Selective Estrogen Receptor Modulators (SERMS)

Clomid- clomiphene citrate- male infertility

Introduction to SERMS


Selective estrogen receptor modulators (SERMs) are medications that impact the function of different estrogen receptors throughout the body.  In terms of male fertility, the important area of impact on SERMs is on the anterior pituitary gland where estrogens have a negative feedback thereby decreasing FSH and LH stimulation.  When SERMs are used, these estrogen receptors are blocked thereby stimulating the release of more FSH and LH.  Increased LH secretion causes the Leydig cells in the testicles to produce more testosterone. Elevated FSH levels drive the spermatogenic cells within the testicles to try and produce more sperm.

There are 3 main SERMs used clinically for the management of male fertility.

1. Clomiphene citrate (Clomid)

2. Tamoxifen (Nolvadex, Soltamox)

3. Enclomiphene (Androxal)

The ability of SERMs to increase testosterone levels is roughly comparable to that of testosterone gels, and has the ability to increase libido, energy and sense of well-being in hypogonadal men. [Katz DJ. BJUI 2012] A long term (mean follow-up 4.5 years) study of 120 men on clomiphene noted sustained normalization of testosterone levels in 88% of men with improvement in their hypogonadal symptoms in 77%. [Krzastek SC. JUrol 2019]

Since SERMs work by increasing LH production by the pituitary gland, if the LH is already elevated (indicating Leydig cell dysfunction), then these medications will not be as effective. Men who have a baseline LH of over 20 IU/L prior to starting any treatment will therefore likely not benefit from using SERMs.


Serms and Estradiol Levels


Another important consideration is that SERMs can increase levels of estradiol in some men. The enzyme aromatase converts some of a man’s testosterone to estradiol. If SERMs are started and testosterone levels increase, then more of this testosterone can be converted to estradiol. Therefore, estradiol levels should be monitored in men on testosterone-enhancing therapies.

Elevated estradiol levels have been documented with the use of SERMs in men, and this effect seems to increase with longer use of the medication. [Moskovic DJ. BJUI 2012]. In a long term follow-up study on clomiphene use, about 14% of them needed to have anastrazole added onto their regimen due to increases in estradiol levels. [Krzastak SC. JUrol 2019]. This need for using anastrazole also increased with more time on clomiphene, with 37% of men needing the anastrazole if they had been taking the clomiphene for longer than 3 years. These findings show the importance of continued routine follow-up of hormone levels (including estradiol) in men taking SERMs.


The Proper Use of SERMs

SERMs have a very specific impact upon the male body in terms of fertility.  As described above, it can increase a man’s endogenous production of testosterone due to increased LH levels.  Therefore, men with infertility issues (such as abnormal semen analysis testing) who have documented hypogonadism (my personal definition being <500 ng/dL) would be a good potential candidate for a SERM such as clomiphene.  The other male patient population who can potentially serve to benefit from SERMs are men whose FSH is inappropriately low in the presence of decreased sperm production. When the normal hormonal feedback loops are working properly, if sperm production is decreased then the pituitary should be producing more FSH to try and drive the testicles harder to make more sperm.  If a man has a sperm production problem and his FSH is in the normal range (1.0-7.6 IU/L) then the feedback look is not working properly.  In this situation, SERMs can potentially stimulate for FSH production (in the presence of a functional pituitary gland) and possibly drive the testicles to increase sperm production.

Where I do not think any of the SERMs work well is in its empiric use which basically means it is not prescribed for a particular reason (low testosterone, and/or inappropriately low FSH) but rather just to give it a try in the hope that it helps.  Data for the empiric use of SERMs has not been impressive.  Some providers don’t even check hormone levels in men before prescribing SERMs like clomiphene.  This approach does not have good data backing it use and can potentially be dangerous if follow-up hormone testing is also not performed.  If testosterone levels get too high then the amount of red blood cells can increase to the point where there is a risk of clots (i.e. DVTs, heart attacks, strokes, etc.).  Elevated levels of estradiol (as mentioned above) can also have a negative impact on male fertility as well general health risks as well.

When properly used in male fertility, baseline hormones (usually total testosterone, estradiol, LH and FSH) are checked prior to starting any SERMs.  If a man is found to have hypogonadism (<500 ng/dL) and/or inappropriately low FSH, then they would be a potential candidate for use of a SERM.  Caveats to this include men who have a baseline LH ³ 20 IU/L are not going to respond to a SERM in terms of increased testosterone production (however, if FSH levels are inappropriately low then they may still respond in this manner).  Also, if a man with low testosterone also has an elevated estradiol (or abnormal T/E ratio) then the use of an aromatase inhibitor instead of or in addition to a SERM may be indicated.

After starting a SERM it is always important to check repeat hormone testing 2-4 weeks after starting a SERM.  Labs to always check include total testosterone (goal 500-1000 ng/dL), estradiol (goal <60 pg/mL and T/E ratio ³ 10:1) and hematocrit (goal <54%).  Possible additional labs include a prolactin (if baseline testosterone was <300 ng/dL) and FSH (if it was inappropriately low at baseline to make sure it increases as expected).  Sometimes an LH is also repeated if it was significantly elevated at baseline- if the testosterone is still low on repeat but the LH is now >20 IU/L, then increasing the SERM dosage is not going to be expected to further increase testosterone levels (but adding or increasing the dosage of an aromatase inhibitor may).  Once hormonal levels are normal, I typically repeat labs (testosterone, estradiol, hematocrit) 6 months later, and then every 12 months while the man is taking the medications.  Any change in hormone medication or dosage should generally have repeat labs 2-4 weeks later to make sure that there was the appropriate change in the corresponding hormones.


CLOMIPHENE Citrate (Clomid)


Originally approved by the FDA for the treatment of female ovulatory dysfunction, clomiphene has been used off-label for the treatment of male hypogonadism for decades.  When used in properly selected patients, clomiphene has been shown to have the ability to improve male fertility potential.  A 2023 meta-analysis of studies looking at clomiphene in men confirmed its ability to improve both sperm counts and motility. [Hujiben M. Andrology 2023].


Dosing of Clomiphene

Clomiphene is generally made in 50mg tablets (some compounding pharmacies have different mg tablets).  Dosing regimens can range from the very low (25mg every other day) to a maximum of 100mg daily.  A typical starting dose for man with baseline testosterone in the mid 300’s ng/dL would be 50mg every other day.

Cost of Clomiphene

Until a few year ago, clomiphene was a very reasonably priced medication due to its availability in generic form.  However, in 2023 the generic form of clomiphene was no longer available- supposedly the ONLY factory making generic clomiphene stopped production.  Not sure how this type of thing happens in a functional market economy.  Prior to this it was common to be able to find a month’s worth of clomiphene for $20 or less. 

The current 2024 cheapest listed price on GoodRx.Com for a month of brand name Clomid (50mg every other day) is $67.50.  Because of this price increase there has been an increasing number of patients who are using tamoxifen instead which is still available in its generic form.

Side Effects of Clomiphene

Clomiphene has a very good safety profile in men using it for fertility purposes.  A meta-analysis of studies on this patient population showed no serious adverse events. [Huijben M. Andrology 2023] Though clomiphene has a bad reputation in women (since it can provoke significant mood swings in some women who use it, men do not seem to experience this same side effect profile.  In fact, low T symptoms are often improved in men taking clomiphene for hypogonadism.

In the above mentioned meta-analysis, about 2.27% of men reported mild adverse side effects such as headache, gynecomastia (which should not occur if estradiol levels are being followed appropriately), dizziness, visual changes, mood changes, and fatigue.  Another review of 393 men taking clomiphene for an average of 2.5 years reported a rate of 9% for adverse side effects. [Krzastek SC. JUrol 2019] These included mood changes (2.3%), blurred vision (1.8%), breast/nipple tenderness (1.5%), weight gain (1.3%) and acne (0.5%). Other side effects effecting 0.25% of patients: hypertension, increased hematocrit, altered taste, flushing, polydipsia, nausea, arthralgias, asthma


comments on SERM-Related Side Effects

1) Mood changes- this was the most common side effect (at 2.3%) and adverse mood changes can occur. However, this must also be weighed against the finding in this study that 78% of men reported an overall improvement in their low-testosterone symptoms.

2) Visual disturbances. Blurred vision, spots in vision, and flashes of light are the most common side effects that I have seen in men taking clomiphene, although they only occur in a small number (less than 2 percent) of them. Generally, the visual side effects resolve within a few weeks of lowering the dosage or stopping the medication. Men with a history of central retinal vein occlusion (CRVO) should consult with their ophthalmologist before starting SERMs.

3) Breast/nipple tenderness- this side effect is generally related to estradiol levels which are too high and should be rare if estradiol levels are followed and kept within the normal range. In this study showing a 1.5% rate of breast-related side effects, only about 20% of men had their estradiol levels monitored regularly.

4) Weight gain. Typically, this is minimal. Some men have reported some mild fluid retention which can cause some weight gain. Low testosterone levels are noted to increase weight gain due to adipose tissue and increasing testosterone levels are an effective adjunct treatment for weight loss in most men. Increases in lean muscle mass are noted in men with improved testosterone levels who are exercising and muscle weighs more than fat (which can increase overall weight as well).

5) Acne. This is due to increased skin gland oil production; it usually subsides after a few months of treatment.


Tamoxifen (Nolvadex, soltamox)


Tamoxifen is a SERM that historically has been used its ability to inhibit the stimulatory effect of estrogens on breast tissue.  It has therefore found a role in the management of estrogen-receptor positive breast cancer as well as gynecomastia.  In terms of male fertility, the mechanism of action is the same as with clomiphene, namely antagonism of the function of estrogen receptors in the pituitary gland which thereby increases the release of LH and FSH. [Wibowo E. Andrology 2016]

Multiple randomized controlled trials over the years have shown the ability of tamoxifen to improve sperm counts and motility in men with hypogonadism and abnormal semen parameters. [Cakan M. UrolInt 2009][Kotoulas I. FertSteril 1994][Maier U. EurUrol 1988]

 

Dosing of Tamoxifen

Tamoxifen is available in 10mg and 20mg tablets.  Dosing regimens can range from the very low (10mg every other day) to a maximum of 30mg twice daily.  A typical starting dose for man with baseline testosterone in the mid 300’s ng/dL would be 10mg twice daily.

Cost of Tamoxifen

The current 2024 cheapest listed price on GoodRx.Com for a month of brand name tamoxifen (10mg twice daily) is $14.08. 

Price is one of the primary drivers of increased use of tamoxifen in the treatment of male fertility because in 2023 generic clomiphene became unavailable.  In 2020, a month’s supply of generic clomiphene (50mg every other day) could be purchased on GoodRx for $17.99- now that same prescription for brand name Clomid is listed for $67.50.

 Side Effects of Tamoxifen

For men taking tamoxifen for fertility reasons, studies have shown minimal adverse side effects (similar to clomiphene) with drop-out rates of <5% reported due to these side effects.  The mild side effects reported were similar to those seen with clomiphene: decreased libido (4%), hot flashes (1%), hair loss (1%), weight gain (0.5%). [Wibowo E. Andrology 1996].  Interestingly, in patients taking tamoxifen for breast cancer the reported side effects are higher, with 10% of patients stopping the medication due to side effects including cardiovascular events (something not seen in men taking the medications for fertility reasons). It is unclear whether the differences are due to the patient population (mostly women in the breast cancer group) or interactions with the underlying disease process.

In my practice, the one side effect difference that I see with tamoxifen is a slightly higher rate of decreased libido (as compared to clomiphene) impacting about 5-10% of men started on the medication.  This generally resolves with switching to clomiphene.


Enclomiphene (androxal)


Biochemically, clomiphene is made up of 2 stereoisomers (defined as molecules with the same composition but just with their atoms lined up in different patterns).  62% of clomiphene is made up of the stereoisomer enclomiphene which has more anti-estrogenic effect, while 38% is zuclomiphene which has more estrogenic effects.  Androxal was produced by a process which isolated just the enclomiphene component while not including the zuclomiphene element in an attempt to produce a medication with a bigger potential impact on fertility with fewer side effects.

Studies have confirmed that enclomiphene has the ability increase the production of LH and FSH in men as well as testosterone levels similar to that of clomiphene. [Wiehle R. BJUI 2013]. Studies have also shown improvements in sperm counts and motility with the use of enclomiphene in men with hypogonadism and fertility issues. [Thomas J. Cureus 2023].  What I have not seen so far is good evidence though that enclomiphene shows superior outcomes in terms of hormonal and fertility outcomes in comparison to the use of clomiphene or tamoxifen which would justify its higher cost.

Dosing of Enclomiphene

Enclomiphene is available in 12.5mg and 25mg tablets and is taken once daily.

Cost of Enclomiphene

Enclomiphene is not currently listed on GoodRx so a direct comparison for price vs. clomiphene and tamoxifen cannot be made.  A brief online search found compounded prices of about $100/month but I cannot verify the legitimacy of the sources.

Side Effects of Enclomiphene

The listed side effects of enclomiphene appear mostly similar to the other SERMs.  Examples include: headache (1.3%), hot flashes (1.1%), nausea (1%), and multiple others at <1% (dizziness, fatigue, ED, acne, irritability/aggressive behavior.  Of note, an elevated hematocrit was noted in 0.5% of men as well as a low risk of thromboembolic events (0.1-0.2%).  [Hill S. IDrugs 2009]


Elevated Hematocrit


Hematocrit is the proportion of blood that is made up of red blood cells with a normal range in men of 38.2-48.6%. Red blood cells are necessary to carry oxygen to the cells of the body. However, if too many red blood cells are present, then the blood can get too “thick” and clots can develop. Clinically, clots can cause problems like deep venous thrombosis, strokes, and heart attacks. Testosterone is one of the factors which drive the bone marrow to make more red blood cells. Therefore, factors which increase testosterone levels in the blood can increase the risk of polycythemia (too many red blood cells in the blood). This is seen most commonly with the use of injectable testosterone (19%) but can also be seen with testosterone pellets (12.5%), gels (5.4%) and any other exogenous androgen. [AUA Updates 2019] Rates of polycythemia are noted to be much lower in men taking clomiphene, being seen in only 0.25% of men taking clomiphene for an average of 2.5 years. [Krzastek SC. JUrol 2019] However, higher rates have been seen when clomiphene is combined with other medications such as anastrazole (3.9%). [Alder NJ. BJUI 2018] Although it remains controversial, I generally recommend to monitor hematocrit levels in men taking clomiphene every 6-12 months with a general goal to keep levels at 54% or lower.


Congenital Vascular Abnormalities

There is some concern about using clomiphene in men with congenital vascular abnormalities (such as Klippel-Trenaunay syndrome) due to the potential impact on estrogen receptors within the abnormal vessels. Therefore, anastrazole or HCG may be a better choice in these patients.

CLOMIPHENE AND OSTEOPOROSIS

Since there are estrogen receptors in the bone, there have been raised some concerns that long-term use of clomiphene may increase the risk of bone weakness (osteoporosis). Although some SERMs such as tamoxifen are known to have the potential for increasing the risk of bone fractures, most studies on clomiphene appear to show improvements in bone mineral density with their use. [Moskovic DJ. BJUI 2012]. More studies on use of clomiphene are needed to more clearly define the relationship between bone health and long term use of this medication in men.