Enclomiphene restart - how long?

38M who has been on TRT + HCG for ~5 years or so. I wanted to see if I could restart production with the help of enclomiphene, as prior to TRT I had a great response to clomid but could not handle the estrogen related sides.

I started 12.5mg ED about a month ago, and just got back labs from a week ago and am clearly still shutdown:

T - 25 (264-916)
LH - 1.3 (1.7-8.6)
E2, Sens - 3.4 (8.0-35)

If this restart was to be successful, how long should it take from the perspective of waiting for that last drop of synthetic T to go out of my system? Is it too early, or does this mean it won't work?

On the bright side, I've lost 10 lbs since starting (not muscle - my app says primarily fat and water) and am less moody and not as hot and sweaty all the time. Bad part is my libido is completely gone (and what makes that worse how little I care about it being gone).

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Enclomiphene Restart: A User's Journey and General Considerations for HPTA Recovery​

This briefing summarizes a detailed user experience and general information regarding the use of enclomiphene for restarting natural testosterone production after a period of Testosterone Replacement Therapy (TRT). The primary source is a forum thread from "Excel Male TRT Forum" titled "Enclomiphene restart - how long?".

Key Themes and Most Important Ideas/Facts:​

1. The Challenge of HPTA Restart Post-TRT:​

The central theme is the difficulty and duration of restarting the Hypothalamic-Pituitary-Testicular Axis (HPTA) after long-term TRT. The user "GeauxBears" was on TRT + HCG for approximately 5 years and sought to restart natural production using enclomiphene. Initial lab results clearly showed a "shutdown" HPTA with very low Testosterone (T - 25 ng/dL, normal range 264-916 ng/dL) and LH (1.3 mIU/mL, normal range 1.7-8.6 mIU/mL) after about a month on enclomiphene.

2. Timeframe for HPTA Recovery with Enclomiphene:​

Restarting the HPTA is not an immediate process. Super Moderator "Seagalmadman" advises giving it "more time (3-6 months)." This is supported by general conclusions cited in the forum:

• "About one in every four patients respond to a CC short trial to 'reboot' the HPT axis physiology."
• "In men prescribed CC for fertility optimization, we observed a maximal improvement in TT at 6 months, followed by a plateau."
• "6 months of CC may be needed to achieve maximal benefit in TT while 9 months may be necessary to observe statistical benefit in sperm concentration."

3. Patient Experience During Restart (GeauxBears' Journey):​

GeauxBears' experience highlights the significant side effects and challenges during the initial months of attempting a restart:

• Initial shutdown: After one month on 12.5mg enclomiphene daily, T was 25 ng/dL, LH 1.3 mIU/mL, and E2 (estradiol) 3.4 pg/mL (normal 8.0-35 pg/mL).
• Worsening symptoms (Month 2-3): After doubling the dose to 25mg enclomiphene daily, labs remained essentially the same (T - 30 ng/dL, LH - 2.5 mIU/mL). Symptoms included:
• Being "cold 95% of the time, until I have a hot flash which lasts 2-3 minutes."
• "Zero libido."
• Inability to achieve erections.
• "Some depression... taking hold."
• "Insulin resistance has exploded."
• Ironically, "testicles are larger than they were on TRT+HCG" and "lost a lot of water weight."
• Signs of recovery (Month 3-4):Mid-March (approx. 1 month after dose increase): T increased to 242 ng/dL, FT 4.4 pg/mL. Still experienced "near-constant swings in body temperature" and "zero libido," but noted subjective improvement and less frequent hot flashes.
• Late March (approx. 1.5 months after dose increase): T further increased to 415 ng/dL, FT 8.5 pg/mL, and LH significantly improved to 7.3 mIU/mL. Libido "slowly began coming back in waves" and hot flashes were "much less prevalent."
• Early May (approx. 3 months after dose increase): T reached 700 ng/dL, FT 10.5 ng/dL. This shows a gradual, albeit difficult, improvement over several months.

4. Important Considerations for Restart:​

• HCG and Restart: "Vince" (Super Moderator) explicitly states, "Don't use HCG with a restart," as it is HPTA suppressive.
• Insulin Resistance and LH: "Systemlord" suggests that "Your insulin resistance is preventing your pituitary from creating more LH and is affecting your testicles production of testosterone." They also link low testosterone to an increased chance of type 2 diabetes.
• Diet and Thyroid: "sammmy" suggests that "Being cold most of the time suggests suppressed thyroid - this may be related to your low carb diet and intermittent fasting." They recommend increasing carb intake and ensuring sufficient calories.
• Enclomiphene Dosing: GeauxBears started at 12.5mg ED and then doubled to 25mg ED. By May, they were still on 25mg daily, hoping to "dial back over time."
• SHBG Changes: GeauxBears observed low SHBG on TRT but higher SHBG on enclomiphene/clomid. "Cataceous" explains that "Androgens tend to lower SHBG while estrogens tend to raise it. TRT, particularly with injections, can result in unnaturally high levels of testosterone. This is what lowers SHBG. Clinical trials suggest that enclomiphene alone does not have much effect on SHBG. So basically your SHBG is bouncing back to a less suppressed state. Clomid contains zuclomiphene in addition to enclomiphene. Zuclomiphene is estrogenic, and consequently helps to raise SHBG."
• LH Pulsatility: "Cataceous" reminds users that "LH is pulsatile, so don't worry too much if you have lower values in the future. Seeing a reading of 7.3 mIU/mL, even at a peak, is good news."

5. Alternatives and Less Painful Restart Strategies:​

"Cataceous" suggests alternatives to a "cold turkey" restart to minimize the period of very low testosterone:

• Switching to faster-acting, less suppressive testosterone: "The idea is to switch to a faster-acting form of testosterone that is less suppressive of HPTA function. The restart may take longer, but you don't have to endure a period of very low testosterone."
• Oral testosterone with enclomiphene.
• Testosterone nasal gel (e.g., Natesto) with or without enclomiphene.
• Speculation: "The combination of enclomiphene and cistanche extract may be able to restart the HPTA even with conventional TRT. However, this idea is untested."

6. Anecdotal Success Stories and Failures:​

• Failed restart: "TLR" recounts a 4-month doctor-supervised Clomid restart where his LH/FSH response was good, but his "balls are dead" and TT never exceeded 330 ng/dL. This highlights that restarts don't always work, even with pituitary stimulation.
• Successful cold-turkey restart (anecdotal): "TLR" shares a story of a 55-year-old friend on TRT for over ten years who quit "COLD TURKEY." After feeling "like shit for about 6 months," his total T became 590 ng/dL, and he felt fine, also incorporating carnivore diet and intermittent fasting. This suggests that some individuals, even after long-term TRT, can achieve natural recovery.

Conclusion:​

Restarting natural testosterone production after long-term TRT, particularly with enclomiphene, is a lengthy and often challenging process, frequently accompanied by significant temporary side effects like severe fatigue, mood changes, and loss of libido. While success is possible, as demonstrated by GeauxBears' eventual recovery of testosterone levels to 700 ng/dL after several months, it requires patience and close monitoring. Factors like insulin sensitivity and thyroid function may also play a role in the success of the restart. Alternative strategies exist to potentially mitigate the harsh withdrawal period.

Q1: What is enclomiphene and why is it used for restarting natural testosterone production?​

Enclomiphene is a selective estrogen receptor modulator (SERM) that is often used to stimulate the body's natural production of testosterone, particularly after a period of Testosterone Replacement Therapy (TRT) or to address hypogonadism. Unlike its isomer clomiphene (which contains both enclomiphene and zuclomiphene), enclomiphene is generally favored because it avoids the estrogenic side effects often associated with clomiphene, such as mood swings and hot flashes, due to the absence of the estrogenic zuclomiphene isomer. It works by blocking estrogen receptors in the hypothalamus and pituitary gland, which in turn signals the pituitary to increase the production of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH). These hormones then stimulate the testes to produce more testosterone.

Q2: How long does it typically take for enclomiphene to restart natural testosterone production, especially after prolonged TRT?​

Restarting natural testosterone production with enclomiphene, especially after prolonged TRT (e.g., 5 years), can take a significant amount of time. Initial lab results might show continued shutdown of the HPTA (Hypothalamic-Pituitary-Testicular Axis), as seen with T and LH levels remaining very low even after a month of enclomiphene. Experts suggest giving it more time, typically 3-6 months, for the HPTA to fully "reboot." In some cases, a maximal improvement in total testosterone (TT) may be observed at 6 months, while sperm concentrations might take up to 9 months to show statistically significant improvement. The process can be challenging, with symptoms like extreme coldness, hot flashes, zero libido, and potential mood disturbances persisting for several months before a positive trend is observed.

Q3: What are some common side effects experienced during an enclomiphene restart?​

During the initial phase of an enclomiphene restart, especially after long-term TRT, individuals may experience significant and challenging side effects due to very low testosterone and estrogen levels. Common symptoms reported include:

• Temperature dysregulation: Near-constant swings in body temperature, alternating between feeling very cold and suddenly getting very hot (hot flashes), which can disrupt sleep.
• Libido loss: Complete absence of sex drive, which can be psychologically distressing.
• Erectile dysfunction (ED): Inability to achieve erections.
• Mood disturbances: General depression and low mood scenarios.
• Insulin resistance: A noticeable increase in blood glucose levels and delayed response to insulin after meals, even in individuals without pre-existing type 2 diabetes.
• Physical changes: Loss of water weight, and ironically, in some cases, testicles becoming larger than they were on TRT+HCG.

These symptoms tend to improve as testosterone levels gradually rise.

Q4: Are there any dietary or lifestyle factors that can influence the success of an enclomiphene restart?​

Yes, certain dietary and lifestyle factors can significantly influence the success of an enclomiphene restart. Insulin resistance, even if not diagnosed as Type 2 Diabetes, can inhibit the pituitary from producing enough LH, thereby affecting testosterone production. A very low-carb or carnivore diet, while potentially beneficial for managing insulin resistance or Type 2 Diabetes, might lead to suppressed thyroid function if calorie intake is insufficient, potentially contributing to symptoms like being constantly cold and depressed. Adequate caloric intake and a balanced diet with normal amounts of carbs are suggested to improve symptoms and aid the restart process.

Q5: Can HCG be used during an enclomiphene restart?​

No, HCG (Human Chorionic Gonadotropin) should generally not be used during an enclomiphene restart when the goal is to stimulate the body's natural testosterone production. While HCG can stimulate the testes directly, it is considered HPTA suppressive, meaning it can hinder the pituitary's ability to "reboot" and produce its own LH and FSH, which is precisely what enclomiphene aims to achieve. The primary objective of an enclomiphene restart is to restore the natural feedback loop, and adding HCG would counteract this process.

Q6: What are potential alternatives or complementary strategies to make the restart process less challenging?​

Stopping TRT "cold turkey" for a restart can be a very difficult experience due to severe low testosterone symptoms. Alternative strategies that might make the transition less painful include:

• Switching to faster-acting testosterone forms: Using less suppressive forms of testosterone, such as oral testosterone or testosterone nasal gel (e.g., Natesto), in combination with enclomiphene. This approach aims to reduce the severity of low testosterone symptoms during the restart period, though the restart may take longer.
• Combinations with other compounds: Speculation exists that combining enclomiphene with certain extracts like cistanche might aid in restarting the HPTA, even while still on conventional TRT. However, this idea is largely untested.

These methods aim to provide a more gradual and tolerable transition back to natural production.

Q7: How does enclomiphene affect Sex Hormone Binding Globulin (SHBG) levels compared to traditional TRT?​

SHBG levels can fluctuate differently with TRT versus enclomiphene. Traditional TRT, particularly with injectable forms, often leads to unnaturally high testosterone levels, which tends to lower SHBG. In contrast, clinical trials suggest that enclomiphene alone does not have a significant effect on SHBG. When transitioning from TRT to enclomiphene, an individual's SHBG may bounce back to a less suppressed, potentially higher, state. This is also influenced by the fact that androgens tend to lower SHBG, while estrogens tend to raise it. Clomid, which contains both enclomiphene and the estrogenic zuclomiphene, can help raise SHBG due to zuclomiphene's estrogenic properties.

Q8: What indicates a successful enclomiphene restart, and how long should treatment continue?​

A successful enclomiphene restart is indicated by a progressive increase in testosterone (T) and Luteinizing Hormone (LH) levels into the normal range, accompanied by an improvement in symptoms like libido, body temperature regulation, and mood. For example, a significant rise in T from severely low levels (e.g., 25 ng/dL) to the normal range (e.g., 400-700 ng/dL) and LH levels accelerating into the normal range (e.g., 7.3 mIU/mL) are positive signs. The individual in the provided source initially took 12.5mg ED, then doubled it to 25mg daily to achieve these results. While it is hoped that the dosage can be dialed back over time, long-term chronic treatment with clomiphene citrate (CC), which shares similar mechanisms with enclomiphene, is often needed in most patients. Maximal benefits for total testosterone can take around 6 months, and for sperm concentration, up to 9 months.

 

Wanted to update this thread with my latest progress. As of 5/7, labs on 25mg enclomiphene ED:

Total T: 700 (264-916)
Free T: 10.5 (8.7-25.1)
E2, Sens: Pending
SHBG: Pending

Pending final results, my sense is my SHBG is high. What’s weird is while on TRT, my SHBG was low, ~10ish.

Why is my SHBG low on TRT but high(er) on enclomiphene? I noticed the same when on clomid several years ago.

This is an awesome thread. Thank you for the updates!

I am on HCG mono myself and would love to try an enclo restart. Your story gives me hope. How do you feel now?

 

This is an awesome thread. Thank you for the updates!

I am on HCG mono myself and would love to try an enclo restart. Your story gives me hope. How do you feel now?

Glad it helps!

Most recent labs as of 6/4:

T, Total: 738 (264-916)
T, Free: 18.4 (8.7-25.1)
LH: 11.2 (1.7-8.6)
Estradiol, Sens: 48.6 (8.0-35.0)
SHBG: 28.2 (16.5-55.9)

I am feeling decently well - morning erections have been more prevalent (they were non existent on TRT+HCG), and no adverse E2 effects that I experienced on clomid years ago (e.g., bloating, irritability/depression, fatigue). Also, my heart rate and blood pressure have come down significantly relative to TRT. I am less sensitive to heat than I was on TRT.

The only thing I'm struggling with is libido - realizing that's a multi-factor process, I'm trying to figure out how to first reduce that E2 a bit. Current dosage is 12.5mg daily.

 

Glad it helps!

Most recent labs as of 6/4:

T, Total: 738 (264-916)
T, Free: 18.4 (8.7-25.1)
LH: 11.2 (1.7-8.6)
Estradiol, Sens: 48.6 (8.0-35.0)
SHBG: 28.2 (16.5-55.9)

I am feeling decently well - morning erections have been more prevalent (they were non existent on TRT+HCG), and no adverse E2 effects that I experienced on clomid years ago (e.g., bloating, irritability/depression, fatigue). Also, my heart rate and blood pressure have come down significantly relative to TRT. I am less sensitive to heat than I was on TRT.

The only thing I'm struggling with is libido - realizing that's a multi-factor process, I'm trying to figure out how to first reduce that E2 a bit. Current dosage is 12.5mg daily.

You might try a low dose of zinc for your E2. As someone with low E2, it turns out that a lot of things inhibit aromatase and zinc is one of them. Melatonin may help as well.

 

Any updates? Better libido?

 

AWESOME THREAD HERE! Thank you GeauxBEARS

 

I did 2 months of enclomiphene and clearly helped for testosterone but literally nothing for libido, probably even worse. I have pfs.

Ow yeah and higher heart rate too but no other negative side effects though. I did 24mg/week split in 2 doses.

 

It trashed my libido. Hypothesis is the estrogen blockage happening in my brain. Cycled off of it and a week later libido came roaring back with increased desire to watch porn, etc.

 

Any update on your current protocol? Thinking about doing an enclomiphene re-start.

 

Any update on your current protocol? Thinking about doing an enclomiphene re-start.

It's great to do a restart as it accelerates the rebooting process. But I didn't get long-term benefit by staying on it monotherapy.

 

Enclomiphene: A Detailed Briefing on its Use for Secondary Male Hypogonadism​

Executive Summary​

Enclomiphene citrate, marketed under names like Androxal®, is a selective estrogen receptor modulator (SERM) that has emerged as a promising alternative to traditional testosterone replacement therapy (TRT) for men with secondary hypogonadism. Unlike exogenous testosterone, enclomiphene works by stimulating the body's natural production of testosterone, thereby maintaining fertility and potentially mitigating some of the side effects associated with TRT, such as testicular shrinkage and suppression of spermatogenesis. While clinical studies have demonstrated its efficacy in significantly increasing testosterone, LH, and FSH levels, the FDA has not yet approved enclomiphene for use in men, primarily due to a lack of rigorously demonstrated symptomatic benefit using validated metrics. Despite regulatory hurdles, its ability to preserve fertility makes it particularly attractive for younger men with obesity-related secondary hypogonadism.

1. Understanding Hypogonadism and Treatment Approaches​

1.1 What is Hypogonadism?​

Hypogonadism is characterized by low serum testosterone levels accompanied by symptoms such as decreased libido, erectile dysfunction, loss of lean muscle mass, fatigue, and depression. It can be categorized as primary (due to testicular dysfunction) or secondary (due to disruption of the hypothalamic-pituitary-gonadal (HPG) axis). Secondary hypogonadism is often linked to conditions like obesity, metabolic syndrome, and type 2 diabetes.

1.2 Traditional Treatment: Testosterone Replacement Therapy (TRT)​

Historically, both primary and secondary hypogonadism have been managed with exogenous testosterone administration. While effective at raising testosterone levels and improving symptoms, TRT is associated with several adverse effects, including:

• Infertility: Exogenous testosterone suppresses the body's natural production of LH and FSH, which are crucial for spermatogenesis. Studies show "men receiving testosterone, none had sperm concentrations above 12 million/mL after three months of treatment."
• Erythrocytosis (increased red blood cell count).
• Elevated serum estrogen levels.
• Alterations in serum lipids.
• Potential cardiovascular risk (though high-quality evidence is still debated).
• Testicular shrinkage.
• Hair loss: TRT can increase the conversion of testosterone to dihydrotestosterone (DHT), a culprit in male pattern baldness.

1.3 Alternative Strategies: SERMs and Aromatase Inhibitors​

Given the drawbacks of TRT, especially for men wishing to preserve fertility, off-label pharmacologic strategies have been employed to stimulate endogenous testosterone production. These include:

• Aromatase Inhibitors (AIs): These drugs suppress estradiol production, leading to increased LH, FSH, and testosterone.
• Selective Estrogen Receptor Modulators (SERMs): Such as clomiphene citrate and enclomiphene, these drugs block estrogen binding to receptors in the hypothalamus, increasing gonadotropin release and subsequent testosterone production. They are particularly useful in treating obesity-related hypogonadism due to the high levels of aromatase in adipose tissue.

2. Enclomiphene: Mechanism and Distinction from Clomiphene​

2.1 Enclomiphene's Mechanism of Action​

Enclomiphene citrate is an oral, non-steroidal estrogen receptor antagonist. Its mechanism centers on "its ability to block hormone receptors in the brain." Specifically, "Enclomiphene binds and occupies the estrogen receptors in the pituitary gland of the hypothalamus, thereby preventing estrogen from binding and promoting the release of gonadotropins (FSH & LH)." This increase in LH and FSH then "stimulates the Leydig cells in the testes to secrete more testosterone," thereby stimulating the body's natural production of testosterone.

2.2 Enclomiphene vs. Clomiphene​

Clomiphene citrate (Clomid®) is a mixture of two stereoisomers:

• (cis) Zuclomiphene citrate: An estrogen receptor agonist with a long half-life (30 days), associated with estrogenic side effects like "mood swings, depressed mood, irritability, anxiety, gynecomastia, and libido issues." It accumulates in the system.
• (trans) Enclomiphene citrate: The active isomer that acts as an estrogen receptor antagonist, raising LH and FSH levels, with a shorter half-life of approximately 10 hours.

The hypothesis is that enclomiphene, by excluding zuclomiphene, "should have more favorable outcomes in treating androgen deficient men with the goal of maintaining fertility, potentially without the side effects associated with clomiphene citrate use and with a more favorable impact on hypogonadal symptoms."

3. Clinical Efficacy and Benefits of Enclomiphene​

3.1 Testosterone, LH, and FSH Increases​

Multiple studies have demonstrated enclomiphene's effectiveness in increasing serum testosterone levels comparable to topical testosterone:

• One user reported their "Total T went from 300 to 1183, E2 did not rise much (33 from 27)" on enclomiphene citrate for 6 months.
• Phase II and III studies show "significant increases in serum testosterone levels when on testosterone... 12.5 mg of enclomiphene citrate... and 25 mg of enclomiphene citrate."
• In contrast to testosterone therapy which decreases LH and FSH, enclomiphene causes these gonadotropin levels to rise. For example, men on 25 mg enclomiphene saw a "greatest rise in LH (5.3 to 11.9 mIU/mL)" and "FSH (9.4 to 14.9 mIU/mL)."

3.2 Preservation of Fertility​

A key advantage of enclomiphene over TRT is its ability to maintain or even improve sperm counts:

• In one study, "among the men receiving testosterone, none had sperm concentrations above 12 million/mL after three months of treatment, in contrast with men receiving enclomiphene citrate, where no participant had a sperm count below 75 million/mL." The mean sperm count for enclomiphene users was 176 million/mL.
• Phase III studies "found to maintain sperm counts, with an 11.7% change in sperm density in one study group treated with enclomiphene citrate... and a 15.2% change in the second study group also receiving enclomiphene citrate. In contrast, men in the testosterone groups... showed a marked decrease in sperm counts." This is crucial for younger men with secondary hypogonadism who "would desire to preserve fertility."

3.3 Symptomatic Improvement​

While the impact of enclomiphene on hypogonadal symptoms needs further rigorous study using validated metrics, anecdotal and limited clinical evidence suggest some benefits:

• One user reported their "brain fog cleared dramatically" and felt "more optimistic, less explosive, less anger, less 'laziness'" with enclomiphene.
• Another user, during a restart attempt, noted feeling "less moody and not as hot and sweaty all the time" and a gradual return of libido, even after initial significant discomfort.
• A 2013 study on clomiphene (containing enclomiphene) found that all five participants experienced "increased libido, sexual potency, and a general sense of well-being."

3.4 Hair-Friendly Option​

"Unlike TRT, taking enclomiphene citrate should not cause hair loss." This is because "enclomiphene maintains balance" in the DHT:TT ratio, whereas TRT can shift it towards DHT, which is linked to male pattern baldness.

4. Dosage and Administration​

4.1 Recommended Dosages​

Studies indicate that enclomiphene increases LH in a dose-dependent manner, but "it reaches a steady-state level at 25mg per day. Using more than 25mg will not result in a bigger increase in LH."

• "Studies have shown that 12.5mg and 25mg Enclomiphene increased testosterone levels significantly over a period of three months. Interestingly, the 25mg dosage was not notably better than the 12.5mg dosage."
• Another study comparing 6.25mg, 12.5mg, and 25mg showed a dose-dependent increase in testosterone.

Individual responses vary, with some achieving very high testosterone levels, though these are considered "outliers, not the norm."

4.2 Importance of Blood Work​

It is critical to obtain enclomiphene through reputable sources that require blood work. Without necessary tests:

• Incorrect dosage may be taken, leading to inefficacy or side effects.
• Body's response to treatment cannot be monitored.
• Risk of undetected "elevated estradiol levels, leading to side effects like headaches, abdominal discomfort, and visual disturbances."

4.3 Restarting HPTA Function​

For individuals coming off long-term TRT, restarting natural testosterone production with enclomiphene can be a "brutal" process, characterized by symptoms like extreme coldness, hot flashes, zero libido, and depression due to very low testosterone levels initially.

• It can take significant time for the HPTA axis to "reboot," with initial labs still showing suppressed LH and T.
• One user experienced very low T (25-30 ng/dL) and LH (1.3-2.5 mIU/mL) for several months before seeing a positive trend, with T eventually rising to 415 ng/dL and LH to 7.3 mIU/mL after several months on 25mg daily.
• "Need to give it more time (3-6 months)."
• HCG should not be used during a restart attempt with enclomiphene as it is "HPTA suppressive."

5. Safety and Tolerability​

5.1 Common Side Effects​

Enclomiphene is generally considered well-tolerated with few adverse effects. Reported side effects in clinical trials include:

• Elevated estradiol levels (though often less pronounced than with clomiphene).
• Headache.
• Abdominal discomfort/distension.
• Nausea.
• Hot flush (vasomotor flushing).
• Joint pain.
• Dizziness.
• Muscle spasms.
• Fatigue.
• Increased appetite.
• Aggression/irritability.
• Acne.
• Increased libido.
• Mood swings (if testosterone levels become too high).

Many of these side effects are "generally mild and transient, and typically subside on their own within a few days or weeks." It's important to note that much of the side effect data for clomiphene (which contains the zuclomiphene isomer) was collected from women, making direct generalization to men using enclomiphene challenging.

5.2 Serious Side Effects and Contraindications​

Rare but serious side effects can include:

• Allergic reactions (difficulty breathing, facial/lip/tongue/throat swelling, hives).
• Alterations in vision (blurred vision, light flashes).
• Signs of blood clots (chest pain, breathing difficulties, leg swelling) – though studies have not shown an increased risk of blood clots with enclomiphene itself.
• Heightened risk of certain cancers, particularly "estrogen-sensitive cancers" such as breast, endometrial, ovarian, and prostate cancer. Enclomiphene "exerts estrogenic effects making it unsuitable for members with a history of estrogen-sensitive cancers."
• Changes in liver function tests, requiring close monitoring, especially for patients with pre-existing liver disease.
• Changes in lipid levels (increases in cholesterol and triglycerides).

Enclomiphene is contraindicated in individuals with:

• Female sex (assigned at birth).
• History of breast, endometrial, ovarian, or prostate cancer.
• History or pre-existing risk of blood clots.
• History of heart disease.
• Current pituitary adenoma.
• History of liver disease.
• Uncontrolled adrenal or thyroid dysfunction.
• Known allergy to enclomiphene or clomiphene citrate.
• History of mania, bipolar disorder, or current manic symptoms (due to risk of mood swings).

6. Regulatory Status and Future Outlook​

6.1 FDA Approval Status​

Clomiphene is FDA-approved for female infertility but is used off-label for men. Enclomiphene citrate, as a distinct entity (Androxal®), has been under FDA review since 2007. However, it "was not approved for the treatment of secondary hypogonadism because the FDA did not consider increases in testosterone levels alone to be sufficient evidence for a non-testosterone therapy for hypogonadism." The FDA also rejected normalization of LH and quality of life improvements as sufficient indications, requesting clear demonstration of "symptomatic benefit" using validated metrics. The New Drug Application (NDA) meeting was canceled in late 2015 due to "concerns over the bioanalytical method of validation."

6.2 Challenges and Prospects​

The future of enclomiphene's FDA approval remains "uncertain" and "bleak at best." Despite its potential, "there is no high quality validated questionnaires that could deliver the evidence that the FDA desires in a clear and unequivocal fashion."

• The original sponsor, Repros Therapeutics Inc., was acquired, and further studies are currently on hold.
• Despite these hurdles, the growing prevalence of obesity-related secondary hypogonadism, particularly in younger men desiring fertility preservation, suggests a "demand for treatment options... is only going to increase." It is "very likely that enclomiphene will resurface in the future in one form or another."

6.3 Potential Combination Therapies​

Future research may explore combining enclomiphene with testosterone replacement therapy to "reap the established benefits of testosterone replacement while limiting dose and potentially preserving fertility." Other speculative combinations include oral testosterone with enclomiphene, or enclomiphene with cistanche extract for easier restart of HPTA.

Conclusion​

Enclomiphene citrate represents a significant advancement in the treatment of secondary male hypogonadism, offering a method to increase endogenous testosterone while notably preserving fertility. Its distinct pharmacological profile, avoiding the estrogenic side effects of zuclomiphene found in clomiphene, makes it a promising therapeutic agent. While its clinical efficacy in raising testosterone, LH, and FSH levels is well-established, the lack of definitive symptomatic benefit data and FDA approval poses a major hurdle to its widespread adoption. Nonetheless, for men concerned about fertility and seeking a more physiological approach to testosterone optimization, enclomiphene stands out as a valuable option. Careful medical supervision, including regular blood work, is essential to ensure appropriate dosing and to monitor for any potential side effects.