Why Clomid Fails: The Zuclomiphene Threshold

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socks

New Member
Part One: Clomid Introduction
- Selective estrogen receptor modulator, which occupies e2 receptors acting as a weak estrogen

- Two parts/isomers, 30-50% zuclomiphene(estrogenic) and 50-70% enclomiphene (non-estrogenic) (1)

- Inhibits negative feedback of e2 primarily at the hypothalamus/pituitary, thus stimulating the following: GnRH-->LH/FSH-->Leydig Cells-->Testosterone

- Antagonist at Hypothalamus and pituitary

- Agonist (increased estradiol) in the liver, hippocampus, brain stem, neocortex, fat, blood plasma (2)

Part 2: The Zuclomiphene Threshold
It seems that most Clomid patients experience some positive results before Zuclomiphene, the estrogenic isomer, accumulates and begins agonizing (pun intended) brain centers associated with mood/libido (2). Thus, it follows that these patients, the majority, are hitting a threshold accumulation of Zuclomiphene and it's primarily this, not e2 levels, which leads to therapy failure. e2 is a red herring, Zuclomiphene appears the culprit.

Doc Saya on Zuclomiphene:
There really isn't a better way to manage the estrogenic effects of the zuclomiphene other than simply LIMITING the burden of zuclomiphene (via dosage adjustment of Clomid) based on the patient's sensitivity. This is superior to DIM, CDG, or AI.

Why is dosage a MORE powerful tool than any estrogen management ancillary in Clomid treatment? The LONG half-life of the zuclomiphene isomer, it's corresponding threshold (different for each individual), and the novel effects it has upon brain regions. This, you will find is the mechanism to Clomid therapy failure in the treatment of Low T symptoms.


For the "great 1st week, bad 2nd week" responders @25mg ED, the threshold appears around 50-75mg (assuming 11day HL pg.49). Although as seen in the introduction, the wildly non-standard quantities of each isomer makes calculations difficult.

Let's hear some patient experiences who had a great first week on Clomid before the Zuclomiphene threshold began negating the benefits of the Enclomiphene isomer.

Part Three: to follow
 
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Defy Medical TRT clinic doctor

socks

New Member
I linked to my sources, might have missed one. I'd been writing this up in Word and its now to the point I thought it would be useful to share.
 
Thanks to the FDA for making fatal last year's release of Androxal which is essentially clomid minus the zuclomiphene, and thus would've avoided the estrogenc double-edged sword effect of clomid. Repros apparently does not have a good rep as a pharmaceutical co., but at least the idea was novel and sounded promising.

I have two friends on low-dose (15-25mg) clomid. Both had dramatic FSH/LH as well as total and free T level increases, but in one, I am seeing an increase in E2 and SHBG. As an alternative to adex, I suggested looking into a natural AI like calcium-d-glucarate to help detox the excess E2. Thoughts?
 

DLK

Member
I had a pretty good first couple of weeks but then my mood became a roller coaster and it felt like a constant headache, It did its job increasing my total T/LH / FSH /free T but also raised my SHBG. I was on clomid for a little over 3 mos. but couldn't take the mood or headaches any longer. I believe things would be different without the zuclomiphene.
 

Nelson Vergel

Founder, ExcelMale.com
The FDA has not declined approval of Androxal yet. They are asking for more data. I am actually happy they did.

February 8, 2016

Repros Holds Meeting With FDA to Discuss Complete Response Letter for Enclomiphene in the Treatment of Secondary HypogonadismTHE WOODLANDS, Texas, Feb. 08, 2016 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that on February 4, 2016, the Company attended a productive meeting with FDA reviewers and senior leaders to discuss resolution of issues identified during the enclomiphene NDA review. The meeting agenda covered a broad range of topics surrounding the NDA data as well as emerging Agency and expert thinking regarding the treatment of hypogonadism. The Company believes that it was clear during the meeting that the FDA is not closed to entertaining secondary hypogonadism as an indication.

January 4, 2016

Repros Updates Enclomiphene ProgramRepros expects to meet with FDA to discuss "Complete Response Letter" for enclomiphene NDA during February 2016
Marketing Authorization Application (MAA) for enclomiphene planned for submission in Europe mid-2016
THE WOODLANDS, Texas, Jan. 04, 2016 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that it has been granted a meeting with the Division of Bone, Reproductive and Urologic Products (DBRUP) of the FDA to discuss aspects of the "Complete Response Letter" received on Nov. 30, 2015 for the enclomiphene NDA. The meeting will be held during February 2016.
European MAA
The Company plans a central filing in Europe for an indication of enclomiphene for the treatment of secondary hypogonadism. The remaining item on the critical path to the submission is manufacture of finished drug product in Europe meeting EU requirements. The Company believes the MAA will be submitted mid-2016. The review cycle for a central filing is 17 months.
 
The FDA has not declined approval of Androxal yet. They are asking for more data. I am actually happy they did.

February 8, 2016

Repros Holds Meeting With FDA to Discuss Complete Response Letter for Enclomiphene in the Treatment of Secondary Hypogonadism

THE WOODLANDS, Texas, Feb. 08, 2016 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that on February 4, 2016, the Company attended a productive meeting with FDA reviewers and senior leaders to discuss resolution of issues identified during the enclomiphene NDA review. The meeting agenda covered a broad range of topics surrounding the NDA data as well as emerging Agency and expert thinking regarding the treatment of hypogonadism. The Company believes that it was clear during the meeting that the FDA is not closed to entertaining secondary hypogonadism as an indication.

January 4, 2016

Repros Updates Enclomiphene Program

Repros expects to meet with FDA to discuss "Complete Response Letter" for enclomiphene NDA during February 2016
Marketing Authorization Application (MAA) for enclomiphene planned for submission in Europe mid-2016
THE WOODLANDS, Texas, Jan. 04, 2016 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that it has been granted a meeting with the Division of Bone, Reproductive and Urologic Products (DBRUP) of the FDA to discuss aspects of the "Complete Response Letter" received on Nov. 30, 2015 for the enclomiphene NDA. The meeting will be held during February 2016.
European MAA
The Company plans a central filing in Europe for an indication of enclomiphene for the treatment of secondary hypogonadism. The remaining item on the critical path to the submission is manufacture of finished drug product in Europe meeting EU requirements. The Company believes the MAA will be submitted mid-2016. The review cycle for a central filing is 17 months.

Good news. Thanks for the update, Nelson!
 

socks

New Member
I have two friends on low-dose (15-25mg) clomid. Both had dramatic FSH/LH as well as total and free T level increases, but in one, I am seeing an increase in E2 and SHBG. As an alternative to adex, I suggested looking into a natural AI like calcium-d-glucarate to help detox the excess E2. Thoughts?

Since both Clomid isomers are excreted primarily (50%) via the gut Cal-D-Glucarate shouldn't have much affect since it works at the renal(kidney) level to increase glucuronidation of different chemicals/hormones. A mere 8% of clomid excretion appears to take place in the kidneys. It certainly shouldn't hurt to take it though. Something like activated charcoal which enhances excretion of toxins/chemicals at the gut level should theoretically prove more useful.

It's also useful to note that zuclomiphene has more bioavailability which accounts for it's greater accumulation in different tissues and half-life. As such, individual excretion rates can vary wildly. There's also the issue of hepatic(liver) recirculation because of it's competitive metabolism with e2.
 
Since both Clomid isomers are excreted primarily (50%) via the gut Cal-D-Glucarate shouldn't have much affect since it works at the renal(kidney) level to increase glucuronidation of different chemicals/hormones. A mere 8% of clomid excretion appears to take place in the kidneys. It certainly shouldn't hurt to take it though. Something like activated charcoal which enhances excretion of toxins/chemicals at the gut level should theoretically prove more useful.

It's also useful to note that zuclomiphene has more bioavailability which accounts for it's greater accumulation in different tissues and half-life. As such, individual excretion rates can vary wildly. There's also the issue of hepatic(liver) recirculation because of it's competitive metabolism with e2.

Given this, for those not already on Clomid and are seeking an alternative to TRT, it sounds better to just wait until Androxal is approved. For those already taking Clomid and experiencing elevated E2/SHBG, do you think it would take going to anastrozole?
 

socks

New Member
Arimidex will of course control e2, but only aromasin/exemstane would help with lowering SHBG. Arimidex also tends to lower the effectiveness of SERMS(clomid/nolva) so that's a contraindication as well.

It's unfortunate that clomid and nolvadex both have the tendency to increase SHBG. http://www.ncbi.nlm.nih.gov/pubmed/22321061
 
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Very interesting, I've been on 12.5mg of clomid for about 6 weeks now. I have not felt a significant change either up or down. I wonder how my body would react to 25mg a day, or would that push me to that threshold and cause me to feel worse.
 

socks

New Member
Very interesting, I've been on 12.5mg of clomid for about 6 weeks now. I have not felt a significant change either up or down. I wonder how my body would react to 25mg a day, or would that push me to that threshold and cause me to feel worse.

There are many variables (severe understatement) to predicting an individuals reaction. The only way to know is by individual experimentation. This does not however mean we cannot make more informed decisions based on research to create potentially ideal dosing/timing/elimination for an optimal end result. In part three, I'll discuss more about potential avenues of dosing/timing and ancillaries that could result in better outcomes.

Key Variables:
1) Hepatic(liver) metabolism of clomiphene into it's "active" metabolites within the body can vary greatly due to individual genetic polymorphisms of the key cytochrome enzyme(CYP2D6) involved in clomiphene metabolism. Also, competitive metabolism with e2 can increase serum e2 levels or delay clomid metabolite clearance. The latter obviously being an issue since the Z-isomer hangs around longer in our systems and unopposed by the E-isomer(leaves system quicker) the Z-isomer can start to cause issues.

2)Excretion/elimination of the Z-isomer(zuclomiphene) is slow for most and even slower in others. It's accumulation in tissues can happen faster in some patients because it's simply not excreted as fast (3). As such, some will approach their Zuclomiphene threshold slowly or rapidly, or never because they do not have as many ER in certain brain regions or metabolize the Z-isomer so quickly it cannot causes issues (the former being a more likely scenario).
 

Nelson Vergel

Founder, ExcelMale.com
Serum levels of enclomiphene and zuclomiphene in hypogonadal men on long-term clomiphene citrate treatment
Helo, S., Mahon, J., Ellen, J., Wiehle, R., Fontenot, G., Hsu, K., Feustel, P., Welliver, C. and McCullough, A. (2016), Serum levels of enclomiphene and zuclomiphene in hypogonadal men on long-term clomiphene citrate treatment. BJU Int. Accepted Author Manuscript.




Abstract

Objectives

To determine the relative concentrations of enclomiphene (ENC) and zuclomiphene (ZUC) isomers in hypogonadal men (HM) on long-term clomiphene citrate (CC) therapy. To determine whether patient age, body mass index, or duration of therapy were predictive of relative concentrations of ENC and ZUC.
Patients and Methods

Men already on CC 25 mg daily therapy for secondary hypogonadism for a minimum of six weeks were recruited to have their ENC and ZUC levels assessed. Total testosterone (T), free testosterone, estradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) prior to initiation of and while on CC therapy were recorded for all patients. Patient demographics including age, body mass index, and medical comorbidites were recorded. Serum samples were obtained at the time of enrollment to determine ENC and ZUC concentrations.
Results

A total of 15 men were enrolled from June 2015 to August 2015. Median patient age was 36 (range 22-70) years, median body mass index 32.0 (range 21.1-40.3)kg/m2, and median duration of treatment 25.9 (range 1.7-86.6) months. Baseline median total T, estradiol, and LH were 205.0 ng/dL, 17.0 pg/mL, and 4.0 mlU/mL, respectively. Post-treatment median total T, estradiol, and LH increased to 488.0 ng/dL 34.0 pg/mL, and 6.1 mIU/mL, respectively (all p<0.001). Median ENC and ZUC concentrations were 2.2 and 44.0 ng/mL, respectively. After at least six weeks of CC therapy median ZUC: ENC serum concentration ratio was 21.3. On linear regression analysis patient age, body mass index, duration of treatment and serum T levels were not predictive of ENC or ZUC concentrations.
Conclusions

Long-term CC therapy resulted in a significant alteration of ENC and ZUC concentrations, with ZUC as the predominant isomer. Given the vastly different biochemical and toxicological properties of ENC and ZUC, this study supports the need for development of a pure selective estrogen receptor antagonist for the treatment of HM.
 

Varner

Member
I'm very interested in this.

If the suboptimal libido results of Clomid are due to the zuclomiphene, wouldn't we (all other things being equal) see better - or at least different - results in guys using other SERMS?

It's very rare to see a guy prescribed Nolva on the Testosterone forums, much less raloxifene et al. Most of the nolva use is by guys on their post-cycle therapy, which adds a ton of variables. So I don't have any real data points to compare.

If there really isn't much difference between clomid and nolva users, could that imply that the lbido issue is not zuclomiphene, but something a bit more basic to every SERM? Or could it be that any failure to increase libido by nolvadex is caused by a different mechanism?

Ditto with enclomiphene. I got some stuff labeled as enclompihene from a research chemicals site. Obviously, I have no idea of the veracity of the product. I've been on it (and off of Clomid) for about two weeks and feel just about the same. Hard to extrapolate anything from this, due the questionable nature of the substance.
 
I'm very interested in this.

If the suboptimal libido results of Clomid are due to the zuclomiphene, wouldn't we (all other things being equal) see better - or at least different - results in guys using other SERMS?

It's very rare to see a guy prescribed Nolva on the Testosterone forums, much less raloxifene et al. Most of the nolva use is by guys on their post-cycle therapy, which adds a ton of variables. So I don't have any real data points to compare.

If there really isn't much difference between clomid and nolva users, could that imply that the lbido issue is not zuclomiphene, but something a bit more basic to every SERM? Or could it be that any failure to increase libido by nolvadex is caused by a different mechanism?

Ditto with enclomiphene. I got some stuff labeled as enclompihene from a research chemicals site. Obviously, I have no idea of the veracity of the product. I've been on it (and off of Clomid) for about two weeks and feel just about the same. Hard to extrapolate anything from this, due the questionable nature of the substance.

I've used tamoxifen for HPTA stimulation in many guys (though not as many as clomid) with overall varying results, but somewhat less potent than clomid with HPTA stimulation.

We have to not only think of the zuclomiphene effect (which is relevant and also specific to clomid), but also the interaction with central E2 receptors (in the brain) of any and ALL SERMS. This interaction with the E receptors is likely to play an equal or greater role in impacting libido than even the zuclomiphene effect. Variable interactions with receptors (agonist/antagonist) can explain why some guys have a good libido response to clomid, while others have a horrible libido response to clomid (much like some guys have great libido at lower E2 levels and others have great libido at higher E2 levels).
 

Varner

Member
Thanks, Dr. Saya. You've got a knack for dropping seriously helpful information on us in ways we can actually understand. Really appreciate it.
 
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