Enclomiphene vs HCG – in this article, we’ll discuss:
- What they are
- How they work
- How effectively do they work
- Who would benefit from them
- Do they work with TRT
In 2006 Mulligan et al. observed that 40% of men over the age of 45 had low serum testosterone levels.
These men are in dire need of a solution.
A few options to resolve low testosterone include:
- Clomid (clomiphene citrate)
- Androxal (enclomiphene)
- TRT (injection, pellet, topical and oral)
Clomid vs Androxal (Clomiphene vs Enclomiphene)
Clomid and Androxil are the drug names for Clomiphene citrate vs Enclomiphene citrate.
Clomid consists of 60% enclomiphene and 40% zuclomiphene, whereas enclomiphene is 100% enclomiphene.
Clomiphene citrate is a SERM (selective estrogen receptor modulator) that has been used since the 1960s to facilitate ovulation induction. Clomiphene has also been used off-label to raise LH, FSH and testosterone levels in men with secondary or idiopathic hypogonadism, and to raise sperm counts in men with a history of infertility or steroid use.
Enclomiphene works by blocking the estrogen receptor (estrogen antagonist) in the hypothalamus and pituitary, thus increasing GnRH, LH and FSH levels.
Zuclomiphene on the other hand is an estrogen receptor agonist, which causes estrogenic side effects often reported with clomiphene use. It doesn’t increase LH, but might actually lower it since it’s estrogenic. Additionally, zuclomiphene has a longer half-life (30 days) when compared to clomiphene citrate (10 hours), resulting in persistent side effects lasting beyond the therapeutic effects of the drug. Zuclomiphene is thought to be responsible for most of Clomid’s side effects.
Although Clomid consists of 60% enclomiphene and 40% zuclomiphene, after at least 6 weeks of Clomid use, the zuclomiphene to enclomiphene ratio was 20:1 (R). This indicates that estrogenic symptoms will become more noticeable with prolonged use.
So clearly Enclomiphene (Androxal) is better than Clomid.
Enclomiphene vs HCG
Enclomiphene & HCG are very different.
A quick summary of HCG includes that HCG:
- Acts like LH and shuts down endogenous LH production.
- Doesn’t increase FSH, thus isn’t that good for fertility.
- Has a long half-life of 24-36 hours, and thus can be taken every other day.
- Doesn’t increase testosterone very effectively, unless very large doses of 4000IU daily are taken.
- Has to be taken via injection.
A quick summary of enclomiphene includes that enclomiphene:
- Increases GnRH, LH and FSH
- Peaks LH 2-3 hours after dosing.
- Has a 10-hour half-life.
- Increases LH in a dose-dependent manner.
- Reaches a steady-state level at 25mg per day (R). Using more than 25mg will not result in a bigger increase in LH.
- Keeps testosterone elevated for up to 7 days after stopping.
- Has fewer side effects than Clomid, due to the lack of zuclomiphene
- Can be taken orally.
However, despite enclomiphene increasing FSH, it’s not very good at improving male fertility.
Enclomiphene vs HCG with TRT?
HCG is regularly used together with testosterone to prevent testicular shrinkage and infertility. Since HCG acts like LH, it does a very good job together with TRT. Even low doses of 150-250mcg every other day is enough to preserve intra-testicular testosterone for fertility.
Enclomiphene inhibits the estrogen receptors in the hypothalamus and pituitary and increases LH and FSH. Since testosterone, DHT and estrogen can inhibit LH release, just blocking the estrogen receptor is unlikely to increase LH when used together with testosterone. Enclomiphene doesn’t prevent the negative feedback loop induced by testosterone and DHT.
Thus, enclomiphene is unlikely to preserve pregnenolone, progesterone and sperm production when on TRT.
However, there are reports that enclomiphene use can prevent testicular shrinkage when used with TRT, although it doesn’t preserve fertility.
On a last note, if Gonadorelin is used (which acts like GnRH), enclomiphene can help promote LH release in conjunction with Gonadorelin. However, once-a-day use of gonadorelin is not likely to produce good results, since, in normal men, since GnRH is pulsed 10-20 times a day.
Who should use enclomiphene or HCG?
Enclomiphene and HCG are best for people with low LH and testosterone (secondary hypogonadism).
If the secondary hypogonadism (low LH and lot T) has been shown to be caused by a congenital gonadotropin releasing hormone deficiency (insufficient GnRH), craniopharingiomas (rare brain tumor that develops in the pituitary gland), haemochromatsis (a buildup of iron in the blood that results in damage to the testis, heart, joints, liver and pancreas) or pituitary tumors, enclomiphene citrate is not recommended.
People with normal LH and low testosterone (primary hypogonadism), will likely not respond well to HCG or enclomiphene.
If LH is high/normal and testosterone low, it indicates testicular insensitivity to LH. This is often due to nutritional deficiencies and/or inflammation.
How effective are enclomiphene and HCG at increasing testosterone
Enclomiphene increase testosterone
Study 1: 25 enclomiphene for 3 months
After 3 months, 12.5mg and 25mg enclomiphene increased testosterone from 210ng/dl and 209.8ng/dl to 471.9ng/dl and 405.8ng/dl, respectively. As you can see, according to this study, 25mg was not better than 12.5mg (R).
Study 2: comparing 6.25, 12.5 and 25mg enclomiphene
Enclomiphene increased testosterone in a dose-dependent manner (R). In the graph below, 25mg was better than 12.5, which was better than 6.25mg.
It also increased LH in a dose-dependent manner.
Here is the morning response in testosterone to 25mg enclomiphene. Most people were between 400-700, whereas there was one just over 800 and another up to 1000ng/dl. This means that everyone responds differently to enclomiphene. It also means that if someone is able to get 1000ng/dl with enclomiphene, they are the outlier, not the norm.
Here is what happened to their testosterone after stopping enclomiphene.
The red square is 25mg, the solid green is 12.5 and the dotted green is 6.25mg. After stopping after the 6th week, testosterone decreased a little on the 6.25 and 12mg doses but increased on the 25mg dose.
After another 7 days (2 weeks after quitting) testosterone levels were the same in all three enclomiphene groups.
One important thing to keep in mind here is that LH increased the most between the 12.5 and 25mg dose, but the 24-h average of total testosterone only increased by 27%, suggesting a dose-limiting effect on the testosterone-producing Leydig cells of the testes. This means that enclomiphene is unable to stimulate testosterone production to supraphysiological levels.
Study 3: 25mg Clomid vs 1mg anastrozole daily
Although this study is not using enclomiphene, but Clomid, it’s still valuable.
In the anastrozole group, testosterone increased from 248 to 408 ng/dL at 12 weeks, whereas 25mg Clomid increased testosterone from 254 to 571 ng/dL at 12 weeks (R).
Estradiol increased from 27 to 50pg/ml. Estradiol increased a lot for the small increase in testosterone. Although the testosterone-to-estradiol ratio improved a bit, this is not favorable IMO, as excess estradiol can contribute to ED. Article: How estrogen can contribute to ED (scroll down to the estrogen section).
Additionally, LH increased from 3.9 to 8.9 and 7.4 after 6 and 12 weeks respectively.
Clomid and enclomiphene are roughly equally effective at increasing testosterone, but I still prefer enclomiphene, since it doesn’t have the estrogenic component.
HCG increase testosterone
Let’s see how effective HCG is at boosting testosterone:
- 120IU was unable to increase serum testosterone in men with normal testosterone (461ng/dl) (R).
- 2,000 IU of HCG per week increased testosterone from 362ng/dL to 519.8 ng/dL (a 49.9% increase) (R).
- 1,500-2,000IU 2-3 times weekly increased testosterone into the normal range in hypogonadal men (R).
- 3,000-10,000IU of HCG every 3rd day with 25mg clomiphene citrate daily increased testosterone from 22ng/dl to 520ng/dl and 565ng/dl after 6 and 12 months respectively (R).
- 2,000IU of HCG 2-3 times per week increased testosterone from 307.36 to 422.11ng/dL.
- 1,500 to 2,000 IU 3 times weekly increased testosterone levels from 26 to 161ng/dl (R).
In summary, regular doses of 250-500IU every other day are unlikely to increase testosterone to any significant extent. However, low-dose HCG injections are effective at increasing intra-testicular testosterone, which is needed for sperm production.
Doses of 2000IU every other day are needed to increase testosterone into the mid-range (500-600ng/dl) and 4000IU daily is needed to increase testosterone into the upper range (1000ng/dl).
Such large doses are most commonly used for fertility treatment.
HCG & clomid increase testosterone
This study looked at the combination of 25mg Clomid and 5000IU twice a week of HCG on testosterone and fertility.
Before treatment, the average testosterone level was 0.76 ± 1.84nmol/mL (22ng/dl 😱😱). After 6 and 12 months, testosterone increased to 17.9 ± 6.07 (516ng/dl) and 19.6 ± 5.6nmol/L (565ng/dl) respectively (R).
Disappointing results am I right?! But it could be because they had such low T, to begin with.
Side effects of enclomiphene and HCG
Side effects of enclomiphene include:
- Elevated estradiol levels
- headache and
- abdominal discomfort
- Visual disturbances (R).
- No boost in libido
- Decreased IGF-1 levels, almost by half (R). IGF-1 is necessary for libido, erections, regeneration, anabolism, etc.
Side effects of clomiphene citrate, which is more completely studied and FDA-approved, include:
- Hot flushes
- Pelvic distension and bloating
- Nausea and vomiting
- Breast/pectoral tenderness and even gyno
- Visual disturbances such as eye floaters and blurry vision
- Acceleration of prostate cancer growth (if cancer is already present) – likely due to the estrogenic effects. Article: Testosterone protects against prostate cancer whereas estradiol worsens it.
- Raising SHBG, likely due to its estrogenic component.
- Brain fog and moodiness.
Side effects of HCG
- Suppressing LH
- Doesn’t increase FSH, similar to enclomiphene
- Speeding up cancer due to stimulation of angiogenesis
- Severe stomach pain or pelvic pain
- Rapid weight gain, swelling around your waist
- Feeling short of breath
- Nausea and vomiting
- Little or no urination.
- Headache, depression;
- Feeling restless or irritable
- breast tenderness or swelling
- pain where the medicine was injected
Both enclomiphene and HCG are effective at increasing testosterone and sperm production in the absence of TRT.
Enclomiphene is unlikely to maintain intratesticular testosterone and fertility while on TRT. This is where HCG shines.
Both have side effects, with low-dose HCG likely to have less.
Although enclomiphene is great at optimizing numbers on your lab results, it very rarely boosts sexual function, such as libido. Some argue that’s because enclomiphene is an estrogen antagonist and estrogen is involved in libido.
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