Importantly, one must consider that these data are carefully collected in men within the tightly controlled, clinical trial environment, and may not be generalizable. Certainly, men with a prior, multiple year history of TRT or AAS use may not expect the same rate of recovery.

AAS are synthetic derivatives of testosterone with chemical modifications intended to mimic the anabolic more than the androgenic effects of testosterone. Many abusers use “stacking” regimens with multiple, high-dose AAS agents to maximize muscle mass and weight gain, which are often “cycled” to minimize side effects. Nevertheless, AAS can still bind the androgen receptor within target cells and exert the same negative feedback effects as endogenous testosterone, often resulting in anabolic steroid-induced hypogonadism (ASIH) and associated reductions in serum gonadotropin levels and ITT.9,15,21,33 With abnormally low ITT and FSH, these patients often exhibit azoospermia or oligospermia with reduced motility and/or morphology on semen analysis.15



Selective estrogen receptor modulators (SERMs)

SERMs are a group of medications that function to disrupt binding of estrogen at estrogen receptors in the hypothalamus through competitive antagonism. In men, normal binding of estrogen at these receptors functions as an indirect negative feedback mechanism of endogenous testosterone production to downregulate GnRH and subsequently pituitary gonadotropin production. Therefore, SERMs function to block estrogen feedback thereby increasing GnRH and gonadotropin production and ultimately increasing ITT levels in men without evidence of primary hypogonadism.16,63,64 Clinically, tamoxifen and CC are two of the most commonly used SERMs, with the former popularized by use in breast cancer treatment protocols and the latter popularized by its initial development for triggering ovulation in women. CC exists as a racemic mixture of shorter acting enclomiphene (purely anti-estrogenic effects) and longer acting zuclomiphene (both estrogen agonist and antagonist effects) and exhibits a serum half-life of approximately 5 days.65




Aromatase inhibitors (AIs)

AIs are a class of medications FDA approved for the treatment of early- and late-stage breast cancer and historically include nonselective steroidal, and highly selective nonsteroidal agents, including anastrozole and letrozole. AIs function by inhibiting the aromatase enzyme, which is a cytochrome P450 converter of testosterone-to-estrogen within the testes, liver, brain, and adipose tissues.16 Estrogen is an indirect mediator of testosterone feedback inhibition of the HPG axis. Therefore, aromatase inhibition in men can result in decreased estrogen levels and ultimately increased gonadotropin production. Their use clinically in men is off-label and has focused upon improving male infertility and symptoms of hypogonadism, particularly in obese men or in those with a serum testosterone-to-estrogen (T/E) ratios <10 where improvements of approximately 77% have been observed.64 In addition, AIs can be prescribed for use with exogenous testosterone or hCG to mitigate side effects of hyperestrogenemia such as gynecomastia.








Anabolic steroid-induced hypogonadism – Towards a unified hypothesis of anabolic steroid action
R.S. Tan, M.C. Scally

The HPTA has two components, both spermatogenesis and testosterone production. In males, luteinizing hormone (LH) secretion by the pituitary positively stimulates testicular testosterone (T) production; follicle-stimulating hormone (FSH) stimulates testicular spermatozoa production. The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates LH and FSH secretion. In general, absent FSH, there is no spermatozoa production; absent LH, there is no testosterone production. Regulation of the secretion of GnRH, FSH, and LH occurs partially by the negative feedback of testosterone and estradiol at the level of the hypothalamo-pituitary. Estradiol has a much larger, inhibitory effect than testosterone, being 200-fold more effective in suppressing LH secretion [57–61].




[57] Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley F. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab 2000;85:3027–35.

[58] Bagatell CJ, Dahl KD, Bremner WJ. The direct pituitary effect of testosterone to inhibit gonadotropin secretion in men is partially mediated by aromatization to estradiol. J Androl 1994;15:15–21.

[59] Finkelstein JS, O’Dea LS, Whitcomb RW, Crowley WF. Sex steroid control of gonadotropin secretion in the human male. II. Effect of estradiol administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 1991;73:621–8.

[60] Veldhuis JD, Dufau ML. Estradiol modulates the pulsatile secretion of biologically active luteinizing hormone in man. J Clin Invest 1987;80:631–8. [61] Schnorr JA, Bray MJ, Veldhuis JD. Aromatization mediates testosterone’s shortterm feedback restraint of 24-h endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle

[61] Schnorr JA, Bray MJ, Veldhuis JD. Aromatization mediates testosterone’s shortterm feedback restraint of 24-h endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle stimulating hormone secretion in young men. J Clin Endocrinol Metab 2001;86:2600–6.

 

[madman]

Some important points:


*AAS can also bind the androgen receptor inside target cells and bring into play the same negative feedback effects as endogenous testosterone.

*Androgens, as well as estrogens and progestins, in turn, cause negative feedback inhibition at the hypothalamus and pituitary, lowering the output of gonadotropins and testosterone when too much hormone is present.

*Additional autocrine, paracrine, and endocrine factors within the hypothalamus, pituitary, and testis can function to further modulate the HPG axis in complex ways including endocannabinoids, GnRH, kisspeptin, norepinephrine, growth hormone, interleukins, and TGF-β 28. Therefore, the HPG axis represents a dynamic, but tightly regulated, system at multiple levels resulting in spermatogenesis, among other things.

*Regulation of the secretion of GnRH, FSH, and LH occurs partially by the negative feedback of testosterone and estradiol at the level of the hypothalamo-pituitary. Estradiol has a much larger, inhibitory effect than testosterone, being 200-fold more effective in suppressing LH secretion [57–61].

 

[M.J]

The SERM most studied in the treatment of testosterone deficiency is clomiphene citrate (CC). CC has long been used as a treatment to restore testosterone levels and promote or preserve spermatogenesis in men with testosterone deficiency desiring to preserve fertility, and multiple studies have shown that CC effectively raises testosterone to eugonadal levels (50-56). This medication is an oral compound administered at doses ranging from 25 mg every other day, to 50 mg daily, based on testosterone response. Moskovic et al. reported on 29 men with a baseline total testosterone level of 228±48 ng/dL treated for >3 years with CC. They demonstrated improvements in testosterone to a mean of 582±227 ng/dL (P<0.001), as well as significant improvements in ADAM questionnaire response (P=0.01) and mean BMI (P<0.05) (50). Similarly, Taylor and Levine demonstrated that compared to testosterone gel therapy, CC treatment resulted in equivalent, significant improvements in testosterone levels at a fraction of the cost, as well as significant improvements in ADAM questionnaire scores. No patients discontinued CC treatment due to side effects, and no adverse events on CC were reported. Additionally, patients on CC treatment did not experience changes in hemoglobin, PSA, or cholesterol levels while on treatment (51). Ramasamy et al. have also demonstrated that quantitative ADAM scores were similar among patients treated with CC as compared to those treated with testosterone gels or injections, with improvements in testosterone levels while on CC treatment to physiologic levels (54).

Still, CC has not historically been offered as a first line treatment for testosterone deficiency in men not desiring fertility preservation given its off-label use and lack of long term data regarding safety and efficacy. In the setting of these limitations, ongoing studies are being conducted to establish long-term treatment outcomes. CC is well tolerated. Rare side effects include headaches, visual changes, and gynecomastia (50). Additionally, CC use has shown to have significantly less risk of increased hematocrit as compared to testosterone therapy (57). Preliminary data on men treated for testosterone deficiency on CC for as long as 7 years show that over 80% of men achieve testosterone levels >450 ng/dL, with 78% of men reporting subjective improvement in hypogonadal symptoms, and only 9% reporting side effects from CC treatment with no significant adverse events (58). This data together suggests that CC may be a safe and effective treatment option for the long-term management of testosterone deficiency, and consideration should be made to offering this therapy to men as a first-line treatment option for testosterone deficiency, regardless of the patient’s desire for fertility preservation.

Enclomiphene citrate (EC) is a trans-isomer of CC and is not currently FDA approved in the United States. Like CC, EC has been shown to raise testosterone and gonadotropin levels, while preserving spermatogenesis (59). Additionally, EC treatment may deliver the androgenic effects of CC without the side effects associated with CC, though further studies need to be conducted to determine if EC has clinically superior selectivity (60).

Like CC, tamoxifen has been shown to increase testosterone and gonadotropin levels, and preserve spermatogenesis, and this SERM is an acknowledged alternative treatment option for testosterone deficiency in men (1,61). Tamoxifen has been used to stimulate gonadotropin production, and to treat gynecomastia in the setting of anabolic steroid-induced hypogonadism or hCG treatment (62). However, the adverse effects associated with tamoxifen appear to be greater than those associated with CC use, including gastrointestinal distress, venous thromboembolic events, and other cardiovascular outcomes (63). As such, tamoxifen is less commonly used for the treatment of testosterone deficiency.




When searching the literature it would seem from the studies done using CC as an alternative treatment for hypogonadal men that many end up experiencing improvements in low-t symptoms with minimal side effects.

Judging by the amount of men we see on the forums that use CC as sole therapy to treat hypogonadism the overall beneficial effects tend be a hit or miss as some do feel better (not many), others feel not much difference and many end up feeling horrible.

There is still lack of long-term data regarding the safety and efficacy of CC aside from preliminary data on men that were treated for low-t using CC for up to 7 years with a large percentage of those men reporting subjective improvement.

Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism. - PubMed - NCBI

Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism.


Abstract

PURPOSE:
Clomiphene citrate may be used as an off label treatment of hypogonadism. There are few long-term data on clomiphene citrate efficacy and safety when administered for more than 3 years. We assessed improvements in testosterone and hypogonadal symptoms while on clomiphene citrate for extended periods.

MATERIALS AND METHODS:
We performed a retrospective review to identify patients treated with clomiphene citrate for hypogonadism (baseline testosterone less than 300 ng/dl) at a total of 2 institutions from 2010 to 2018. We assessed the duration of clomiphene citrate therapy, serum testosterone levels, symptom improvement and clomiphene citrate side effects.

RESULTS:
A total of 400 patients underwent clomiphene citrate treatment for a mean ± SD of 25.5 ± 20.48 months (range 0 to 84). Of the patients 280 received clomiphene citrate for 3 years or less (mean 12.75 ± 9.52 months) and 120 received it for more than 3 years (mean 51.93 ± 10.52 months). Of men on clomiphene citrate for more than 3 years 88% achieved eugonadism, 77% reported improved symptoms and 8% reported side effects. Estradiol was significantly increased following clomiphene citrate treatment. Results did not significantly differ between patients treated for more than 3, or 3 or fewer years. The most common side effects reported by patients treated more than 3 years included changes in mood in 5, blurred vision in 3 and breast tenderness in 2. There was no significant adverse event in any patient treated with clomiphene citrate.

CONCLUSIONS:
Clomiphene citrate is not typically offered as primary treatment of hypogonadism in men who do not desire fertility preservation. These data demonstrate that clomiphene citrate is safe and effective with few side effects when used as long-term treatment of hypogonadism.








Enclomiphene (EC) may very well be more effective overall.....let alone minimize any potential side-effects but again rigorous long-term studies are lacking.

Enclomiphene citrate: A treatment that maintains fertility in men with secondary hypogonadism

ABSTRACT Introduction: Hypogonadism is an important issue among the male population. Treatments such as exogenous testosterone have become very popular. One of the adverse effects of testosterone is its suppression of fertility. This has led to the use of alternative therapies such as selective...

www.excelmale.com

Use of tamoxifen and aromatase inhibitors have their own potential downfalls and although many try either hCG mono or clomid.....those using hCG mono tend to not feel as good overall compared to trt.

Madman does this mean long term use of CC can increase nature testosterone level ?

I have tried 25mg daily, morning wood came back daily plus testosterone went to 16/17 nmol/L which was really good however libido was zero. I guess this is the side effect from it.

also estrogen was in reasonable range not crazy high.

any chance EC could work better for me in this case ? Or even long term CC ?

 

[madman]

Madman does this mean long term use of CC can increase nature testosterone level ?

I have tried 25mg daily, morning wood came back daily plus testosterone went to 16/17 nmol/L which was really good however libido was zero. I guess this is the side effect from it.

also estrogen was in reasonable range not crazy high.

any chance EC could work better for me in this case ? Or even long term CC ?

Of course, it can but as to what level one achieves and how effective it is regarding overall improvements in low-t symptoms would come down to the individual/protocol (dose/duration) and keep in mind that use of CC is known to significantly increase estradiol.

As you know not everyone does well using CC.

Have you tried increasing your dose as 25 mg/daily only resulted in you achieving a not so impressive TT of 16-17 nmol/L (461-490 ng/dL) and even then with such numbers it would be hard to achieve a healthy FT level even with an average SHBG.

You should be more concerned with where your SHBG levels sit and what your FT level is on such protocol.

You easily have room to increase your TT which would improve your FT but again you will also drive your e2 up.

Much more involved regarding libido than simply TT/FT/e2 levels although in your case it could very well be related to your FT levels being too low.

EC may very well be more effective but again you did not achieve a decent TT with CC and more importantly, your FT levels are most likely sub-par on such protocol (25 mg daily).

There are other members on the forum who have switched from CC--->EC and you should look into other's feedback and come to your own conclusion on what would be best for you.

 

[M.J]

Of course, it can but as to what level one achieves and how effective it is regarding overall improvements in low-t symptoms would come down to the individual/protocol (dose/duration) and keep in mind that use of CC is known to significantly increase estradiol.

As you know not everyone does well using CC.

Have you tried increasing your dose as 25 mg/daily only resulted in you achieving a not so impressive TT of 16-17 nmol/L (461-490 ng/dL) and even then with such numbers it would be hard to achieve a healthy FT level even with an average SHBG.

You should be more concerned with where your SHBG levels sit and what your FT level is on such protocol.

You easily have room to increase your TT which would improve your FT but again you will also drive your e2 up.

Much more involved regarding libido than simply TT/FT/e2 levels although in your case it could very well be related to your FT levels being too low.

EC may very well be more effective but again you did not achieve a decent TT with CC and more importantly, your FT levels are most likely sub-par on such protocol (25 mg daily).

There are other members on the forum who have switched from CC--->EC and you should look into other's feedback and come to your own conclusion on what would be best for you.

I shifted to 50mg twice weekly did a thread on it, I got multiple honeymoons! First two weeks, and around 40 days got another maybe 10 days. Using sustanon.
daily strong morning wood! it was amazing.
I even got good results between those two honeymoons.
Sustanon EOD 25was a total failure even the honey moon I got there was not significant.

I am restarting now (clomid ) trying to get my wife pregnant then i will try once weekly or shift to cream.( if I can get it)

seems fast movement in testosterone and fluctuation (multiple easters) maybe did all this. sustanon EOD total failure.

 

[M.J]

Of course, it can but as to what level one achieves and how effective it is regarding overall improvements in low-t symptoms would come down to the individual/protocol (dose/duration) and keep in mind that use of CC is known to significantly increase estradiol.

As you know not everyone does well using CC.

Have you tried increasing your dose as 25 mg/daily only resulted in you achieving a not so impressive TT of 16-17 nmol/L (461-490 ng/dL) and even then with such numbers it would be hard to achieve a healthy FT level even with an average SHBG.

You should be more concerned with where your SHBG levels sit and what your FT level is on such protocol.

You easily have room to increase your TT which would improve your FT but again you will also drive your e2 up.

Much more involved regarding libido than simply TT/FT/e2 levels although in your case it could very well be related to your FT levels being too low.

EC may very well be more effective but again you did not achieve a decent TT with CC and more importantly, your FT levels are most likely sub-par on such protocol (25 mg daily).

There are other members on the forum who have switched from CC--->EC and you should look into other's feedback and come to your own conclusion on what would be best for you.

My experience with clomid 25 ED was
Estrogen 22
Testosterone 16 nmol/l

really good results not bad I believe I can do good at this range but I read somewhere that clomid have this bad effect libido not so good.

but do I understand this correctly, is a long term use of clomid can increase testosterone without clomid? Cuz as soon as I stop it I my t go down to 10 nmol/l.