FERTILITY-FRIENDLY HORMONE THERAPY IN MEN: GUIDE TO ENCLOMIPHENE, CLOMIPHENE, AND ANASTROZOLE

Introduction

Men of reproductive age with hypogonadism (low testosterone, or “low T”) often face a dilemma: while testosterone replacement therapy (TRT) can effectively raise serum testosterone, exogenous testosterone suppresses the hypothalamic-pituitary-gonadal (HPG) axis and can dramatically reduce sperm production. This is because TRT provides negative feedback to the pituitary, lowering luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels necessary for testicular function. For men desiring to preserve fertility, alternative treatments are used to restore endogenous testosterone production without impairing spermatogenesis. Three such alternatives are commonly discussed: clomiphene citrate, enclomiphene citrate, and anastrozole. Clomiphene citrate (CC) is a selective estrogen receptor modulator (SERM) long used off-label to stimulate testosterone in men. Enclomiphene citrate (EC) is the purified trans-isomer of clomiphene, engineered to provide the testosterone-boosting benefits of clomiphene with potentially fewer side effects. Anastrozole, on the other hand, is an aromatase inhibitor (AI) traditionally used in other contexts (like breast cancer) but employed off-label in men to raise testosterone by lowering estradiol levels.

This article will compare enclomiphene, clomiphene, and anastrozole in hypogonadal men of reproductive age – examining their mechanisms, efficacy in raising testosterone, impact on sperm parameters and fertility, effects on patient quality of life, and side effect profiles. We will also clarify which are FDA-approved or off-label in the U.S., and include data on use in both younger and older men. The goal is a balanced, evidence-based review to help patients and healthcare professionals understand these options for treating low T while preserving fertility.

Mechanisms of Action

Clomiphene Citrate (CC): Clomiphene is a nonsteroidal SERM that blocks estrogen receptors in the hypothalamus and pituitary gland. By antagonizing estrogen’s negative feedback, clomiphene causes increased release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and boosts pituitary secretion of LH and FSH. The rise in LH stimulates the Leydig cells in the testes to produce more testosterone endogenously. In essence, CC “tricks” the HPG axis into ramping up the body’s own testosterone production. Clomiphene is actually a mixture of two stereoisomers: enclomiphene (trans-clomiphene) and zuclomiphene (cis-clomiphene). Enclomiphene is the more active isomer in terms of anti-estrogenic effect on the HPG axis, whereas zuclomiphene has a longer half-life and some weak estrogenic agonist activity. Together, the isomers increase LH/FSH and thereby testosterone, but the presence of zuclomiphene is thought to contribute to certain side effects (like elevated estradiol levels or mood changes) during clomiphene therapy.

Enclomiphene Citrate (EC): Enclomiphene is essentially a refined version of clomiphene that contains only the trans-isomer. Mechanistically, enclomiphene works the same way as clomiphene – by blocking estrogen receptors in the hypothalamus/pituitary to drive up gonadotropin release and testosterone production. The key difference is that enclomiphene excludes zuclomiphene, theoretically avoiding the latter’s prolonged estrogenic effects. As a result, enclomiphene may raise testosterone without as much rise in estradiol as seen with clomiphene. In fact, one comparative study found enclomiphene therapy led to significantly lower estradiol levels than clomiphene therapy in men (enclomiphene caused a slight decrease in serum estradiol on average, vs. a notable increase with clomiphene). By isolating the active isomer, enclomiphene aims to preserve the fertility- and testosterone-restoring benefits of clomiphene while minimizing estrogen-related side effects.

Anastrozole: Anastrozole is an aromatase inhibitor (specifically a non-steroidal third-generation AI) that prevents the conversion of androgens to estrogen. In men, anastrozole binds the aromatase enzyme and reduces the synthesis of estradiol from testosterone in peripheral tissues. Lower estradiol levels, in turn, lessen estrogenic negative feedback on the pituitary, which leads to increased release of LH and FSH. Thus, anastrozole can increase endogenous testosterone production indirectly by removing the “brake” that estrogen puts on the HPG axis. This mechanism is particularly relevant in men who have a high estradiol-to-testosterone ratio (for example, obese men, in whom excess aromatase in adipose tissue converts more testosterone to estradiol). By reducing estradiol, an AI like anastrozole raises the testosterone/estradiol (T/E) ratio and often modestly increases absolute testosterone levels. It’s important to note that unlike SERMs, AIs do not directly stimulate GnRH or block estrogen receptors at the hypothalamus – rather, they lower circulating estrogen levels. The net result is increased gonadotropin output (since the pituitary senses less estrogen feedback) and a boost in testosterone, provided the testes have adequate capacity to respond.

In summary, clomiphene and enclomiphene act as “estrogen blockers” at the brain level to drive up LH/FSH, whereas anastrozole acts as an “estrogen production blocker”, lowering estradiol and thereby also stimulating LH/FSH release. Both strategies can restore a more youthful hormonal balance internally. These medications are only effective if the hypogonadism is due to secondary causes (central or functional hypogonadism) where the testes are capable of producing testosterone if properly stimulated. In cases of primary hypogonadism (testicular failure), neither SERMs nor AIs will be very effective, since the limiting factor is the testes themselves not responding to stimulation. For the large majority of men with low testosterone in the reproductive age group – often presenting with low or inappropriately normal gonadotropin levels (i.e. secondary hypogonadism, which accounts for ~85% of male hypogonadism cases) – these treatments can meaningfully raise T.

Efficacy in Raising Testosterone Levels

Clomiphene Citrate: Clomiphene has been shown in numerous studies to significantly increase serum testosterone in hypogonadal men. The magnitude of increase can be substantial. For instance, an early study by Shabsigh et al. demonstrated that low-dose clomiphene (25 mg daily) raised testosterone from subnormal levels into the mid-normal range in young hypogonadal men. A long-term follow-up series from Memorial Sloan Kettering reported that men on clomiphene (average age 44, baseline T ~228 ng/dL) reached mean testosterone levels of ~612 ng/dL after 1 year of therapy – an increase of roughly 2.5-fold. Notably, this improvement was sustained: even at 2–3 years of continuous clomiphene, testosterone remained in the ~550–580 ng/dL range, well within normal. Clomiphene effectively “restored” these men from hypogonadal to eugonadal levels. In another comparative trial, clomiphene increased total testosterone by about 130% of baseline over 3 months, significantly more than anastrozole did (+69%) in a similar timeframe. Most men on clomiphene achieve testosterone levels >300 ng/dL (often mid-normal) with proper dosing; one retrospective noted ~89% of men on clomiphene reached eugonadal T levels (>300 ng/dL). The typical dosing for men is 25 mg daily or every other day, titrated to symptom relief and target T levels. Clomiphene’s effectiveness in raising testosterone has been demonstrated in both younger and middle-aged men, including those with idiopathic hypogonadotropic hypogonadism or secondary hypogonadism due to obesity or metabolic syndrome. It’s worth noting that clomiphene also tends to raise estradiol levels somewhat (because more testosterone is available to aromatize, and zuclomiphene may have some estrogen agonism) – in the long-term MSKCC study, mean estradiol roughly doubled from baseline by 1 year. Even so, the testosterone/estrogen ratio (T/E) typically improves on clomiphene therapy, as T rises more robustly than E in most patients.

Enclomiphene Citrate: Enclomiphene has shown comparable efficacy to clomiphene in boosting testosterone – and in direct comparisons, enclomiphene might achieve similar or slightly greater increases with less estrogen elevation. In randomized controlled trials of enclomiphene in men with secondary hypogonadism, enclomiphene (12.5–25 mg daily) has been as effective as standard TRT in normalizing testosterone. Kaminetsky et al. reported that oral enclomiphene raised total testosterone into the normal range in hypogonadal men to a degree comparable with testosterone gel, whereas placebo had no effect. Importantly, enclomiphene maintained the pituitary drive: in these trials, LH and FSH increased on enclomiphene (but not on exogenous T), demonstrating restoration of the axis. A phase II trial found enclomiphene raised T from hypogonadal baseline to ~500–600 ng/dL after 3 months, while simultaneously preserving spermatogenesis, in contrast to a testosterone gel group that also achieved normal T but experienced marked reductions in sperm counts. In head-to-head retrospective data, enclomiphene (given after prior clomiphene use in the same patients) produced a median testosterone increase of +166 ng/dL, versus +98 ng/dL with clomiphene (although this difference was not statistically significant). Thus, enclomiphene raises testosterone at least as effectively as clomiphene, with some studies suggesting enclomiphene might have a slight edge in hormonal potency. Both enclomiphene and clomiphene can often get testosterone into the mid-normal range (500–800 ng/dL) if titrated appropriately. A major distinction, however, is enclomiphene’s effect on estradiol: enclomiphene tends to avoid significant estrogen elevation. The Baylor College group observed that switching men from clomiphene to enclomiphene led to a significantly lower estradiol change (actually a slight decrease in E2 on enclomiphene vs. a rise of ~+17.5 pg/mL on clomiphene). This is consistent with the notion that enclomiphene lacks the lingering estrogenic isomer. In summary, enclomiphene effectively “restores” testosterone levels by stimulating endogenous production – earning the description in one study title as “restoration instead of replacement” – and achieves healthy T levels without the gonadotropin suppression seen in TRT.

Anastrozole: Aromatase inhibition yields a more modest rise in testosterone relative to SERMs, but can still produce meaningful improvements, especially in men with elevated baseline estrogen. In older men (over 60) with low-normal T, anastrozole 1 mg daily increased total T from ~300–350 ng/dL into the 500–600 ng/dL range over 3 months. For example, in a controlled trial of 62–74 year-old men with T <350, anastrozole 1 mg daily raised total testosterone from ~343 ng/dL to 572 ng/dL on average (vs. no change on placebo). Even a lower dosing (1 mg twice weekly) elevated T from ~397 to 520 ng/dL. In that study, bioavailable testosterone roughly doubled with anastrozole. These results indicate that AIs can significantly boost T in men with mild hypogonadism, albeit typically not as dramatically as clomiphene can in more severely hypogonadal men.

Anastrozole also raises testosterone by increasing pituitary output: LH and FSH have been observed to rise by ~50–80% with anastrozole therapy. In a more contemporary study focusing on younger subfertile men with low T and obesity (BMI >25), daily anastrozole for ~5 months increased total testosterone from ~271 ng/dL to 412 ng/dL on average (a ~50% jump). Notably, estradiol in that cohort dropped by half (from 32 pg/mL to ~16 pg/mL) and the T/E ratio tripled from 9 to 26.5, reflecting a much more androgen-dominant hormonal milieu. This significant shift in T/E ratio is a hallmark of AI therapy. By contrast, clomiphene therapy often raises T but also allows some rise in E2, meaning the T/E ratio improvement is more modest. It’s important to tailor AI use to the right patient: men with normal or low estradiol to begin with may not experience a large T boost from anastrozole, since there isn’t much excess estrogen to cut down. But in men with hyperestrogenism or obesity-related secondary hypogonadism (who often have low T and high estrogen), AIs can be quite effective in rebalancing hormones. For example, clinicians have observed that obese men or those with baseline estradiol ≥ ~20 pg/mL are more likely to need and respond to anastrozole therapy on top of clomiphene. In summary, anastrozole improves testosterone by a moderate degree (often bringing low-normal T into mid-normal range) and is especially useful in men with a high estradiol component to their hypogonadism.

Older vs. Younger Men: The above therapies have been used in both younger and older men with low testosterone. Younger men with secondary hypogonadism (including those with idiopathic hypogonadotropic hypogonadism, metabolic syndrome, or prior anabolic steroid use) respond well to clomiphene and enclomiphene, often achieving normal T and symptom improvement. Older men can also respond biologically – for instance, clomiphene was effective in men in their 50s–60s in improving testosterone and even bone density (as discussed below). However, the clinical benefits in older men may be less pronounced: in one trial, despite raising T significantly in men over 60, anastrozole did not improve their overall vitality or sexual function scores (more on this under Quality of Life). This suggests that simply normalizing T in an older population may not translate to dramatic symptom changes over short periods, possibly because age-related androgen deficiency involves other factors (and excessively low estradiol might counter some benefits). Nonetheless, from a hormonal standpoint, both SERMs and AIs can restore “youthful” T levels even in older hypogonadal men. The decision to use them in older patients often depends on individual goals (e.g. fertility in older fatherhood) and weighing risks (e.g. bone effects with AIs, which we will discuss).

Effects on Sperm Counts and Fertility

A crucial advantage of these therapies over exogenous testosterone is that they preserve or even improve sperm production instead of impairing it. Exogenous TRT can severely suppress spermatogenesis, frequently causing oligospermia or azoospermia by lowering gonadotropins to near zero. In contrast, clomiphene and enclomiphene maintain or raise FSH and LH levels, which supports sperm production in the testes. Anastrozole, by increasing gonadotropins and the testosterone/estradiol ratio, can also create a more favorable environment for spermatogenesis in certain men. Here’s what studies show:

Clomiphene Citrate: Clomiphene has a long history of use as an empiric treatment for male infertility, especially in idiopathic oligospermia. By boosting gonadotropins, clomiphene can increase sperm output if the initial problem is inadequate hormonal stimulation. It has been reported in multiple studies that clomiphene therapy can increase sperm concentration and motility in hypogonadal or subfertile men. For example, one meta-analysis of clomiphene (or the similar SERM tamoxifen) in idiopathic male infertility found a significant improvement in sperm concentration compared to placebo. Clinically, clomiphene is known not to adversely affect semen parameters in men – unlike TRT, it does not cause testicular atrophy or drop in sperm count. Instead, CC often leads to either stable or improved sperm counts. In hypogonadal infertile men treated with clomiphene for 3+ months, studies have observed mild improvements in sperm density and motility on average, though results vary (some men respond with marked sperm count increases, others see little change if they were already normal). A recent retrospective comparison (University of Miami) noted that men on clomiphene for ~3–6 months had a slight increase in sperm motility and total motile count, but the changes were not statistically significant in that cohort. Nonetheless, numerous case reports show restored fertility in men on clomiphene: men who were previously subfertile due to secondary hypogonadism have gone on to conceive naturally once testosterone and sperm parameters improved on CC therapy. In men who are azoospermic due to anabolic steroid abuse, clomiphene (often combined with hCG) has been used successfully to recover spermatogenesis. Overall, clomiphene is considered a fertility-friendly therapy for low T. Guidelines from urologic associations emphasize that symptomatic hypogonadal men desiring fertility should be offered therapies like clomiphene or hCG rather than TRT.
Enclomiphene Citrate: Enclomiphene’s impact on sperm has been very encouraging in clinical trials. The mantra for enclomiphene has been the ability to “increase testosterone without negatively impacting semen parameters”. In randomized studies, enclomiphene maintained sperm counts within normal range over the treatment period, in stark contrast to the TRT group which experienced significant oligospermia. Kaminetsky et al. (J Sex Med 2013) showed that 3 months of enclomiphene therapy stimulated sperm production alongside testosterone – men had stable or higher sperm concentrations compared to baseline, whereas men on transdermal testosterone gel saw their sperm counts plummet (many becoming oligospermic). Another trial reported enclomiphene prevented the development of oligospermia that was seen in all men on topical T, effectively preserving fertility while restoring T levels. More recent data comparing enclomiphene to clomiphene found that only enclomiphene led to a statistically significant increase in total motile sperm count (TMSC), whereas clomiphene did not show a significant change in TMSC in the same timeframe. In that study, enclomiphene also significantly raised FSH (which is crucial for spermatogenesis) and LH, whereas clomiphene’s effect on FSH/LH was smaller. The implication is that enclomiphene may provide a stronger stimulus to the testicular Sertoli cells via FSH, potentially benefiting sperm production. Indeed, enclomiphene is being viewed as a therapy that can treat hypogonadism while preserving or even enhancing fertility – a key reason it has been under development as a novel treatment for secondary hypogonadism. In summary, enclomiphene’s effect on sperm is similar to clomiphene or better: it keeps the HPG axis active (LH/FSH up) and does not impair spermatogenesis; early data even suggest slight improvements in counts and motility, though fertility outcomes (pregnancy rates) need further long-term study.
Anastrozole: Anastrozole can also have a positive impact on sperm parameters in select men, particularly those with obesity or elevated estradiol. The reasoning is that high estrogen in men can impair intratesticular testosterone levels and sperm production; by lowering estradiol and increasing gonadotropins, anastrozole might improve spermatogenesis. A notable study by Shah et al. looked at 30 subfertile hypogonadal men (mean BMI ~ Thirty) treated with anastrozole 1 mg daily. Over ~5 months, sperm concentration increased from a median ~7.8 million/mL to 14.2 million/mL – nearly doubling. Total motile sperm count improved significantly (from ~12.6 million to 17.7 million), and even strict morphology showed a slight uptick. These improvements in semen parameters translated into pregnancies in 46.6% of couples during the study’s follow-up, although most achieved conception via assisted means (IVF or IUI), likely due to underlying fertility factors. Still, that near-50% pregnancy rate underscores that anastrozole therapy can aid fertility outcomes, especially as part of a broader infertility treatment plan. Other smaller studies and case series have similarly reported that aromatase inhibitors (like anastrozole or letrozole) improve sperm counts in men with low T/E ratios and infertility. By increasing intratesticular testosterone (through higher LH stimulation and less local T->E conversion), AIs create a hormonal environment conducive to spermatogenesis. It must be noted that not all men will see large gains – the effect is most pronounced in those who have an element of estrogen excess (for example, obese men with secondary hypogonadism). In men with normal weight and low estrogen, AIs might not substantially change sperm counts. Unlike clomiphene, which is often broadly effective in secondary hypogonadism, anastrozole’s role is a bit more niche in fertility: it’s frequently used in combination with clomiphene when estradiol levels climb on SERM therapy, or as a second-line if clomiphene isn’t sufficient. For instance, about 30% of men on clomiphene in one large series were eventually given anastrozole as well, due to high E2; these men tended to be more obese and had higher baseline E2. The combination of CC + anastrozole can synergistically optimize T while keeping E2 in check, thus benefiting sperm parameters in men who need both approaches.

In summary, all three therapies avoid the sperm suppression seen with exogenous testosterone. Clomiphene and enclomiphene actively support sperm production by raising FSH/LH (with enclomiphene showing perhaps a stronger FSH rise). Anastrozole improves the hormonal milieu for spermatogenesis by elevating T and FSH modestly and lowering excess estradiol. Clinical outcomes reflect these mechanisms: men on these therapies generally maintain sperm counts, and many experience improved semen quality – sometimes enough to achieve pregnancies naturally or with assisted reproduction. This fertility-preserving aspect is the paramount reason to choose clomiphene, enclomiphene, or anastrozole (or combinations thereof) in a hypogonadal man who wishes to have children.

Patient Quality of Life and Symptom Improvement

Raising testosterone in hypogonadal men is typically done to alleviate symptoms: low energy, diminished libido, erectile dysfunction, depressed mood, etc. It is therefore important to consider how clomiphene, enclomiphene, and anastrozole affect patient-reported outcomes and overall quality of life (QoL). The data here are a bit mixed, and each approach has nuances in terms of symptomatic benefit.

Clomiphene Citrate: Many men report symptomatic improvement on clomiphene – increased energy, improved mood, better libido – corresponding to their rise in testosterone. In a long-term study, patients’ Androgen Deficiency in the Aging Male (ADAM) questionnaire scores significantly improved on clomiphene: the average ADAM score dropped from 7 symptoms at baseline to 3 after one year of therapy, indicating fewer hypogonadal symptoms. This suggests that clomiphene not only normalized labs but also produced tangible clinical benefits (e.g., improved vigor, sexual function, etc.) in those patients. Other studies have shown improvements in erectile function and bone mineral density, which can translate to better quality of life. However, not all symptom changes are positive, and there is some variability. A prospective trial comparing clomiphene vs testosterone therapy found that both treatments reduced overall symptom scores (ADAM symptom count decreased on average). Men on clomiphene reported fewer symptoms after treatment than before (from ~3.5 positive ADAM responses to 1.5, on a 10-point yes/no scale). This indicates a general improvement in well-being. On a more detailed quantitative ADAM (qADAM) scale, though, that same study uncovered an interesting nuance: while clomiphene maintained or improved most domains, the libido sub-score actually worsened slightly in the clomiphene group (from 3.75 to 3.2 on a 1–5 scale, where a higher score means better libido). This was a statistically significant drop in libido rating, even though testosterone levels had increased. By contrast, men on exogenous testosterone in that study had significant improvements in libido and erectile function scores. This finding has led to speculation that clomiphene’s unique pharmacology might, in some cases, blunt libido despite raising testosterone. Potential explanations include the relative rise in estrogen (estradiol increased in clomiphene-treated men, which could dampen sexual desire in some) or perhaps clomiphene’s mixed estrogen agonist/antagonist effects in different tissues (it might act as a partial agonist in certain brain areas affecting libido). Clinically, some men do report that clomiphene does not improve their sexual symptoms as robustly as TRT, or even that they feel moodiness or decreased libido on clomiphene despite good T numbers. On the other hand, many men tolerate it well and feel “back to normal” energetically. Overall, clomiphene certainly can improve hypogonadal symptoms, but there may be a subset of men who experience less improvement in libido or mood on CC than they would on direct testosterone. Long-term data (up to 3 years) are reassuring in that clomiphene maintained symptom relief (ADAM scores remained low at 3) with no reports of new side effects. This suggests that for most, any initial side effects or adjustments subside, and benefits persist.

Enclomiphene Citrate: Because enclomiphene is so similar to clomiphene in raising testosterone, one would expect similar symptom improvements, with the hope that enclomiphene’s cleaner pharmacologic profile might avoid the occasional CC-related issues (like low libido or mood swings). Direct studies on patient-reported outcomes with enclomiphene are somewhat limited (as enclomiphene was investigational in trials focusing on hormonal endpoints). However, evidence from the Baylor retrospective series provides insight: enclomiphene was associated with significantly fewer adverse symptom complaints compared to clomiphene. In that analysis, patients who had been on both medications sequentially were much less likely to report decreased libido, low energy, or mood changes during enclomiphene therapy than they were on clomiphene. Specifically, reports of diminished libido on enclomiphene were significantly lower (P=0.001) – an important point, given the clomiphene libido concern above. Similarly, complaints of fatigue and negative mood were lower on enclomiphene (and overall odds of any adverse symptom were about 5-fold lower with enclomiphene vs CC). These findings support what many hypothesized: by not raising estradiol as much and lacking zuclomiphene, enclomiphene may avoid the subtle estrogenic effects that sometimes affect mood/libido on clomiphene. Enclomiphene essentially behaves like a pure antagonist in men, so the body sees rising testosterone without a disproportionate estrogen increase. Patients often subjectively report feeling similarly well on enclomiphene as they do on clomiphene – increased energy, better workouts, stable mood – but with fewer complaints of bloating or emotional lability that occasionally are attributed to clomiphene. While formal patient surveys on enclomiphene’s symptom improvement aren’t widely published, expert opinion holds that enclomiphene improves hypogonadal symptoms while minimizing side effects. It treats “testosterone deficiency in men while maintaining fertility,” thereby addressing both the biochemical and life-goal aspects of QoL. It’s reasonable to say enclomiphene should confer all the benefits that clomiphene does (improved mood, sexual function, strength, etc., in men whose low T was causing those issues) – and perhaps do so with a more neutral impact on libido and emotional well-being. As enclomiphene use grows (currently via off-label or research channels), more data will clarify its QoL impact, but early indicators are quite positive in terms of patient satisfaction.

Anastrozole: The effect of anastrozole on symptoms is more variable and, in some studies, disappointingly minimal. The older men’s trial by Leder et al. is instructive: despite doubling testosterone levels in these men, anastrozole did not significantly change their overall quality of life scores (SF-36 health survey) or sexual function scores (IIEF – International Index of Erectile Function) over 12 weeks. In other words, raising a 65-year-old man’s T from ~300 to ~550 ng/dL via an AI did not make him report feeling considerably better over that short period. Additionally, no improvement was seen in measures like muscle strength or body composition in that brief timeframe. Similarly, a randomized trial of letrozole (a similar AI) in obese hypogonadal men found no improvements in psychological or metabolic endpoints despite higher T – leading authors to speculate that the concurrent lowering of estradiol might blunt benefits. Estradiol in men plays a role in libido, cognitive function, and vascular health; too little estrogen might negate some of testosterone’s positive effects. That said, anecdotal and some clinical reports suggest that some men do feel better on anastrozole, particularly those who had high estrogen symptoms (e.g., nipple sensitivity from gynecomastia, or obesity-related fatigue). By reducing estrogen, AIs can relieve estrogen-related symptoms and possibly improve testosterone-related symptoms if low T was the main driver. In younger men with secondary hypogonadism, AIs have shown improvements in sperm counts and partner pregnancy rates as noted, which indirectly can improve quality of life by aiding in family-building success. But in terms of day-to-day symptoms, anastrozole is not a classic “feel-good” medication. Many patients do not subjectively report the same boost in libido or energy that they might get from TRT or even clomiphene. In cases where anastrozole is used adjunctively (for example, added to clomiphene to control estrogen), patients often notice improvement in symptoms that were related to excess estrogen (less breast tenderness, perhaps a bit more weight loss due to reduced water retention). Overall, anastrozole’s clinical symptom benefits are subtle. The drug’s main use is to optimize hormones and enable fertility, rather than directly to improve libido or mood. It’s also possible that the type of patient who gets anastrozole (often heavier men with metabolic issues) might have other factors blunting symptom changes. In contrast, men on clomiphene/enclomiphene may be somewhat younger or have purely functional hypogonadism, where restoring T yields a more noticeable vitality boost.

In summary, clomiphene and enclomiphene generally improve hypogonadal symptoms, with enclomiphene potentially having an edge in avoiding any negative impact on libido or mood that clomiphene might rarely cause. Clomiphene has demonstrated significant improvements in standardized symptom scores in long-term studies, though in the short term, some domains (like libido) may not improve as much as with direct T therapy. Enclomiphene appears to maintain symptom relief with fewer side effects – men feel the benefits of higher testosterone without the same degree of estrogen-related complaints. Anastrozole’s impact on quality of life is less pronounced; it should not be viewed as an “energizer” in the way TRT can be. Instead, its value is in fine-tuning the hormone balance and supporting fertility. Many clinicians observe that if a man’s primary issues are fatigue and low libido, a SERM (or even low-dose hCG) might do more for him than an AI, unless he has clear signs of high estrogen. It’s a reminder that more testosterone doesn’t always equal feeling better if estrogen is simultaneously pushed too low. Thus, patient monitoring and symptom-guided adjustments are important – for instance, if a man on clomiphene has great T numbers but still feels low libido and has high-normal estradiol, adding a tiny dose of AI might help; conversely, if a man on anastrozole has sky-high T but still no improvement, perhaps a SERM or different approach is needed.

Side Effects and Safety Profile

Each of these therapies is generally well tolerated, especially compared to some other hormonal treatments, but they do have distinct side effect considerations. It’s crucial to note that all these uses are off-label (discussed further below), so formal long-term safety data in large populations of men are still somewhat limited. Nevertheless, the existing studies and clinical experience provide a good picture of safety:

Clomiphene Citrate: Clomiphene has a favorable side effect profile in men, even with prolonged use. A 3-year study reported no significant adverse events in any patient on clomiphene. The most commonly reported side effects of clomiphene in men are relatively mild and include: mood changes (some men report irritability or mood swings), fluctuations in libido, headaches, and occasionally gynecomastia or breast tenderness (due to increased estradiol). Some men experience blurry vision or visual disturbances, which is a known but rare side effect of clomiphene. In women, higher doses of clomiphene have been associated with reversible vision changes (spots or flashes of light), and cases have been reported in men as well. The incidence of visual symptoms in clomiphene studies is low (~1–2%), but patients should be cautioned to report any vision changes, and discontinuation is advised if serious visual disturbance occurs. Clomiphene can also cause dermatological reactions in rare cases (e.g., rash), and very high doses could potentially affect liver enzymes (though standard doses in men are low and liver issues are not commonly seen). Importantly, clomiphene does not carry the risks associated with exogenous testosterone such as polycythemia (excess red blood cells), prostate enlargement progression, or severe HDL suppression. In fact, in long-term clomiphene therapy, metabolic profiles (lipids, etc.) remain stable, and bone density can improve. One early concern was whether extended estrogen blockade might harm bone density, but a study actually showed bone mineral density improved in men on >12 months of clomiphene, likely because their testosterone (which converts to some estrogen in bone) rose and they engaged in more activity, etc.. Clomiphene’s safety in terms of cardiovascular risk is not well studied, but by raising endogenous testosterone moderately (and not supraphysiologically), it is not believed to incur the theoretical clotting or CV risks that high-dose TRT might. In fact, one retrospective analysis even found an association of clomiphene use with lower all-cause mortality compared to TRT in a VA population, though that was observational. Overall, clomiphene is considered a safe, well-tolerated medication for men, with decades of use in the male fertility realm. Regular monitoring of hormone levels is recommended, and if estradiol climbs excessively (some men on clomiphene get E2 >50–60 pg/mL), an aromatase inhibitor can be added or dose adjusted to mitigate estrogenic side effects like moodiness or breast tenderness. But in most cases, clomiphene’s side effects are mild and manageable.
Enclomiphene Citrate: As enclomiphene is essentially “clomiphene lite” (minus the zuclomiphene), its side effect profile appears even more benign. In clinical trials, enclomiphene was well tolerated, with reported side effects similar to placebo in frequency. According to an expert review, enclomiphene did not demonstrate significant estrogen-related side effects – patients did not experience increases in gynecomastia or mood disturbances vs. baseline. The Baylor study explicitly showed lower odds of side effects on enclomiphene: men had significantly fewer instances of low libido, fatigue, or mood swings when they were on enclomiphene compared to when they were on clomiphene. This points to enclomiphene’s lack of agonist action on estrogen receptors (since zuclomiphene, which could act as an estrogen agonist in some tissues, is absent). Enclomiphene tends not to raise estradiol much, so side effects related to high estradiol (water retention, breast tenderness) are minimized. Also, by avoiding big estradiol spikes, enclomiphene likely has less risk of reactive emotional changes. Of course, enclomiphene can still cause the class-specific effects like headache or mild nausea in some, but those are uncommon. To date, no enclomiphene-specific serious adverse events have been highlighted in the literature. The drug was tested in multiple trials up to 1 year long, without major safety signals. Some men might experience transient acne or oily skin when their T increases (just as they might with any T rise), and enclomiphene is no exception, but this is anecdotal. A possible consideration: enclomiphene, by raising LH a lot, could theoretically increase testicular testosterone production so much in some individuals that a proportion gets aromatized, but since enclomiphene also blocks estrogen receptors centrally, the net estradiol effect is kept in check. In summary, enclomiphene’s safety profile is very favorable, closely mirroring that of clomiphene but with even fewer side effects related to estrogen. Men on enclomiphene should still be monitored periodically (for testosterone, estradiol, hematocrit, etc.), but major adverse effects are rare. The main “side effect” might simply be the lack of FDA approval currently, meaning patients have to obtain it through off-label routes (research compounding pharmacies or clinical trials), which introduces concerns about consistency of the product – but the pharmacological safety of the molecule itself is well-established.
Anastrozole: Anastrozole is generally well tolerated in men at the doses used (usually 0.5–1 mg 1–3 times per week in practice). However, because it lowers estradiol, some side effects relate to estrogen depletion. Common side effects men report on anastrozole include: joint or muscle aches (estrogen has a role in joint health; low E2 can cause stiffness or arthralgias), decreased bone mineral density with long-term use (prolonged estrogen suppression can lead to bone loss, as seen in one study where spinal BMD decreased after a year of anastrozole therapy in older men), and possible mood changes (some men feel a bit more irritable or have low-grade depression if estrogen is chronically very low). High-dose anastrozole can also cause hot flashes in men, again due to low estrogen (though this is more noted with higher doses or in men who achieve near-castrate estrogen levels). In the short term (3–6 months), studies have not shown significant changes in markers like cholesterol, inflammatory markers, or insulin sensitivity on anastrozole – it appears metabolically neutral in hypogonadal men. But one must be cautious about bone health: estrogen is crucial for male bone maintenance. A delicate balance is needed, aiming to keep E2 in a healthy male range (perhaps 10–30 pg/mL). Anastrozole will often reduce E2 to low-normal levels; as long as E2 isn’t driven undetectably low, bone risk is manageable. In older men, monitoring bone density might be considered if an AI is used for a long duration. Another consideration is that anastrozole can occasionally elevate liver enzymes (rarely) and cause minor rash or allergic reactions (uncommon). Unlike clomiphene, which raises estradiol, anastrozole might cause issues from too little estradiol – e.g., lowered libido or erectile function if E2 falls below ~5–10 pg/mL. Indeed, extremely low estrogen in men (like those with aromatase gene mutations) causes low libido, fatigue, and osteoporosis. Thus, the key with anastrozole side effects is dosage: using the lowest effective dose to avoid complete estrogen suppression. In practice, many clinicians will start with 0.25–0.5 mg twice a week rather than 1 mg daily, to moderate the effect and minimize side effects, titrating as needed. Anastrozole does not directly cause any reproductive harm; if anything, it can improve sperm as discussed. It also does not seem to affect the prostate directly (though long-term data on AI use and prostate health are sparse; one study noted a slight PSA rise in men on anastrozole, but within normal range). Overall, anastrozole is safe when used judiciously, with its side effects being essentially the flipside of its mechanism (symptoms of low estrogen). These can be managed by dose adjustment or combination therapy (e.g., combining with clomiphene, which allows a bit more testosterone and some estrogen back).

Monitoring and Precautions: For all three treatments, periodic monitoring of testosterone and estradiol levels is important to ensure the balance is right. Monitoring LH/FSH can also confirm the drug’s expected action (they should be high-normal on SERMs, slightly high on AIs). Hematocrit should be watched when raising testosterone (though huge jumps as with TRT are uncommon here, it can still increase slightly with clomiphene as T rises). Liver enzymes are rarely an issue but a baseline and follow-up if clinically indicated (especially for clomiphene use beyond a year) could be considered. Men on anastrozole long-term might consider periodic DEXA scans for bone density. And men on clomiphene should be counseled about visual symptoms, discontinuing the drug if any significant visual changes occur. Psychologically, checking in on mood and libido is crucial, as adjustments (like switching from clomiphene to enclomiphene, or adding a small AI) can be made to optimize how the patient feels. The good news is that no life-threatening risks have emerged with these therapies in the context of male hypogonadism treatment – unlike some controversies that have been seen with high-dose TRT in older men, for example.

In comparing side effects: Clomiphene vs Enclomiphene vs Anastrozole, a concise summary would be:

Clomiphene: Mostly mild side effects; watch for high estradiol-related issues (mood swings, breast tenderness). Rarely causes visual disturbances. Long-term appears safe with benefits to bone.
Enclomiphene: Even fewer side effects; less estrogenic activity means lower risk of mood/libido problems. Essentially similar to CC without CC’s rare downsides. Main limitation is availability (discussed below) rather than safety.
Anastrozole: Side effects stem from reduced estrogen – possible joint pain, reduced bone density over time, or low-estrogen symptoms (e.g. decreased sexual function if over-suppressed). Generally well tolerated in the short-term, but requires careful dosing.

Availability, Regulatory Status, and Use in Practice

In terms of what’s available to patients, there are important distinctions:

Clomiphene (brand name Clomid or Serophene) is FDA-approved in the U.S. for use in women (for ovulatory dysfunction in infertility). It is not specifically approved for men, but its use in men is common and used as an off-label prescription. Doctors (urologists, endocrinologists, fertility specialists) have prescribed clomiphene for male hypogonadism for decades off-label, given the evidence of safety and efficacy. It is relatively inexpensive and easy to obtain from pharmacies. Clomiphene is available internationally as well, often approved for female fertility but used off-label for men in many countries. So in practice, clomiphene is currently the most accessible and frequently utilized option among these three for men who want to boost testosterone while preserving fertility. Insurance coverage for clomiphene in men can be hit or miss (since off-label), but the out-of-pocket cost is not prohibitive for most short-term.

Enclomiphene (formerly under development under the name Androxal) is not FDA-approved for any indication as of 2025. Repros Therapeutics, the company that developed enclomiphene, sought FDA approval around 2014–2015 for secondary hypogonadism, but the FDA did not approve it, citing insufficient data on long-term outcomes (and possibly questioning whether low testosterone in obese men was a condition needing a new drug, since clomiphene existed off-label). The drug was also not approved by the European Medicines Agency (EMA) – a marketing application was withdrawn after regulators indicated it was unlikely to be approved without more evidence on safety/efficacy compared to existing therapies. Therefore, enclomiphene is not commercially available in pharmacies as a licensed medication. However, enclomiphene can be obtained via compounding pharmacies or research chemical suppliers in the U.S. Some men obtain enclomiphene through specialty wellness clinics or compounding pharmacies that prepare it (legally, a licensed provider can prescribe a compounded enclomiphene citrate since it’s not a controlled substance; though the FDA has at times scrutinized compounding of substances that are essentially analogs of approved drugs like clomiphene). There was even discussion at the FDA’s advisory committee on pharmacy compounding about enclomiphene in 2022. For now, enclomiphene use in practice is growing, but patients should be aware they are using an investigational/off-label substance. On the positive side, the clinical data behind enclomiphene is robust enough that many experts are comfortable with it – it’s essentially like taking clomiphene but likely with fewer side effects. Prescribing practices: If a U.S. patient asks for enclomiphene, some physicians may instead prescribe clomiphene due to familiarity and availability. Others, especially in the men’s health field, may help the patient obtain enclomiphene from a compounder if they believe it’s superior for that individual. Internationally, enclomiphene is also not formally approved anywhere to my knowledge, though it might be accessible via similar avenues. Until enclomiphene is revisited for approval or included in guidelines, clomiphene remains the go-to SERM for men – but enclomiphene is essentially an off-label refinement that knowledgeable providers may use in select cases.

Anastrozole (brand name Arimidex) is FDA-approved for treating breast cancer in postmenopausal women. It is not approved specifically for male infertility or hypogonadism, but it is widely used off-label for these indications. Anastrozole is readily available in pharmacies and is relatively inexpensive as a generic. In the U.S., many fertility specialists will prescribe anastrozole to men who have low T with high estradiol or as an adjunct to clomiphene. It’s also used in bodybuilding circles (to mitigate high estrogen from steroid use), so it has a known profile in men. There is no special regulatory restriction on a doctor prescribing it to a man for hypogonadism – it’s purely at the clinician’s discretion. Notably, because anastrozole is approved (for another purpose), insurance might sometimes cover it even for a man (though that’s case-by-case). In clinical practice, anastrozole might be given alone for a man who has borderline low T and signs of high estrogen (e.g. obese with T 280 ng/dL and E2 50 pg/mL), or given in combination with clomiphene if clomiphene alone raised E2 too much or didn’t fully normalize T. The 2020 WJMH paper we reviewed suggests ~30% of men on clomiphene eventually had anastrozole added in one clinic’s experience. This combined approach is somewhat common in men with obesity. Another scenario is the man on injectable testosterone who wants to regain fertility: doctors may stop testosterone and use clomiphene + hCG, sometimes adding an AI if E2 surges during that restart. The use of AI in men is, however, to be done cautiously – guidelines for male infertility do not universally endorse aromatase inhibitors unless specific indications (like low T/E ratio) are present.

All causes of low T, including older men: We have primarily focused on functional secondary hypogonadism. It’s worth mentioning that if a man’s low T is due to a specific treatable cause (like he’s on opioids, or has untreated sleep apnea, or high prolactin), addressing those causes is important too – often these medications are used in conjunction with treating underlying factors. In older men with age-related low T, these therapies are an alternative approach when fertility is a consideration or when one wants to avoid the logistical issues of TRT. Some older men who don’t want to start lifelong testosterone injections or gels opt for clomiphene off-label; studies like Moskovic 2012 have shown it can be safe and effective in men in their 40s, 50s, even early 60s. They get improvement in bone density and maintenance of testicular volume, which is beneficial. Anastrozole in older men can raise T modestly but, as noted, one must weigh the potential effect on bone if used long-term. There was a recent push to define which older men might benefit from AI – one concept is to treat only those with low T and high estradiol, because in those men lowering E2 could improve T and symptoms, whereas an older man with low T and low E2 might actually feel worse on an AI.

Finally, none of these medical therapies preclude moving to TRT in the future. For example, a young man might use clomiphene to father a child and feel better; later, if fertility is no longer desired, he could transition to testosterone therapy if that would be more straightforward for long-term hypogonadism management. Similarly, some men use clomiphene or enclomiphene as a “bridge” to maintain fertility until they are done with family-building, knowing that TRT is always an option later. Encouragingly, some data (e.g. Krzastek et al. 2019) suggest that clomiphene can be used for many years safely, so there isn’t a strict limit on how long one can stay on it. Enclomiphene, if it becomes more formally available, could also be a long-term solution given its favorable safety in trials up to 1 year and mechanistically being similar to clomiphene.

Conclusion and Comparative Summary

For men of reproductive age with hypogonadism, enclomiphene, clomiphene, and anastrozole each offer a way to boost testosterone levels while preserving (and potentially enhancing) fertility – but they do so via different mechanisms and have unique profiles. All three have shown efficacy in raising serum testosterone into the eugonadal range and avoiding the suppression of spermatogenesis that accompanies direct testosterone therapy. The choice among them (or the decision to use a combination) should be individualized based on the man’s baseline hormones, symptom profile, and family-planning timeline. Below is a brief comparison of these options:

Clomiphene Citrate: A time-tested off-label therapy that reliably increases LH, FSH, and testosterone in men. It usually brings testosterone to mid-normal levels and improves symptoms of hypogonadism, with the added benefit of maintaining sperm counts or even improving them in men with secondary infertility. It is taken orally (typically 25 mg daily or alternate days). Clomiphene’s side effects are minimal for most; rare issues include elevated estradiol-related effects (mood changes, gynecomastia) or visual disturbances. Studies have shown it to be safe even with multi-year use, with improvements in bone density and no adverse cardiovascular signals. It’s widely accessible and inexpensive. Clomiphene is a great first-line for young men with low T who want to preserve fertility, essentially “tricking” the body to make its own testosterone without testicular shutdown.
Enclomiphene Citrate: A refined SERM (trans-clomiphene only) that has demonstrated equal effectiveness in raising testosterone as clomiphene or even testosterone gel, while better preserving sperm output (in head-to-head trials vs TRT). Enclomiphene tends to raise testosterone without significantly increasing estradiol, thereby reducing estrogenic side effects. Patient-reported side effects like low libido and fatigue are significantly less frequent on enclomiphene than on clomiphene. It is taken as a daily pill (typically 12.5–25 mg). The main drawback is that enclomiphene is not yet an approved medication – it must be obtained through compounding pharmacies or clinical trials in the U.S.. For those who can obtain it, enclomiphene offers a very appealing profile: “all of the gain, less of the pain,” meaning normalized testosterone and maintained fertility with fewer adverse effects. It is essentially an improved clomiphene, and recent research supports its use as a safe alternative for hypogonadal men.
Anastrozole: An aromatase inhibitor that raises gonadotropins and testosterone by lowering estradiol. Particularly useful in men who have elevated estradiol or are overweight/obese with secondary hypogonadism. Anastrozole is often dosed around 1 mg twice a week (dosing is adjusted to avoid oversuppression of E2). It typically produces moderate increases in testosterone (often into low-to-mid normal range). Alone, it may not improve hypogonadal symptoms dramatically in every case, but it does improve the T/E ratio and can increase sperm counts in men with low T and high E. It is frequently used as an adjunct to fine-tune therapy (for example, added to clomiphene if estradiol is high, or used short-term in men coming off testosterone to kick-start the axis). Side effects center on low estrogen: joint aches, potential bone density loss if used long-term, and possibly reduced libido if too much E2 is suppressed. These can be managed by careful dosing. Anastrozole is readily available (off-label for men) and inexpensive. It may not be the best monotherapy for symptomatic hypogonadism unless an elevated estradiol is part of the picture, but it’s a key tool in the armamentarium for hypogonadal men with fertility goals, especially in those who would benefit from weight loss and metabolic improvements alongside hormonal therapy.

Ultimately, studies show that both SERMs (like clomiphene or enclomiphene) and AIs (like anastrozole) are effective at increasing testosterone without impairing sperm production. For example, one randomized trial found clomiphene and anastrozole both significantly raised testosterone after 3 months, although clomiphene achieved a higher absolute T level than anastrozole. Neither had detrimental effects on semen parameters in that short timeframe. The key differences lie in their side effect profiles and specific use-cases: enclomiphene/clomiphene directly stimulate gonadotropins and tend to be more potent T-raisers, whereas anastrozole modulates the hormonal balance and is particularly helpful in hyperestrogenic men. Many practitioners actually combine these approaches when needed – for instance, a common regimen for a man with low T and borderline high E is clomiphene plus a low-dose anastrozole, achieving robust T increase while keeping E2 in check and maximizing sperm quality.

From a patient’s perspective, these medical therapies provide a conversational yet effective way to manage low testosterone. Unlike TRT, you’re not introducing an outside hormone but nudging your body to work better on its own. Men often appreciate that their testicles won’t shrink (in fact, they may be slightly larger on these drugs due to increased gonadotropins) and that they can maintain fertility for future family plans. Quality of life can improve, though perhaps not as instantaneously or dramatically as with direct testosterone shots – it might be more gradual and natural. Importantly, these medications need to be overseen by a knowledgeable healthcare provider, with follow-up labs to tailor the regimen.

In conclusion, clomiphene citrate remains a cornerstone off-label therapy for hypogonadal men desiring fertility, with strong evidence of safety and efficacy in raising testosterone and helping sperm parameters. Enclomiphene citrate is an emerging alternative that appears to offer similar benefits with fewer side effects, though access is currently limited. Anastrozole (aromatase inhibition) provides another strategy, either as a standalone in men with high estrogen or as an adjunct, to maximize testosterone while minimizing estrogen’s inhibitory effects. All these treatments are used worldwide (with clomiphene and anastrozole available in the U.S., and enclomiphene used in research/off-label contexts). By presenting the data without bias, we see that each has pros and cons, but all can play a role in the personalized care of men who want to feel the benefits of normal testosterone without sacrificing their fertility potential.

References (AMA Style)

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AUA and ASRM Male Infertility Guideline (Practice Committee, 2021) – recommends considering SERMs/AIs in select cases of male infertility with hormonal abnormalities.

Disclaimer: Clomiphene citrate and anastrozole are not FDA-approved for treating male hypogonadism or infertility; their use in men is off-label. Enclomiphene citrate is an investigational drug (not FDA-approved as of this writing). Any therapy should be under medical supervision, with informed consent about its off-label status. The information provided is for educational purposes and should not substitute for professional medical advice.