Clomiphene / Clomid for Male Infertility
Introduction to Clomiphene / Clomid for Male Infertility
Clomiphene is a selective estrogen receptor modulator (SERM) that competitively binds to estrogen receptors in the body, including the hypothalamus and pituitary gland. Estrogen normally has a negative feedback action on the hypothalamus and pituitary gland, so when the actions of estrogen on these structures are blocked, the pituitary is stimulated to increase the secretion of LH and FSH. The extra LH secreted causes the Leydig cells in the testicles to make more testosterone. If FSH levels are inappropriately low, then an increase in FSH secretion can also increase sperm production.
The ability of clomiphene 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 clomiphene works by increasing LH production by the pituitary gland, if the LH is already elevated (indicating Leydig cell dysfunction), then clomiphene 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 clomiphene.
Clomiphene and Estradiol Levels
Another important consideration is that clomiphene can increase levels of estradiol in some men. The enzyme aromatase converts some of a man’s testosterone to estradiol. If clomiphene is started and testosterone levels increase, then more of this T can be converted to estradiol. Therefore, estradiol levels should be monitored in men on testosterone-enhancing therapies.
Estradiol levels have been documented with the use of clomiphene 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 clomiphene.
HOW CLOMIPHENE IS USED
Clomiphene is taken by mouth. Unlike in women, who typically need to take higher doses of clomiphene on certain days of their cycle, clomiphene in men is taken on an every other day or daily basis at lower doses. Clomiphene comes in 50mg tablets, and typical starting dosage is 50mg every other day.
Here is a sample range of dosages:
• 25 mg every third day
• 25 mg every other day
• 50 mg every other day (typical starting dosage)
• 75 mg every other day
• 50 mg daily
• 75 mg daily
• 100 mg daily (I usually do not go above this dosage)
Because clomiphene is much more commonly used in women than in men, I have had pharmacists who are unfamiliar with the treatment of male infertility call the office to question the accuracy of a clomiphene prescription when they see that it is written for a man. I have therefore taken to printing “This is for a male patient” on my clomiphene prescription sheets to decrease the number of phone inquiries from pharmacists.
COST OF CLOMIPHENE
Clomiphene may be covered by your insurance company. However, if you do not have insurance coverage for your medications, you may want to consider the use of on-line coupons such as www.GoodRx.com which have some really good prices for many medications. For more information see the "Fertility Medications Cost" section of this website.
Side Effects of CLomiphene
Clomiphene has a bad reputation in terms of side effects, since it can provoke significant mood swings in some women who use it. In men, clomiphene has a good safety profile, and most men do not experience the same negative mood-related side effects with clomiphene that women do. Most men feel no different while taking clomiphene, and some actually feel better in terms of mood, energy, and libido due to the increased testosterone levels. Adverse side effects do occur in <10% of men taking clomiphene, although these are usually mild.
A 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%
Acne 0.5%
Other side effects effecting 0.25% of patients: hypertension, increased hematocrit, altered taste, flushing, polydipsia, nausea, arthralgias, asthma
Comments on clomiphene 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 clomiphene.
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.
If you experience any significant negative side effects, it is best to stop the medication and contact your doctor.
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.