Why clinical trials for enclomiphene were aborted

[Forty2]

Does anyone know why the clinical trials for enclomiphene ended prematurely?
Was it because of low participant satisfaction or some other reason?

 

[Systemlord]

Does anyone know why the clinical trials for enclomiphene ended prematurely?
Was it because of low participant satisfaction or some other reason?

The FDA banned enclomiphene.

 

[Cataceous]

Does anyone know why the clinical trials for enclomiphene ended prematurely?
Was it because of low participant satisfaction or some other reason?

I believe this was the final nail in the coffin. Repros perhaps sensed moving goalposts and couldn't risk additional expenditures.

In the letter, the FDA stated that, based on recent scientific developments, the design of enclomiphene Phase 3 studies is no longer adequate to demonstrate clinical benefit and recommended that Repros conduct an additional Phase 3 study or studies to support approval in the target population. The FDA also noted concerns regarding study entry criteria, titration and bioanalytical method validation in the Phase 3 program.​

More recently the FDA declined to add enclomiphene to the 503A Bulks List, which in time will make pharmaceutical-grade enclomiphene unavailable in the U.S. I can't vouch for its accuracy, but a couple months ago an online source claimed that the Bulks List had not been updated yet, allowing a temporary stay of execution.

 

[tareload]

I believe this was the final nail in the coffin. Repros perhaps sensed moving goalposts and couldn't risk additional expenditures.

In the letter, the FDA stated that, based on recent scientific developments, the design of enclomiphene Phase 3 studies is no longer adequate to demonstrate clinical benefit and recommended that Repros conduct an additional Phase 3 study or studies to support approval in the target population. The FDA also noted concerns regarding study entry criteria, titration and bioanalytical method validation in the Phase 3 program.​

More recently the FDA declined to add enclomiphene to the 503A Bulks List, which in time will make pharmaceutical-grade enclomiphene unavailable in the U.S. I can't vouch for its accuracy, but a couple months ago an online source claimed that the Bulks List had not been updated yet, allowing a temporary stay of execution.

Thank you Dear Heavenly Father/Mother/Other for our beloved Cataceous.

 

[Forty2]

I believe this was the final nail in the coffin. Repros perhaps sensed moving goalposts and couldn't risk additional expenditures.

In the letter, the FDA stated that, based on recent scientific developments, the design of enclomiphene Phase 3 studies is no longer adequate to demonstrate clinical benefit and recommended that Repros conduct an additional Phase 3 study or studies to support approval in the target population. The FDA also noted concerns regarding study entry criteria, titration and bioanalytical method validation in the Phase 3 program.​

More recently the FDA declined to add enclomiphene to the 503A Bulks List, which in time will make pharmaceutical-grade enclomiphene unavailable in the U.S. I can't vouch for its accuracy, but a couple months ago an online source claimed that the Bulks List had not been updated yet, allowing a temporary stay of execution.

Thanks, Cat.
Do you know why most guys feel pretty much the same in all areas when taking enclomiphene, even when testosterone can raise by more than 3 times baseline?

 

[FunkOdyssey]

Thanks, Cat.
Do you know why most guys feel pretty much the same in all areas when taking enclomiphene, even when testosterone can raise by more than 3 times baseline?

I think there are two possibilities:

1) Testosterone is just a prohormone for DHT and estradiol in most tissues and is relatively inert by itself, with some exceptions like anabolic effects in muscle. Blocking estrogen receptors with estradiol may block many of the benefits of higher testosterone which are mediated by conversion to estradiol. This is especially relevant in the brain.

2) In some guys (many guys?), there is just not that much subjective difference between low normal and high normal testosterone levels. I wouldn't have believed this before spending a few months on TRT myself. Some percentage of men underwhelmed by enclomiphene will also be underwhelmed by TRT for this reason.

 

[CKO]

Having tried enclomiphene several times and getting great labs from it, I can attest it doesn't make you feel better. I think it has to do with the way it acts on your estrogen receptors. That being said, I think enclomiphene could be successful if it wasn't taken daily. An every other day schedule would prevent the excess interaction with e2 receptors. I'm planning to try this in the near future, I'll post how it goes.

 

[madman]

Does anyone know why the clinical trials for enclomiphene ended prematurely?
Was it because of low participant satisfaction or some other reason?

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

 

[Forty2]

I think there are two possibilities:

1) Testosterone is just a prohormone for DHT and estradiol in most tissues and is relatively inert by itself, with some exceptions like anabolic effects in muscle. Blocking estrogen receptors with estradiol may block many of the benefits of higher testosterone which are mediated by conversion to estradiol. This is especially relevant in the brain.

2) In some guys (many guys?), there is just not that much subjective difference between low normal and high normal testosterone levels. I wouldn't have believed this before spending a few months on TRT myself. Some percentage of men underwhelmed by enclomiphene will also be underwhelmed by TRT for this reason.

When taking enclomiphene, my estraiol was 50% above the reference range and DHT had doubled from baseline levels. Despite that, I noticed no increase in libido, no increase in muscle strength, no increase in energy level or improvement in mood.
What I did notice was that the skin on my face became a lot more oily and my appetite increased, which resulted in an 8lb weight gain over 2 months.

When I took regular clomid, I noticed a significant increase in libido and muscle strength over the first month before the negative side effects kicked in.
Why would this occur from clomid but not enclomiphene?

Also when I tried hCG monotherapy, it did not bring my T level up as high as clomid and enclomiphene did, but energy and libido were much higher.
Muscle strength, however, was lower. I suspect that this may be because hCG also increases progesterone, which when too high, can weaken muscles.

 

[Systemlord]

Also when I tried hCG monotherapy, it did not bring my T level up as high as clomid and enclomiphene did, but energy and libido were much higher.

Clomid and enclomiphene blocks neurotransmitter estrogen receptors, blocks receptors in the heart, liver and the pancreas.

HCG doesn't block any receptors whatsoever.

 

[Cataceous]

When taking enclomiphene, my estraiol was 50% above the reference range and DHT had doubled from baseline levels. Despite that, I noticed no increase in libido, no increase in muscle strength, no increase in energy level or improvement in mood.
What I did notice was that the skin on my face became a lot more oily and my appetite increased, which resulted in an 8lb weight gain over 2 months.

When I took regular clomid, I noticed a significant increase in libido and muscle strength over the first month before the negative side effects kicked in.
Why would this occur from clomid but not enclomiphene?
...

Possibly because with Clomid you're counteracting the reduction in estrogenic activity caused by enclomiphene; the zuclomiphene isomer of Clomid acts as an estrogen. It's been suggested that serum estradiol measurements have less value when one is using a SERM—they're not accurately reflecting overall estrogenic activity, and they can't tell you anything about shifts in relative estrogenic activity between various sites.

 

[Nelson Vergel]

Repros ran out of money and gave up in 2015 after trying for 5 years to get the FDA to approve Androxal (enclomiphene)

Repros Therapeutics Receives Complete Response Letter From FDA for Enclomiphene

Androxal (enclomiphene citrate) is a new drug in development for the treatment of hypogonadism. Androxal information includes news, clinical trial results and side effects.

www.drugs.com

This year, the FDA also banned compounded enclomiphene since it was not FDA approved.

 

[FunkOdyssey]

Here are my interpretations of your experience:

When taking enclomiphene, my estradiol was 50% above the reference range and DHT had doubled from baseline levels. Despite that, I noticed no increase in libido, no increase in muscle strength, no increase in energy level or improvement in mood.

Increased testosterone with estrogen receptor blockade = benefit blockade in many people.

What I did notice was that the skin on my face became a lot more oily

You still had plenty of AR agonism despite the ER shenanigans.

When I took regular clomid, I noticed a significant increase in libido and muscle strength over the first month before the negative side effects kicked in.
Why would this occur from clomid but not enclomiphene?

ER agonism of zuclomiphene might have countered the ER antagonism of enclomiphene for awhile and allowed some beneficial effects to sneak through.

Also when I tried hCG monotherapy, it did not bring my T level up as high as clomid and enclomiphene did, but energy and libido were much higher.

Increased testosterone with unblocked estrogen receptors = benefits realized.

 

[Forty2]

Possibly because with Clomid you're counteracting the reduction in estrogenic activity caused by enclomiphene; the zuclomiphene isomer of Clomid acts as an estrogen. It's been suggested that serum estradiol measurements have less value when one is using a SERM—they're not accurately reflecting overall estrogenic activity, and they can't tell you anything about shifts in relative estrogenic activity between various sites.

I think you're probably right!
Btw the serum estradiol test was just the regular estradiol test, not the sensitive estradiol test.
Could you please explain why the sensitive estradiol test is the correct one that men should use?

 

[Forty2]

Here are my interpretations of your experience:


Increased testosterone with estrogen receptor blockade = benefit blockade in many people.


You still had plenty of AR agonism despite the ER shenanigans.


ER agonism of zuclomiphene might have countered the ER antagonism of enclomiphene for awhile and allowed some beneficial effects to sneak through.


Increased testosterone with unblocked estrogen receptors = benefits realized.

Thanks. I think that's an accurate assessment of what occurred.
Just wondering why the AR agonism that caused the oily skin did not also result in greater muscle strength? I thought that elevation in DHT normally increases muscle strength?
One other side effect I got from enclomiphene was that my muscles and joints felt a bit more sore than usual even though I did not make any changes to my exercise routine. Could this be because enclomiphene blocks estrogen receptors in the muscles too?

 

[FunkOdyssey]

Just wondering why the AR agonism that caused the oily skin did not also result in greater muscle strength? I thought that elevation in DHT normally increases muscle strength?
One other side effect I got from enclomiphene was that my muscles and joints felt a bit more sore than usual even though I did not make any changes to my exercise routine. Could this be because enclomiphene blocks estrogen receptors in the muscles too?

The usual benefits of testosterone on muscle strength and growth will be at least partially countered by enclomiphene's reduction of IGF-1. Estradiol also has anabolic effects in both muscle and connective tissue. I think Enclomiphene could cause the joint soreness associated with low estradiol by blocking estrogen receptors in the joints.

 

[JmarkH]

As I understand it, CPC-1295/Ipamorelin or CPC-1295/GHRP6 could be used to counteract the reduction of IGF-1.

 

[Cataceous]

...
Btw the serum estradiol test was just the regular estradiol test, not the sensitive estradiol test.
Could you please explain why the sensitive estradiol test is the correct one that men should use?

I don't agree that the "sensitive" test is necessarily the correct one. For me it has been highly problematic, such that I rely exclusively on the regular immunoassay test. However, the standard test can have significant cross-reactivities, so you have to be confident that these don't apply to your situation before relying on it.

References:

Difference between ECLIA (Regular) vs LC/MS (Sensitive) Estradiol Test Methods

Hello. i read many articles saying LC/MS is really more accurate system for hormon blod test. But this method is not available in a lot of country. Sensitive Estradiol Blood Test: The Only Accurate Assay for Men In Italy there is not ONE lab that use this method. Most part of Lab use ECLIA...

www.excelmale.com

Read this and following posts:

Why All Men Should be Tested with the Sensitive Estradiol Test

I didn't know that! Thanks.

www.excelmale.com

 

[Simbarn]

Possibly because with Clomid you're counteracting the reduction in estrogenic activity caused by enclomiphene; the zuclomiphene isomer of Clomid acts as an estrogen. It's been suggested that serum estradiol measurements have less value when one is using a SERM—they're not accurately reflecting overall estrogenic activity, and they can't tell you anything about shifts in relative estrogenic activity between various sites.

Dr. Crisler mentioned many times, you cannot assay estrogen properly whilst taking a SERM.